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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. [ABSTRACT FROM AUTHOR]

Key unmet needs in multiple sclerosis (MS) include detection of early pathology, disability worsening independent of relapses, and accurate monitoring of treatment response. Collaborative approaches to address these unmet needs have been driven in part by industry–academic networks and initiatives such as the Grant for Multiple Sclerosis Innovation (GMSI) and Multiple Sclerosis Leadership and Innovation Network (MS-LINK™) programs. We review the application of recent advances, supported by the GMSI and MS-LINK™ programs, in neuroimaging technology to quantify pathology related to central pathology and disease worsening, and potential for their translation into clinical practice/trials. GMSI-supported advances in neuroimaging methods and biomarkers include developments in magnetic resonance imaging, positron emission tomography, ocular imaging, and machine learning. However, longitudinal studies are required to facilitate translation of these measures to the clinic and to justify their inclusion as endpoints in clinical trials of new therapeutics for MS. Novel neuroimaging measures and other biomarkers, combined with artificial intelligence, may enable accurate prediction and monitoring of MS worsening in the clinic, and may also be used as endpoints in clinical trials of new therapies for MS targeting relapseindependent disease pathology [ABSTRACT FROM AUTHOR]

Key unmet needs in multiple sclerosis (MS) include detection of early pathology, disability worsening independent of relapses, and accurate monitoring of treatment response. Collaborative approaches to address these unmet needs have been driven in part by industry–academic networks and initiatives such as the Grant for Multiple Sclerosis Innovation (GMSI) and Multiple Sclerosis Leadership and Innovation Network (MS-LINK™) programs. We review the application of recent advances, supported by the GMSI and MS-LINK™ programs, in neuroimaging technology to quantify pathology related to central pathology and disease worsening, and potential for their translation into clinical practice/trials. GMSI-supported advances in neuroimaging methods and biomarkers include developments in magnetic resonance imaging, positron emission tomography, ocular imaging, and machine learning. However, longitudinal studies are required to facilitate translation of these measures to the clinic and to justify their inclusion as endpoints in clinical trials of new therapeutics for MS. Novel neuroimaging measures and other biomarkers, combined with artificial intelligence, may enable accurate prediction and monitoring of MS worsening in the clinic, and may also be used as endpoints in clinical trials of new therapies for MS targeting relapse-independent disease pathology.

Background and Objectives: Although multiple sclerosis (MS) can be conceptualized as a network disorder, brain network analyses typically require advanced MRI sequences not commonly acquired in clinical practice. Using conventional MRI, we assessed cross-sectional and longitudinal structural disconnection and morphometric similarity networks in people with MS (pwMS), along with their relationship with clinical disability., Methods: In this longitudinal monocentric study, 3T structural MRI of pwMS and healthy controls (HC) was retrospectively analyzed. Physical and cognitive disabilities were assessed with the expanded disability status scale (EDSS) and the symbol digit modalities test (SDMT), respectively. Demyelinating lesions were automatically segmented, and the corresponding masks were used to assess pairwise structural disconnection between atlas-defined brain regions based on normative tractography data. Using the Morphometric Inverse Divergence method, we computed morphometric similarity between cortical regions based on FreeSurfer surface reconstruction. Using network-based statistics (NBS) and its extension NBS-predict, we tested whether subject-level connectomes were associated with disease status, progression, clinical disability, and long-term confirmed disability progression (CDP), independently from global lesion burden and atrophy., Results: We studied 461 pwMS (age = 37.2 ± 10.6 years, F/M = 324/137), corresponding to 1,235 visits (mean follow-up time = 1.9 ± 2.0 years, range = 0.1-13.3 years), and 55 HC (age = 42.4 ± 15.7 years; F/M = 25/30). Long-term clinical follow-up was available for 285 pwMS (mean follow-up time = 12.4 ± 2.8 years), 127 of whom (44.6%) exhibited CDP. At baseline, structural disconnection in pwMS was mostly centered around the thalami and cortical sensory and association hubs, while morphometric similarity was extensively disrupted ( p FWE < 0.01). EDSS was related to frontothalamic disconnection ( p FWE < 0.01) and disrupted morphometric similarity around the left perisylvian cortex ( p FWE = 0.02), while SDMT was associated with cortico-subcortical disconnection in the left hemisphere ( p FWE < 0.01). Longitudinally, both structural disconnection and morphometric similarity disruption significantly progressed ( p FWE = 0.04 and p FWE < 0.01), correlating with EDSS increase (ρ = 0.07, p = 0.02 and ρ = 0.11, p < 0.001), while baseline disconnection predicted long-term CDP (accuracy = 59% [58-60], p = 0.03)., Discussion: Structural disconnection and morphometric similarity networks, as assessed through conventional MRI, are sensitive to MS-related brain damage and its progression. They explain disease-related clinical disability and predict its long-term evolution independently from global lesion burden and atrophy, potentially adding to established MRI measures as network-based biomarkers of disease severity and progression.

Primary progressive multiple sclerosis (MS) is a demyelinating autoimmune disease with only a single class of FDA-approved treatment, B cell depletion. Novel treatments could emerge from a deeper understanding of the interplay between multiple cell types within diseased tissue throughout progression. We initially describe an engineered biomaterial-based immunological niche (IN) as a surrogate for diseased tissue to investigate immune cell function and phenotype dynamics throughout a chronic progressive mouse model of MS. Using these niches, we identify an array of dysregulated CC chemokine signaling as potential targets. We then develop antigen-loaded nanoparticles that reduce CC chemokine signaling, while delivering antigen. These nanoparticles serve as an antigen-specific treatment, and a single injection reduces disease burden, even if administered after symptomatic disease onset. This report demonstrates proof of principle of a biomaterial scaffold as a diseased tissue surrogate that can monitor immune function, identify potential drug targets, and guide the development of a therapeutic., Competing Interests: Competing interests statement:This manuscript uses NPs for which L.D. Shea has an interest in Cour Pharmaceutical, who have licensed the technology. A patent application has been filed on the engineered niche idea (US17/286,154).

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) targeting myelinated axons. Pathogenesis of MS entails an intricate genetic, environmental, and immunological interaction. Dysregulation of immune response i.e. autoreactive T & B-Cells and macrophage infiltration into the CNS leads to inflammation, demyelination, and neurodegeneration. Disease progression of MS varies among individuals transitioning from one form of relapsing-remitting to secondary progressive MS (SPMS). Research advances have unfolded various molecular targets involved in MS from oxidative stress to blood-brain barrier (BBB) disruption. Different pathways are being targeted so far such as inflammatory and cytokine signaling pathways to overcome disease progression. Therapeutic innovations have significantly transformed the management of MS, especially the use of disease-modifying therapies (DMTs) to reduce relapse rates and control disease progression. Advancements in research, neuroprotective strategies, and remyelination strategies hold promising results in reversing CNS damage. Various mice models are being adopted for testing new entities in MS research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background: Natural glucocorticoids (GCs) have been widely used to treat acute multiple sclerosis (MS) attacks. However, they also cause significant side effects related to immunosuppression. Our previous study found that C16 peptide combined with angiopoietin-1 (Ang-1) inhibited inflammatory cell infiltration and protected blood vessels in animal models of inflammatory neurodegenerative diseases., Methods: An acute experimental autoimmune encephalomyelitis model was established in Lewis rats to explore the effects of these drugs on MS. One hundred rats were equally and randomly assigned into five groups: normal control, vehicle, low-dose methylprednisolone (MP), high-dose MP, and C16 + Ang-1 (C+A). Histological examinations, behavioral tests, and high-throughput 16S rRNA gene sequencing were conducted to determine inflammation levels in the central nervous system, neuronal survival, functional recovery and gut microbiota., Results: The results illustrated that C+A exerted a neuroprotective effect in MS rats, with fewer side effects observed in the C+A group than in the high-dose MP group. The abundance of Campylobacter was increased in vehicle-treated rats, indicating an imbalance of the gut microbiota after MS. The abundance of probiotic Lactobacillus plantarum was increased in the C+A group. Low-dose MP failed to reverse the gut microbiota imbalance, whereas both the C+A and high-dose MP groups exhibited gut microbiota profiles more similar to those of the normal controls, with C+A displaying superior efficacy., Conclusions: C16 plus Ang-1 might serve as a complement to GCs for the treatment of MS. Changes in the abundance of Campylobacter and L. plantarum suggest their essential roles in the pathogenesis of MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Poor understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. To address this gap, we analyzed 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples of MS and control donors to examine inter- and intra-donor heterogeneity. We found distinct cell type-specific gene expression changes between MS gray and white matter, highlighting clear pathology differences. MS lesion subtypes had different cellular compositions but surprisingly similar cell-type gene expression patterns both within and across patients, suggesting global changes. Most gene expression variability was instead explained by patient effects, allowing us to stratify patients and describe the different pathological processes occurring between patient subgroups. Future mapping of these brain molecular profiles with blood and/or CSF profiles from living MS patients will allow precision medicine approaches anchored in patient-specific pathological processes., Competing Interests: Declaration of interests The study was funded by F. Hoffmann-La Roche Ltd. D.C., J.B., W.M., L.C.F., L.C., E.U., and S.S. are full-time employees of F. Hoffmann-La Roche Ltd. D.M. was a full-time employee of F. Hoffmann-La Roche Ltd. and now works for Biogen., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder, with limited treatment options. This disease is characterized by differential pathophysiology between grey matter (GM) and white matter (WM). The predominant WM hallmark is the perivascular plaque, associated with blood brain barrier (BBB) loss of function, lymphocytic infiltration, microglial reactivity, demyelination and axonal injury and is adequately addressed with immunomodulatory drugs. By contrast, mechanisms underlying GM damage remain obscure, with consequences for neuroprotective strategies. Cortical GM pathology is already significant in early MS and characterized by reduced BBB disruption and lymphocytic infiltration relative to WM, but a highly inflammatory environment, microglial reactivity, demyelination and neuro/axonal loss. There is no satisfactory explanation for the occurrence of neurodegeneration without large-scale inflammatory cell influx in cortical GM. A candidate mechanism suggests that it results from soluble factors originating from meningeal inflammatory cell aggregates, which diffuse into the underlying cortical tissue and trigger microglial activation. However, the recent literature highlights the central role of platelets in inflammation, together with the relationship between coagulation factors, particularly fibrinogen, and tissue damage in MS. Using the experimental autoimmune encephalomyelitis (EAE) model, we identified platelets as drivers of neuroinflammation and platelet-neuron associations from the pre-symptomatic stage. We propose that fibrinogen leakage across the BBB is a signal for platelet infiltration and that platelets represent a major and early participant in neurodegeneration. This concept is compatible with the new appreciation of platelets as immune cells and of neuronal damage driven by inflammatory cells sequestered in the meninges., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s).)

Inflammatory demyelination, a hallmark of multiple sclerosis (MS) lesions, leads to functional impairments and progressive axonal loss over time. Although remyelination is thought to protect axons, endogenous regenerative processes are often incomplete or fail entirely in many MS patients. While the precise reasons for remyelination failure remain unclear, repeated demyelination in previously affected white matter regions is a recognized contributing factor. In a previous study, we demonstrated that the sphingosine-1-phosphate modulator Siponimod ameliorates metabolic oligodendrocyte injury in an MS animal model. In this study, we explored the potential of Siponimod to enhance remyelination in a non-supportive environment. To this end, male mice were subjected to Cuprizone intoxication for seven weeks. From the onset of the fifth week, when oligodendrocyte progenitor cells begin to differentiate, mice were administered either a vehicle or Siponimod solution. Post-treatment, brain specimens were processed for (immune-) histochemical analyses. After four weeks of Cuprizone intoxication, staining intensities for various myelination markers, were significantly reduced. At the end of week seven, loss of myelin staining intensities was still pronounced, but anti-myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) expression was significantly higher in Siponimod- versus vehicle-treated mice. Consistent with this finding, densities of OLIG2 + oligodendrocytes significantly recovered in Siponimod-treated but not in vehicle-treated mice. This enhanced recovery was paralleled by the trend of lower densities of Ki67 + proliferating oligodendrocyte progenitor cells. Our findings suggest that Siponimod has modest pro-regenerative capacities, partly explaining the amelioration of disease progression in secondary progressive MS patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background and Purpose: The study of T2-weighted hyperintense lesions resulting from autoimmune inflammatory injury and associated volumes within the CNS remains fundamental to the diagnosis and disease surveillance of MS. We investigated the dynamic changes of individual T2-weighted hyperintense MS lesions on MRI and hypothesized that variations may be present below the threshold of visual perception when evaluating longitudinal data., Materials and Methods: A retrospective study was performed of people with MS, incorporating data from 3 consecutive MRI time points acquired within a single academic center. All included MRI studies lacked formal imaging interpretations of newly enlarging or contracting T2-weighted hyperintensities. Well-defined, noncoalescing, individual T2-weighted hyperintense lesions were targeted. A total of 8-12 lesions were randomly selected in a blinded fashion at MRI time point 1 and 3D lesion volumes were followed over MRI time points 2 and 3. The impact of treatment on lesion expansion and relationship to brain MRI advancement, patient-reported progression of disease, and physician-identified progression was also studied., Results: The study cohort comprised 115 people (81 (70.4%) women; mean disease duration of 9.36 years [standard deviation: 7.72 years]) who were primarily White (79.1%). A total of 1426 focal T2-weighted hyperintense MS lesions were identified on MRI time point 1 and longitudinally followed over MRI time points 2 and 3. In the evaluation of raw changes in individual T2-weighted hyperintense lesion volumes from MRI time point 1 to MRI time point 2, a similar number of individuals were observed with predominantly expanding (49/115; 42.6%) or contracting (51/115; 44.3%) lesions. However, most lesions expanded in volume (48/115; 41.7%) versus those that contracted (45/115; 39.1%) when evaluating MRI time point 3 to time point 1. Those individuals not on active treatment had a 67.15% reduction in the odds of more individual lesions predominantly contracting in volume relative to those on low-efficacy disease modifying therapy treatment (95% CI = [-83.89% to -33.01%], P = .0008) and 74.02% reduction relative to high-efficacy treatment individuals (95% CI = [-87.37% to -46.56%], P < .0001)., Conclusions: Dynamic changes in T2-weighted hyperintense lesions are abundant, occurring below the threshold of visual perception and are present more frequently in untreated individuals., (© 2025 by American Journal of Neuroradiology.)

Multiple sclerosis (MS), the leading cause of disability in young adults, is an inflammatory disease of the central nervous system characterized by localized areas of demyelination. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been shown to be implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Interestingly, ASK1 signaling regulates glial cell interactions and drives neuroinflammation in EAE mice. To further investigate its clinical significance, in the present study, we examined the activation of ASK1 in the post-mortem brain of MS patients. ASK1 activation was found in active lesions of the corpus callosum in both microglia/macrophages and astrocytes. Moreover, ASK1 activation in astrocytes was higher than that in microglia/macrophages, which was in line with our findings in EAE mice. Our results suggest an important role of ASK1 in glial cells, indicating that ASK1 might be a good therapeutic target for MS., (© 2024 Japanese Society of Neuropathology.)

Ceramide C16 is a sphingolipid detected at high levels in several neurodegenerative disorders, including multiple sclerosis (MS). It can be generated de novo or from the hydrolysis of other sphingolipids, such as sphingomyelin or through the recycling of sphingosine, in what is known as the salvage pathway. While the myelin damage occurring in MS suggests the importance of the hydrolytic and salvage pathways, the growing interest on the importance of diet in demyelinating disorders, prompted us to investigate the involvement of de novo ceramide C16 synthesis on disease severity. A diet rich in saturated fats such as palmitic acid, as found in many highly processed foods, provides substrates for the ceramide C16 synthetic enzymes ceramide synthase 6 (CERS6) and 5 (CERS5), which are expressed in the central nervous system. Using the experimental autoimmune encephalomyelitis (EAE) model of inflammatory demyelination, we show here that mice with CamK2a+ neuronal specific deletion of both CerS6 and CerS5 show a milder course of EAE than wild type mice, even when fed a diet enriched in palmitic acid. At a cellular level, neurons lacking both CerS6 and CerS5 are protected from the mitochondrial dysfunction arising from exposure to oxidative stress and palmitic acid in the medium. These data underscore the importance of a healthy diet avoiding processed foods for demyelinating disorders and identifies endogenous neuronal synthesis of ceramide C16 as an important determinant of disease severity., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Objective: Prevalence, susceptibility genes, and clinical and radiological features may differ across different ethnic groups of multiple sclerosis (MS). We aim to characterize brain lesions in Chinese patients with MS by use of 7-T MRI., Methods: MS participants were enrolled from the ongoing China National Registry of Neuro-Inflammatory Diseases (CNRID) cohort. 7-T MRI of the brain was performed. Each lesion was evaluated according to a standardized procedure. Central vein sign (CVS) and paramagnetic rim lesions were identified. The characteristics of lesions at patient-level and at lesion-level from previous 7-T MRI literature were also summarized., Results: We included 120 MS patients. Their mean (SD) age was 34.6 (9.4) years. The female-to-male ratio was 1.7:1 and mean disease duration of patients with MS was 5.5 ± 6.1 years. The median EDSS score was 2 (range, 0-8). A total of 8502 lesions were identified with a median lesion count of 45 (IQR, 18-90) (range, 2-370). The median (IQR) percentage for these special locations were as follows: cortical lesions (CLs) 2.7% (0%-5.7%), juxtacortical lesions 16.2% (7.8%-25.7%), periventricular lesions 30.2% (17.2%-38.7%), and infratentorial lesions 5.8% (0.4%-11.9%). CLs occurred in 70 (58%) patients, accounting for only 443 (5%) of the total lesions. Out of the 443 CLs, 309 (69.8%) were leukocortical lesions. CVS appeared in 5392 (63%) lesions from 117 (98%) patients. 1792 (21%) lesions and 104 (87%) patients exhibited a paramagnetic rim., Interpretation: Our study elaborated on the lesion features of Chinese patients with MS by use of 7-T MRI. Lesion burden is heavy in Chinese patients with MS. The median lesion count and proportion of PRL are high. The reported heavy lesion burden calls for ramping up regional and global efforts to care for MS patients. The management and research of Chinese population with MS needs to be further strengthened., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Baseline paramagnetic rim lesion (PRL) load predicts disease progression in people with multiple sclerosis (pwMS). Understanding how PRLs relate to other known MS-related factors, and the practical utility of PRLs in clinical trials, is crucial for informing clinical decision-making and guiding development of novel disease-modifying treatments (DMTs)., Methods: This study included 152 pwMS enrolled in a larger prospective, longitudinal cohort study who had 3T MRI scans and clinical assessments at baseline and 5- or 10-year follow-ups. PRLs were identified on baseline 3T quantitative susceptibility maps and classified as persisting, disappearing, or newly appearing at follow-up. The relationships between PRL evolution and clinical, radiological, environmental, and genetic characteristics were assessed, and clinical trial sample sizes were estimated using PRL appearance or disappearance as outcome measures., Results: DMT use was associated with lower odds of new PRL appearance (for high-efficacy DMTs: odds ratio = 0.088, p = 0.024), but not disappearance. Current smoking status was associated with greater baseline PRL number (B = 0.527 additional PRLs, p = 0.013). A 24-month clinical trial in people with progressive MS for a DMT that doubles the rate of PRL rim disappearance would require an estimated 118 people with progressive MS per group at 80% statistical power., Interpretation: Early MS diagnosis and subsequent DMT initiation may reduce new chronic active inflammation. However, the utility of PRL disappearance or new PRL appearance as outcome measures in clinical trials is limited by potentially large sample sizes that are needed for moderate efficacy drugs., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The chronic inflammatory condition known as multiple sclerosis (MS) causes inflammation and demyelination in the central nervous system (CNS). The activation of multiple cell types, including the CNS's resident immune cells called microglia, is a component of the immunological response in MS. Recently, the triggering receptor expressed on myeloid cells (TREM) family has emerged as a crucial player in modulating microglial function and subsequent neuroinflammation. Understanding the role of TREM receptors in MS pathogenesis could provide insightful information on how to develop new therapeutic approaches., Main Body: The TREM family consists of several receptors, including TREM-1 and TREM-2, which can be expressed on both immune cells, such as myeloid cells and microglia, and non-immune cells. These receptors interact with their respective ligands and regulate signaling pathways, ultimately leading to the control of microglial activation and inflammatory reactions. TREM-2, in particular, has garnered significant interest because of its connection with MS and other neurodegenerative diseases. The activation of microglia through TREM receptors in MS is thought to influence the equilibrium between helpful and detrimental inflammatory responses. TREM receptors can promote the phagocytosis of myelin debris and remove apoptotic cells, thus contributing to tissue repair and regeneration. However, excessive or dysregulated activation of microglia mediated by TREM receptors can lead to the release of pro-inflammatory cytokines and neurotoxic factors, exacerbating neuroinflammation and neurodegeneration in MS., Conclusion: The emerging role of the TREM family in demyelinating diseases highlights the importance of microglia in disease pathogenesis. Understanding the mechanisms by which TREM receptors modulate microglial function can provide valuable insights into the development of targeted therapies for these disorders. By selectively targeting TREM receptors, it may be possible to harness their beneficial effects on tissue repair while dampening their detrimental pro-inflammatory responses. Further research is warranted to elucidate the precise signaling pathways and ligand interactions involved in TREM-mediated microglial activation, which could uncover novel therapeutic avenues for treating MS and other neuroinflammatory disorders., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS., Methods: Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration., Results: We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1 high ) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1 low ), MS-A1 high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1 high cases., Interpretation: hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2025;97:313-328., (© 2024 American Neurological Association.)

Introduction: Longitudinally extensive spinal cord lesions (LESCL) are characterized by T2-hyperintense signals spanning at least three vertebral body segments, with neuromyelitis optica spectrum disorders (NMOSD) being a significant cause. This study aimed to characterize the clinical, radiological, serological, and cerebrospinal fluid (CSF) features of LESCL and to compare NMOSD and non-NMOSD cases., Methods: We conducted a retrospective cross-sectional study of adult patients diagnosed with LESCL at our center over a twelve-year period collecting data on demographics, clinical presentations, MRI findings, CSF analysis, and serological testing for AQP4-IgG and MOG-IgG antibodies. Etiologies were reviewed based on current diagnostic criteria, with comparisons made between NMOSD and non-NMOSD LESCL., Results: We identified 41 LESCL cases, with NMOSD as the most common etiology (29.3 %) followed by ischemia (14.6 %) and multiple sclerosis (9.8 %). The median length of lesions was seven vertebral segments. Pleocytosis was present in 48.6 % of CSF analyses, with oligoclonal bands found in 10 cases. AQP4-IgG antibodies were positive in 11 of 12 NMOSD patients. NMOSD patients were more likely to be female (p = p.006), and exhibit severe symptoms, such as quadriparesis (p = 0.03) and a cervical sensory level (p = 0.04). MRI findings showed a preference for cervical lesions in NMOSD (p = 0.001) and thoracic lesions in non-NMOSD LESCL (p = 0.007)., Conclusions: LESCL exhibit considerable clinical diversity, with NMOSD being the predominant etiology. Characteristics such as female sex and cervical MRI involvement may indicate a higher likelihood of NMOSD, while cases in males with thoracic segment involvement may suggest non-NMSOD etiologies such as ischemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A recent paper published in Cell by Woo et al. reported that autophagy-dependent ferroptosis mediated by STING1 is involved in neuronal death associated with multiple sclerosis (MS). This research broadens our understanding of the pathogenesis of MS and opens new avenues for therapeutic interventions.

Background: Alterations in structural connectivity of brain networks have been linked to complex cognitive functions in people with multiple sclerosis (PwMS). However, a definitive consensus on the optimal diffusion tensor imaging (DTI) markers as indicators of cognitive performance remains incomplete and inconclusive. This systematic review and meta-analysis aimed to explore the evidence on the correlation between DTI metrics and cognitive functions in PwMS., Methods: A comprehensive literature search was conducted across PubMed/MEDLINE, Embase, Scopus, and the Web of Science up to March 2024 to identify studies reporting the correlation between DTI metrics and cognitive functions. Cognitive function was assessed using the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT), and Brief Visuospatial Memory Test-Revised (BVMT-R). The pooled correlation coefficients were estimated using R software version 4.4.0 with the random effect model., Results: Out of 1952 studies, 38 studies on 2055 PwMS fulfilled the inclusion criteria. The meta-analysis indicated that the SDMT exhibited the greatest correlation with corpus callosum fractional anisotropy (FA) (r = 0.54, 95 % CI: 0.4 to 0.66, p-value < 0.001, I 2 = 34.1 %, p-heterogeneity = 0.19) and mean diffusivity (MD) (r = -0.48, 95 % CI: 0.61 to -0.33, p-value < 0.001, I 2 = 0 %, p-heterogeneity = 0.77), white matter FA (r = 0.39, 95 % CI: 0.24 to 0.52, p-value < 0.001, I 2 = 0 %, p-heterogeneity = 0.1), and fornix FA (r = 0.35, 95 % CI: 0.12 to 0.54, p-value = 0.003, I 2 = 50.7 %, p-heterogeneity = 0.18) and MD (r = -0.35, 95 % CI: 0.49 to -0.19, p-value < 0.001, I 2 = 0 %, p-heterogeneity = 0.5)., Conclusion: DTI measurements, including corpus callosum FA and MD, white matter FA, and fornix FA and MD, represent the indicators of cognitive performance in PwMS. Nonetheless, these findings warrant cautious interpretation due to the restricted kinds of cognitive tests and methodological variability across studies., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Memory decline is common in multiple sclerosis (MS), although pathophysiological mechanisms are not fully understood., Objective: The objective was to investigate the relationship of changes in structural and functional neuroimaging markers to memory decline over 3-year follow-up., Methods: Participants with MS underwent cognitive evaluation and structural, diffusion, and functional 3T magnetic resonance imaging (MRI) scans at baseline and 3-year follow-up. Changes in neuroimaging metrics from baseline to follow-up were compared between memory stable and memory decline groups. Our hypothesis that structural and functional connectivity changes mediate the association of atrophy to memory decline was tested., Results: A total of 249 MS patients completed baseline visit; 169 (67.8%) returned at 3-year follow-up. Based on ⩾10% decline, memory decline was observed in 44.4% ( n = 75). Those with memory decline showed marginally greater whole-brain volume loss over time compared with those with stable memory performance ( p = 0.08). In those with memory decline, changes in white matter tract integrity were related to regional cortical thinning ( p < 0.01). Exploratory mediation analysis revealed structural and functional connectivity to mediate the relationship of atrophy to verbal and visual memory decline., Conclusion: Further work is needed to characterize complex interrelationships of atrophy and structural/functional connectivity changes to memory decline in MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Berberine (BBN) is a naturally occurring alkaloid as a secondary metabolite in many plants and exhibits several benefits including neuroprotective activities. However, data on the neuromodulating potential of nanoformulated BBN are still lacking. In the present study, BBN loaded within iron oxide nanoparticles (BBN-IONP) were prepared and characterized by transmission electron microscopy FTIR, X-ray photoelectron spectroscopy particle-size distribution, zeta potential, and HPLC. The remyelinating neuroprotective potential of BBN-IONP relative to free BBN was evaluated against cuprizone (CPZ)-induced neurotoxicity (rats administered 0.2% CPZ powder (w/w) for five weeks). CPZ rats were treated with either free BBN or IONP-BBN (50 mg/kg/day, orally) for 14 days. Cognitive function was estimated using Y-maze. Biochemically, total antioxidant capacity lipid peroxides and reduced glutathione in the brain tissue, as well as, serum interferon-gamma levels were estimated. Moreover, the genetic expression contents of myelin basic protein Matrix metallopeptidase-9 Tumor necrosis factor-α (TNF-α), and S100β were measured. The histopathological patterns and immunohistochemical assessment of Glial Fibrillary Acidic Protein in both cerebral cortex and hippocampus CA1 regions were investigated. CPZ-rats treated with either free BBN or IONP-BBN demonstrated memory restoring, anti-oxidative, anti-inflammatory, anti-astrocytic, and remyelinating activities. Comparing free BBN with IONP-BBN revealed that the latter altered the neuromodulating activities of BBN, showing superior neuroprotective activities of IONP-BBN relative to BBN. In conclusion, both forms of BBN possess neuroprotective potential. However, the use of IONPs for brain delivery and the safety of these nano-based forms need further investigation., Competing Interests: Declarations. Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Ferroptosis is a recently characterized form of cell death that has gained attention for its roles in both pathological and physiological contexts. The existence of multiple anti-ferroptotic pathways in both neoplastic and healthy cells, along with the critical regulation of iron metabolism involved in lipid peroxides (lipid-ROS) production-the primary mediators of this cell death process-underscores the necessity of precisely controlling or preventing accidental/unwanted ferroptosis. Conversely, dysregulated iron metabolism and alterations in the expression or activity of key anti-ferroptotic components are linked to the development and progression of various human diseases, including multiple sclerosis (MS). In MS, the improper activation of ferroptosis has been associated with the progressive loss of myelinating oligodendrocytes (myOLs). Our study demonstrates that the physiological and maturation-dependent increase in iron accumulation within oligodendrocytes acts as a pro-ferroptotic signal, countered by the concurrent expression of AKR1C1. Importantly, MS-related neuroinflammation contributes to the down-regulation of AKR1C1 through miRNA-mediated mechanisms, rendering mature oligodendrocytes more vulnerable to ferroptosis. Together, these findings highlight the role of ferroptosis in MS-associated oligodendrocyte loss and position AKR1C1 as a potential therapeutic target for preserving oligodendrocyte integrity and supporting neuronal function in MS patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual system is frequently impaired in MS. In previous studies, we observed early malfunctions of rod photoreceptor ribbon synapses in the EAE mouse model of MS that included alterations in synaptic vesicle cycling and disturbances of presynaptic Ca 2+ homeostasis. Since these presynaptic events are highly energy-demanding, we analyzed whether synaptic mitochondria, which play a major role in synaptic energy metabolism, might be involved at that early stage. Rod photoreceptor presynaptic terminals contain a single large mitochondrion next to the synaptic ribbon. In the present study, we analyzed the expression of functionally relevant mitochondrial proteins (MIC60, ATP5B, COX1, PINK1, DRP1) by high-resolution qualitative and quantitative immunofluorescence microscopy, immunogold electron microscopy and quantitative Western blot experiments. We observed a decreased expression of many functionally relevant proteins in the synaptic mitochondria of EAE photoreceptors at an early stage, suggesting that early mitochondrial dysfunctions play an important role in the early synapse pathology. Interestingly, mitochondria in presynaptic photoreceptor terminals were strongly compromised in early EAE, whereas extra-synaptic mitochondria in photoreceptor inner segments remained unchanged, demonstrating a functional heterogeneity of photoreceptor mitochondria.

Background: Multiple sclerosis (MS) is a chronic autoimmune condition that damages the myelin sheath of neurons in the central nervous system, resulting in compromised nerve transmission and motor impairment. The astrocytopathy is considered one of the prominent etiological factor in the pathophysiology of demyelination in MS. The expression level of ceramide synthase-2 (CS-2) is yet to be established in the pathophysiology of astrocytopathy although the derailed ceramide biosynthetic pathways is well demonstrated in the pathophysiology of demyelination. Therefore, in the present study, the expression level of CS-2 has been evaluated in lysophosphatidylcholine (LPC)-challenged primary astrocytes in the presence of anti-demyelinating agents such as Fingolimod, a clinically approved anti-demyelinating drug, and Ursolic Acid (UA), an experimentally accepted anti-demyelinating agent, in MS., Methods and Results: LPC (150 µg/ml) caused astrocytopathy evident by decrease in percentage of viable astrocytes, increase in percentage of apoptotic astrocytes, increase in the level of reactive oxygen species (ROS), and increase in the level of activated astrocytes. Interestingly, LPC significantly increased the expression level of CS-2 in the primary culture of astrocytes where as fingolimod and UA (1, 10, and 100 µM) were able to attenuate the extent of LPC-induced astrocytopathy in the primary culture model of MS. Further, both the drugs drastically reduced the LPC-induced increase in the level of expression of CS-2 in the astrocytes., Conclusions: These observations indicate the fact that CS-2 could be a potential target in the management of astrocytopathy and astrocytopathy-related neurological disorders including MS. In conclusion, CS-2-targeted drugs could be potential therapeutic options in the management of MS., Competing Interests: Declarations. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethical approval: All procedures in this study are in accordance with the Guide for the Care and Use of Laboratory Animals of the National Research Council US Committee for the update of the guide for the care and use of laboratory animals, 2011 and were approved by the Institutional Animal Ethics Committee approval (CUPB/IAEC/2022/54) of the Central University of Punjab. Consent to participate: Not applicable. Consent to publication: The Author confirms that the work described has not been published before., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

The cuprizone (CPZ) model of multiple sclerosis (MS) is excellent for studying the molecular differences behind the damage caused by poisoning. Metabolic differences in the kynurenine pathway (KP) of tryptophan (TRP) degradation are observed in both MS and a CPZ mouse model. Our goal was to analyze the kynurenine, serotonin, and indole pathways of TRP degradation on the periphery, in the neurodegenerative processes of inflammation. In our study, mice were fed with 0.2% CPZ toxin for 5 weeks. We examined the metabolites in the three pathways of TRP breakdown in urine, plasma, and relevant visceral organs with bioanalytical measurements. In our analyses, we found a significant increase in plasma TRP, 5-hydroxytryptophan (5-HTP), and indole-3-acetic acid (IAA) levels, while a decrease in the concentrations of 3-hydroxy-L-kynurenine (3-HK), xanthurenic acid (XA), kynurenic acid (KYNA), and quinaldic acid in the plasma of toxin-treated group was found. A marked decrease in the levels of 3-HK, XA, KYNA, quinaldic acid, and indole-3-lactic acid was also observed in the visceral organs by the end of the poisoning. Furthermore, we noticed a decrease in the urinary levels of the TRP, KYNA, and XA metabolites, while an increase in serotonin and 5-hydroxyindoleacetic acid in the CPZ group was noticed. The toxin treatment resulted in elevated tryptamine and indoxyl sulfate levels and reduced IAA concentration. Moreover, the urinary para-cresyl sulfate concentration also increased in the treated group. In the present study, we showed the differences in the three main metabolic pathways of TRP degradation in the CPZ model. We confirmed the relationship and correlation between the content of the kynurenine metabolites in the plasma and the tissues of the visceral organs. We emphasized the suppression of the KP and the activity of the serotonin and indole pathways with a particular regard to the involvement of the microbiome by the indole pathway. Consequently, this is the first study to analyze in detail the distribution of the kynurenine, serotonin, and indole pathways of TRP degradation in the periphery.

In multiple sclerosis (MS), there is significant evidence indicating that both progression independent of relapse activity (PIRA) and relapse-related worsening events contribute to the accumulation of progressive disability from the onset of the disease and throughout its course. Understanding the compartmentalized pathophysiology of MS would enhance comprehension of disease progression mechanisms, overcoming the traditional distinction in phenotypes. Smoldering MS activity is thought to be maintained by a continuous interaction between the parenchymal chronic processes of neuroinflammation and neurodegeneration and the intrathecal compartment. This review provides a comprehensive and up-to-date overview of the neuropathological and immunological evidence related to the mechanisms underlying PIRA phenomena in MS, with a focus on studies investigating the impact of currently available therapies on these complex mechanisms.

Multiple sclerosis (MS) is a neurological disease causing myelin and axon damage through inflammatory and autoimmune processes. Despite affecting millions worldwide, understanding its genetic pathways remains limited. The choroid plexus (ChP) has been studied in neurodegenerative processes and diseases like MS due to its dysregulation, yet its role in MS pathophysiology remains unclear. Our work re-evaluates the ChP transcriptome in progressive MS patients and compares gene expression profiles using diverse methodological strategies. Samples from patient and healthy control RNASeq sequencing of brain tissue from post-mortem patients (GEO: GSE137619) were used. After an evaluation and quality control of these data, they had their transcripts mapped and quantified against the reference transcriptome GRCh38/hg38 of Homo sapiens using three strategies to identify differentially expressed genes in progressive MS patients. Functional analysis of genes revealed their involvement in immune processes, cell adhesion and migration, hormonal actions, amino acid transport, chemokines, metals, and signaling pathways. Our findings can offer valuable insights for progressive MS therapies, suggesting specific genes influence immune cell recruitment and potential ChP microenvironment changes. Combining complementary approaches maximizes literature coverage, facilitating a deeper understanding of the biological context in progressive MS., Competing Interests: Declarations. Information Sharing Statement: From GEO, you can obtain all raw RNA-Seq data in .sra format. More information is described in the first topic of the methodology. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroinflammation is often characterized by immune cell infiltrates in the cerebrospinal fluid (CSF). Here, we apply single-cell RNA sequencing to explore the functional characteristics of these cells in patients with various inflammatory, infectious, and non-inflammatory neurological disorders. We show that CSF is distinct from the peripheral blood in terms of both cellular composition and gene expression. We report that the cellular and transcriptional landscape of CSF is altered in neuroinflammation but is strikingly similar across different neuroinflammatory disorders. We find clonal expansion of CSF lymphocytes in all disorders but most pronounced in inflammatory diseases, and we functionally characterize the transcriptional features of these cells. Finally, we explore the genetic control of gene expression in CSF lymphocytes. Our results highlight the common features of immune cells in the CSF compartment across diverse neurological diseases and may help to identify new targets for drug development or repurposing in multiple sclerosis (MS)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer's disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: To identify early changes in hippocampal quantitative parameters in multiple sclerosis (MS) patients using synthetic MRI, and to correlate these changes with clinical variables., Methods: 45 MS patients and 26 healthy controls (HCs) underwent synthetic MRI and 3D-T1 MRI. The hippocampus volumes were assessed by using voxel-based morphometry. Synthetic MRI parameters (T1, T2, and proton density (PD)) from hippocampus and its subfield were measured and compared, and their associations with the Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT) scores were further investigated., Results: There was no significant difference in hippocampal volume between MS patients and HCs. Compared with HCs, the T1, T2 and PD values of hippocampus and its subfield increased in MS patients. T2 values showed positive correlation with EDSS and negative correlation with SDMT., Conclusions: Synthetic MRI can detect subtle quantitative changes of the hippocampus in MS patients with normal hippocampal volume. Specifically, Synthetic MRI parameters may apply as potentially effective imaging biomarker for hippocampus evaluation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Married or long-term partnered patients with chronic diseases generally have better outcomes than unmarried patients, likely due to the potential for multifaceted support. However, the impact of marital status on multiple sclerosis (MS) radiographic disease burden is currently unknown., Objective: To compare total white matter hyperintensity lesion volumes, periventricular lesion volumes, and whole brain and grey matter volumes in married and unmarried people with MS (PwMS)., Methods: We utilized multivariable linear regression to assess for differences in brain atrophy and lesion volumes between these two groups controlling for sex, MS disease duration in years, hypertension, history of smoking, alcohol consumption, history of depression and/or anxiety, and medication possession ratio (MPR)., Results: Married PwMS had significantly lower total lesion volumes (β =  - 6.3, 95% CI - 12.1 to - 0.5, p = 0.033), lower PV lesion volumes (β =  - 6.1, 95% CI - 11.7 to - 0.6, p = 0.030), higher normalized whole brain volumes (β = 38.3, 95% CI 6.0 to 70.7, p = 0.021), and higher normalized grey matter volumes (β = 20.9, 95% CI - 0.7 to 42.6, p = 0.058) than unmarried PwMS., Conclusion: Being married may be associated with improved MS outcomes as evidenced by decreased radiographic MS disease burden., Competing Interests: Declarations. Conflict of interest: A. Balshi reports no disclosures relative to the manuscript; J. Dempsey reports no disclosures relative to the manuscript; S. Kumbar reports no disclosures relative to the manuscript; U. Baber reports no disclosures relative to the manuscript; J.A. Sloane has grant funding from National MS Society and has consulted for Biogen, Genentech, Teva, Banner, Sanofi, and Cellgene. Data availability: Deidentified data and statistical analyses may be shared with qualified investigators on reasonable request to the corresponding author., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and neurodegeneration. Our original study analyzes the interactions between blood platelets and leukocytes in MS, focused on their potential role in modulating immune responses. We demonstrated, for the first time, a significant increase in leukocyte migration towards platelets, indicating their higher chemotactic capabilities in MS. This novel finding is supported by microscopic imaging of platelet-leukocyte hetero-aggregates (PLAs). Our study included platelet activation status and platelet-lymphocyte cross-talk analysis distinguishing lymphocytic subpopulation in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS) compared to healthy controls (HC). Flow cytometry method revealed an elevated expression of platelet activation typical markers i.e. PAC-1 and CD62P in both phenotypes of MS, especially in RRMS, and higher GPVI level in SPMS. Detailed immunophenotyping and confocal imaging showed an increased pool of platelet-lymphocyte aggregates (PLAs-Ly), particularly involving B-cells over T-cells across both MS phenotypes. The study also explored the involvement of the CD40-CD40L pathway, discovering significant correlations between platelet CD40L expression and lymphocytic antigen CD40, especially on B-cells in SPMS. This novel finding may indicate the special significance of platelet-B-cell cross-talk in progressive disease phenotype. Our research identified potential platelet-leukocyte interaction pathways that may influence the lymphocyte-mediated immune response in MS, highlighting the unexplored formation of platelet-B cell hetero-aggregates (PLAs-LyB)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Previous investigations on optical coherence tomography (OCT) in multiple sclerosis (MS) focused on generalizable macular and peri-papillary regions without considering the anatomic variations of the retinal layer thickness., Objective: This study aimed to assess the utility of parafoveal retinal layer thickness measured by OCT, underscoring its relationships with clinical outcomes in MS., Methods: In this cross-sectional study, 214 people with MS (pwMS) and 57 age- and sex-matched healthy controls (HCs) were enrolled. Spectral domain OCT evaluation using 1, 3, 6 mm Early Treatment Diabetic Retinopathy Study grid were conducted. The macular and parafoveal thickness (excluding the 1 mm foveal/umbo contribution) of the retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), ganglion cell layer (GCL), inner plexiform layer (IPL), and the peri-papillary RNFL (pRNFL) were measured. Multivariable step-wise logistic, linear and generalized estimating equation (GEE) regression models were used to assess the association between the OCT parameters and clinical MS outcomes., Results: The parafoveal RNFL thickness (d = 0.27, p = 0.023), GCL (d = 0.87, p < 0.001), IPL (d = 0.82, p < 0.001), and GCIPL (d = 0.85, p < 0.001) were all significantly lower in pwMS than HCs. Optic neuritis history [odds ratio (OR) = 0.84, p < 0.001] and progressive MS (PMS) status (OR = 0.92, p < 0.001) were both best predicted by parafoveal GCL. The Expanded Disability Status Scale (EDSS) was associated with the parafoveal thickness of GCL (standardized β = -0.472, p < 0.001) and pRNFL (standardized β = 0.187, p = 0.021). The parafoveal GCL thickness as predictor of MS disability was also confirmed by the GEE models., Conclusion: This investigation supports the potential use of parafoveal OCT segmentation as an alternative assessment method in detecting neuroinflammatory and neurodegenerative processes in MS. Averaging of the parafoveal retinal layer thickness into the OCT measures may increase the sensitivity of the standard macular OCT segmentation outcomes. Further studies should aim at exploring the reproducibility of this OCT outcome and its longitudinal responsiveness., Competing Interests: Declarations. Conflicts of interest: Omid Mirmosayyeb and Dejan Jakimovski have nothing to disclose. Bianca Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme, Sanofi, Genentech, Novartis, Celgene/BMS, Janssen and Horizon Dr Weinstock-Guttman received research funds from Biogen Idec, EMD Serono, Genzyme, Genentech, Sanofi, Novartis. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Protembis, Janssen, 415 Capital, and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Cognitive impairment (CI) in multiple sclerosis (MS) is only partially explained by whole-brain volume measures, but independent component analysis (ICA) can extract regional patterns of damage in grey matter (GM) or white matter (WM) that have proven more closely associated with CI. Pathology in GM and WM occurs in parallel, and so patterns can span both. This study assessed whether joint-ICA of GM and WM features better explained cognitive function compared to single-tissue ICA. 89 people with MS underwent cognitive testing and magnetic resonance imaging. Structural T1 and diffusion-weighted images were used to measure GM volumes and WM connectomes (based on fractional anisotropy weighted by the number of streamlines). ICA was performed for each tissue type separately and as joint-ICA. For each tissue type and joint-ICA, 20 components were extracted. In stepwise linear regression models, joint-ICA components were significantly associated with all cognitive domains. Joint-ICA showed the highest variance explained for executive function (Adjusted R 2  = 0.35) and visual memory (Adjusted R 2  = 0.30), while WM-ICA explained the highest variance for working memory (Adjusted R 2  = 0.23). No significant differences were found between joint-ICA and single-tissue ICA in information processing speed or verbal memory. This is the first MS study to explore GM and WM features in a joint-ICA approach and shows that joint-ICA outperforms single-tissue analysis in some, but not all cognitive domains. This highlights that cognitive domains are differentially affected by tissue-specific features in MS and that processes spanning GM and WM should be considered when explaining cognition., Competing Interests: Declarations. Conflicts of interest: N.S. has been a clinical research fellow in a post supported by Merck (supervised by D.C.) and subsequently by MRC (MR/W019906/1). D.C. is a consultant for Hoffmann-La Roche. In the last 3 years, he has been a consultant for Biogen, has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, the Medical Research Council, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and has been a speaker’s honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. Ethical approval and consent: This study had research ethics committee approval (09/H0716/77). Informed consent: All participants in the study gave written informed consent., (© 2025. The Author(s).)

Background: In multiple sclerosis (MS), susceptibility-weighted imaging (SWI) may reveal white matter lesions (WML) with a paramagnetic rim ("paramagnetic rim lesions" [PRLs]) or diffuse hypointensity ("core-sign lesions"), reflecting different stages of WML evolution., Objective: Using the soma and neurite density imaging (SANDI) model on diffusion-weighted magnetic resonance imaging (MRI), we characterized microstructural abnormalities of MS PRLs and core-sign lesions and their clinical relevance., Methods: Forty MS patients and 20 healthy controls (HC) underwent a 3 T brain MRI. Using SANDI, the fractions of neurite (f neurite ) and soma (f soma ) and size of soma (r soma ) were quantified in PRLs (including their core and rim separately), and core-sign lesions identified on SWI-phase., Results: Among 1811 WMLs, 122 (6.7%) core-sign lesions and 97 (5.4%) PRLs were identified. Compared to HC and MS normal-appearing white matter, all MS WML showed significantly lower f neurite and f soma and higher r soma (FDR-p < 0.001). Compared to SWI-isointense WML, core-sign lesions showed a significantly higher f neurite , and lower f soma and r soma (FDR-p ≤ 0.005). Compared to SWI-isointense WML and core-sign lesions, PRLs showed a significantly lower f neurite , higher f soma, and higher r soma (FDR-p ≤ 0.001). The PRL-core showed significantly lower f neurite , and higher r soma than PRL-rim (FDR-p < 0.001). Lower PRL f neurite (β ≤ -0.006, FDR-p ≤ 0.015) and higher r soma (β ≥ 0.032, FDR-p ≤ 0.024) were significantly associated with a longer disease duration and more severe disability., Conclusions: In PRLs, the significant and clinically relevant neurite loss and increased soma fraction and size possibly reflect increased astrogliosis and activated microglia. Core-sign lesions exhibit milder axonal loss, microglia density and astrogliosis, supporting their less destructive nature., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no competing interests in relation to this work. Potential conflicts of interest outside the submitted work are as follows: P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck, Bristol Myers Squibb, Genzyme, Horizon and Sanofi, he has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla; E. Pagani has nothing to disclose; A. Meani has nothing to disclose; M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral; M. Rubin has nothing to disclose; F. Esposito has nothing to disclose; M. Palombo has nothing to disclose; M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA, participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme, he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla; M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva, she receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla, she is Associate Editor for Multiple Sclerosis and Related Disorders. Ethical approval: Approval was received from the institutional ethical standards committee on human experimentation of IRCCS Ospedale San Raffaele for any experiments using human subjects (Protocol N° 2015–33). Written informed consent was obtained from all subjects prior to study participation according to the Declaration of Helsinki., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Remyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular and cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation between microglia activation and remyelination activity in MS., Methods: We correlated regenerative (CD163 + ) and inflammatory (iNOS + ) microglia with BCAS1 + oligodendrocytes, subdivided into early-stage (<3 processes) and late-stage (≥3 processes) cells in brain donors with high or low remyelinating potential in remyelinated lesions and active lesions with ramified/amoeboid (non-foamy) or foamy microglia. A cohort of MS donors categorized as efficiently remyelinating donors (ERDs; n=25) or poorly remyelinating donors (PRDs; n=17) was included, based on their proportion of remyelinated lesions at autopsy., Results and Discussion: We hypothesized more CD163 + microglia and BCAS1 + oligodendrocytes in remyelinated and active non-foamy lesions from ERDs and more iNOS + microglia with fewer BCAS1 + oligodendrocytes in active foamy lesions from PRDs. For CD163 + microglia, however, no differences were observed between MS lesions and MS donor groups. In line with our hypothesis, we found that INOS + microglia were significantly increased in PRDs compared to ERDs within remyelinated lesions. MS lesions, more late-stage BCAS1 + oligodendrocytes were detected in active lesions with non-foamy or foamy microglia in comparison with remyelinated lesions. Although no differences were found for early-stage BCAS1 + oligodendrocytes between MS lesions, we did find significantly more early-stage BCAS1 + oligodendrocytes in PRDs vs ERDs in remyelinated lesions. Interestingly, a positive correlation was identified between iNOS + microglia and the presence of early-stage BCAS1 + oligodendrocytes. These findings suggest that impaired maturation of early-stage BCAS1 + oligodendrocytes, encountering inflammatory microglia, may underlie remyelination deficits and unsuccessful lesion repair in MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Chen, Wever, McNamara, Bourik, Smolders, Hamann and Huitinga.)

Background and Objectives: In multiple sclerosis (MS), brain reserve serves as a protective factor against cognitive impairment. Previous research has suggested a structural counterpart in the spine-spinal cord reserve-seemed to be associated with physical disability. This study aimed to investigate the potential of the cervical canal area (CCaA) as a proxy for spinal cord reserve in a multicentric cohort of people with MS (PwMS)., Methods: This retrospective, multicentric, longitudinal study included PwMS and healthy controls (HCs) from 9 European MAGNIMS sites. Baseline cervical 3D T1-weighted images were acquired, excluding poor-quality images. CCaA was estimated independently at the C2/C3 and C3/C4 levels. The Expanded Disability Status Scale (EDSS) score was assessed at baseline and 5-year follow-up. We analyzed mean CCaA differences between groups and the association of CCaA with baseline EDSS scores and disability progression using multivariable regression models adjusted for age, sex, spinal cord parenchymal fraction, and cervical cord lesions., Results: After quality check, the cohort included 177 HCs (mean age 39.8 years, 57.6% women) and 428 PwMS (mean age 46.5 years, 60.8% women), comprising 289 people with relapsing MS (PwRMS) and 139 people with progressive MS (PwPMS). No significant differences in CCaA were found between HCs and PwRMS at C2/C3 or C3/C4 levels. Conversely, PwPMS showed a smaller CCaA at the C2/C3 level (210.51 mm 2 ) than HCs (214.62 mm 2 , estimated mean difference [EMD] -4.11, 95% CI -6.28 to -1.00, p = 0.007) and PwRMS (213.68 mm 2 , EMD -3.17, 95% CI -5.22 to -0.34, p = 0.026). PwPMS also had a smaller CCaA at C3/C4 (165.16 mm 2 ) than HCs (169.67 mm 2 , EMD -4.51, 95% CI -5.50 to -1.60, p < 0.001) and PwRMS (169.44 mm 2 , EMD -3.81, 95% CI -5.22 to -0.34, p < 0.001). At the C3/C4 level, CCaA and baseline EDSS scores were significantly associated (β = -0.13, p < 0.001); in addition, PwMS with clinical worsening at 5-year follow-up displayed a smaller baseline CCaA (worsened vs stable: 167.03 mm 2 vs 169.13 mm 2 , EMD -2.10, 95% CI -3.98 to -023, p = 0.028)., Discussion: CCaA was associated with baseline EDSS scores and clinical worsening in a multicentric MS cohort, suggesting the existence of spinal cord reserve. PwPMS had a smaller CCaA, indicating that reduced spinal cord reserve might be characteristic of progressive MS. Therefore, spinal cord reserve may represent a novel radiologic marker for better understanding physical disability in MS.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that results in motor, sensory, cognitive, and affective deficits. Hippocampal demyelination, a common occurrence in MS, is linked to impaired cognitive function and mood. Despite this, the precise mechanisms underlying cognitive impairments in MS remain elusive. Pleiotrophin (PTN), secreted by neural stem cells and astrocytes, plays a crucial role in regulating cognition. This study investigates the role of astrocyte-derived PTN. We found that genetic deletion of astrocyte-derived PTN hinders hippocampal neurogenesis. Additionally, conditional ablation of PTN in astrocytes exacerbates neurogenic deficits in the demyelinated hippocampus. Importantly, overexpression of PTN in astrocytes reverses neurogenic and cognitive impairments caused by demyelination, underscoring PTN's protective role in MS. PTN cooperates with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) or anaplastic lymphoma kinase (ALK) receptors to activate the AKT signaling pathway, thereby enhancing hippocampal neurogenesis and cognition in demyelinated mice. These findings illuminate novel effects of astrocyte-derived PTN on hippocampal neurogenesis and cognition., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The conventional statistical approach for analyzing resting state functional MRI (rs-fMRI) data struggles to accurately distinguish between patients with multiple sclerosis (MS) and those with neuromyelitis optic spectrum disorders (NMOSD), highlighting the need for improved diagnostic efficacy. In this study, multilevel functional metrics including resting state functional connectivity, amplitude of low frequency fluctuation (ALFF), and regional homogeneity (ReHo) were calculated and extracted from 116 regions of interest in the anatomical automatic labeling atlas. Subsequently, classifiers were developed using different combinations of these selected features to distinguish between MS and NMOSD. Compared to models based on individual MRI features, support vector machine (SVM) and logistic regression (LR) models that integrated multilevel functional features such as RSFC, ALFF, and ReHo demonstrated the highest levels of performance on the testing cohorts (SVM, AUC = 0.857; LR, AUC = 0.929). Adding structural features of gray matter volume (GMV) data did not notably improve the classification performance of the machine learning models using multilevel rs-fMRI features. Notably, similar trends were observed across different brain templates, with models based on RSFC, ALFF, and ReHo yielding optimal performance. These findings suggest that utilizing multilevel fMRI features can effectively differentiate between MS and NMOSD patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Intrathecal immunoglobulin A (IgA) synthesis in multiple sclerosis (MS) has long earned little attention, despite a potential significance in disease pathogenesis and prognosis. The presence of IgA-positive plasma cells in MS lesions and along damaged axons suggests a role in disease pathogenesis. Available clinical evidence about a potential positive or negative prognostic role is scarce and inconclusive. Recent observations, however, highlight the migration of immune regulatory IgA-producing plasma cells from the gut to the central nervous system (CNS) in experimental autoimmune encephalitis models. A connection between intrathecal IgA synthesis and the gut-brain axis in MS was further corroborated by the discovery of gut microbiota-specific IgA+ B cells in human CNS during relapse. In this review, we summarize current evidence on the occurrence and immunopathology of intrathecal IgA synthesis in MS, explore its biological implications, and address methodological challenges regarding the detection of IgA as a major limitation and possible source of inconsistencies in clinical studies. By synthesizing these diverse lines of evidence, we highlight the importance of further research and the need for standardized detection methods to clarify the role of IgA in MS pathogenesis, disease progression, and as potential biomarker.

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance among demyelination, neurodegeneration, and myelin repair. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, shifts the transcriptional programs of microglia and CNS-associated macrophages from a proinflammatory phenotype to a regenerative phenotype in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevented the activation of neuroinflammatory reactive astrocytes while also promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment of mice with bryo-1 augmented remyelination after a focal demyelinating injury. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin-regenerative and supportive agents in MS and other neurologic diseases.

Background and Purpose: Structural MRI (sMRI) is used in monitoring multiple sclerosis (MS) but lacks sensitivity in detecting clinically relevant damage to normal-appearing white matter (NAWM), that is, pre-lesional tissue, and specificity for identifying the underlying substrate of injury. In this longitudinal study, we identified pre-lesional tissue in MS patients and investigated its microstructure by modeling diffusion-weighted imaging (DWI) data using diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI)., Methods: We enrolled 18 patients with relapsing-remitting MS (10 females, 31.92 ± 8.09 years, disease duration 0.91 ± 1.81 years) and 18 healthy controls (10 females, 31.89 ± 8.15 years). Participants underwent two sMRI and DWI sessions (baseline and follow-up) with the same protocols. Average apparent diffusion coefficient (ADC), fractional anisotropy (FA), orientation dispersion index (ODI), and neurite density index (NDI) were estimated in data-driven regions of interest: nonpersistent lesional tissue (lesional tissue at baseline, resolved at follow-up), lesions that only existed at follow-up (pre-lesional tissue at baseline, lesions at follow-up), persistent lesional tissue (lesions at baseline and follow-up), and NAWM., Results: Compared to NAWM, pre-lesional tissue showed lower ODI, and resolved lesional tissue showed higher FA and ADC and lower ODI and NDI. Over time, persistent lesional tissue showed a decrease in FA and ODI and an increase in NDI. Compared to nonpersistent lesional tissue, persistent lesional tissue showed higher ADC and lower NDI., Conclusions: DWI and, more particularly, NODDI, can reveal the unique microstructure of persistent, resolved, and pre-lesional tissue in MS., (© 2025 American Society of Neuroimaging.)

Progressive multiple sclerosis (MS) represents the worsening phase of the disease, characterized by increasing neurodegeneration and disability and mainly refractory to current treatments. Finding therapeutic options remains challenging partially not only because of the lack of understanding of pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should start early in disease development, and therapeutic strategies for progressive MS should combine anti-inflammatory and neuroprotective aspects. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, has shed light on some ligand receptor pairs, such as growth-arrest-specific 6 (GAS6)/protein tyrosine kinase receptor (TYRO3) and protein S (PROS1)/AXL receptor tyrosine kinase (AXL), required to dampen inflammation, promote tissue repair, and engage remyelination. Understanding the role of these proteins in the early stages of MS is a critical step toward preventing or stopping neurodegeneration. Herein, we will discuss the receptor/ligand pairs that might be targetable for therapeutic intervention in progressive MS. SIGNIFICANCE STATEMENT: The aim for progressive multiple sclerosis treatment should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. Targeting the TYRO3, AXL, and MER tyrosine kinase receptor (TAM) signaling axis, particularly as growth-arrest-specific 6/TYRO3 and protein S/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients in the early stages of progressive multiple sclerosis., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

This paper explores uncertainty quantification (UQ) as an indicator of the trustworthiness of automated deep-learning (DL) tools in the context of white matter lesion (WML) segmentation from magnetic resonance imaging (MRI) scans of multiple sclerosis (MS) patients. Our study focuses on two principal aspects of uncertainty in structured output segmentation tasks. First, we postulate that a reliable uncertainty measure should indicate predictions likely to be incorrect with high uncertainty values. Second, we investigate the merit of quantifying uncertainty at different anatomical scales (voxel, lesion, or patient). We hypothesize that uncertainty at each scale is related to specific types of errors. Our study aims to confirm this relationship by conducting separate analyses for in-domain and out-of-domain settings. Our primary methodological contributions are (i) the development of novel measures for quantifying uncertainty at lesion and patient scales, derived from structural prediction discrepancies, and (ii) the extension of an error retention curve analysis framework to facilitate the evaluation of UQ performance at both lesion and patient scales. The results from a multi-centric MRI dataset of 444 patients demonstrate that our proposed measures more effectively capture model errors at the lesion and patient scales compared to measures that average voxel-scale uncertainty values. We provide the UQ protocols code at https://github.com/Medical-Image-Analysis-Laboratory/MS&#95;WML&#95;uncs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AM: work done while at Yandex and Isomorphic Labs. HM: mandates with Roche. MG: work done while at IBM Research. CG: The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory boards and consultancy fees from Actelion, Novartis, Genzyme-Sanofi, GeNeuro, Hoffmann La Roche and Siemens; (ii) speaker fees from Biogen, Hoffmann La Roche, Teva, Novartis, Merck, Jannsen Pharmaceuticals and Genzyme-Sanofi; (iii) research grants: Biogen, Genzyme Sanofi, Hoffmann La Roche, GeNeuro. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. NM, VR, FLR, AD, MBC nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microglia and astrocytes are the main components of the central nervous system (CNS). Upon activation, microglia is able to phagocyte cell debris, pathogens, and toxins; astrocytes support neuronal functions, blood-brain barrier (BBB) homeostasis, and neurotransmitter uptake and metabolism. Furthermore, both cell types can produce cytokines and chemokines. Aging impacts microglia and astrocytes by promoting the production of pro-inflammatory cytokines, impairing microglial phagocytosis and motility and astrocyte glutamate uptake. During neurodegenerative and neuroinflammatory diseases, the aging process may be accelerated contributing to the alteration of CNS glial cells functions. Multiple sclerosis (MS) is an autoimmune, demyelinating disease in which immunosenescence can promote the conversion from relapsing-remitting form to progressive disease. The murine model of experimental autoimmune encephalomyelitis (EAE) allows to investigate MS pathogenesis. Furthermore, EAE can be developed as acute or progressive, mimicking different forms of human MS. Microglia and astrocytes report morphological and functional changes during neuroinflammation that can be investigated in different ways. We here present a protocol for the study of glial cell activation in the spinal cord tissue of EAE mice., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To assess the interrelationship between cortical lesions and cortical thinning and volume loss in people with multiple sclerosis within cortical networks, and how this relates to future cognition., Methods: In this longitudinal study, 230 people with multiple sclerosis and 60 healthy controls underwent 3 Tesla MRI at baseline and neuropsychological assessment at baseline and 5-year follow-up. Cortical regions (N = 212) were divided into seven functional networks. Regions were defined as either lesional or normal-appearing cortex based on presence of a cortical lesion on artificial intelligence-generated double inversion-recovery scans. Cortical volume and thickness were determined within lesional or normal-appearing cortex., Results: Prevalence of at least one cortical lesion was highest in the limbic (73%) followed by the default mode network (70.9%). Multiple sclerosis-related cortical thinning was more pronounced in lesional (mean Z-score = 0.70 ± 0.84) compared to normal-appearing cortex (-0.45 ± 0.60; P < 0.001) in all, except sensorimotor, networks. Cognitive dysfunction, particularly of verbal memory, visuospatial memory, and inhibition, at follow-up was best predicted by baseline network volume of normal-appearing cortex of the default mode network [B (95% CI) = 0.31 (0.18; 0.43), P < 0.001]. Mediation analysis showed that the effect of cortical lesions on future cognition was mediated by volume loss of the normal-appearing instead of lesional cortex, independent of white matter lesion volume., Interpretation: Multiple sclerosis-related cortical thinning was worse in lesional compared to normal-appearing cortex, while volume loss of normal-appearing cortex was most predictive of subsequent cognitive decline, particularly in the default mode network. Mediation analyses indicate that cortical lesions impact cognitive decline plausibly by inducing atrophy, rather than through a direct effect., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Paramagnetic rim lesions (PRLs) are chronic active lesions associated with a severe disease course in multiple sclerosis (MS). This study was undertaken to investigate an association between retinal layer thinning (annualized loss of peripapillary retinal nerve fiber layer [aLpRNFL] and ganglion cell-inner plexiform layer [aLGCIPL]) and PRLs in patients with MS (pwMS)., Methods: In this study, pwMS with brain magnetic resonance imaging and ≥2 optical coherence tomography scans were included. Cox proportional hazard regression models were performed using progression independent of relapse activity (PIRA) as the dependent variable, and aLpRNFL, aLGCIPL, or the number of PRLs as independent variables, adjusted for covariates., Results: We analyzed data from 97 pwMS (mean age = 35.2 years [SD = 9.9], 71.1% female, median disease duration = 2.3 years [interquartile range = 0.9-9.0]). The number of PRLs was associated with aLpRNFL and aLGCIPL. PIRA was observed in 18 (18.6%) pwMS, with aLpRNFL (hazard ratio [HR] = 1.44 per %/year), aLGCIPL (HR = 1.61 per %/year), and the number of PRLs (HR = 1.24 per PRL) being associated with increased risk of PIRA., Conclusions: The number of PRLs is associated with inner retinal layer thinning and increased risk of PIRA. A combination of PRLs and retinal layer thinning could serve as a surrogate for pwMS at highest risk of disability progression., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neurological diseases are central nervous system (CNS) disorders affecting the whole body. Early diagnosis of the diseases is difficult due to the lack of disease-specific tests. Adding new biomarkers external to the CNS facilitates the diagnosis of neurological diseases. In this respect, the retina has a common embryologic origin with the CNS. Retinal imaging technologies including optical coherence tomography (OCT) can be used in the understanding and processual monitoring of neurological diseases. Retinal imaging has been recently recognized as a potential source of biomarkers for neurological diseases, increasing the number of studies in this direction. In this review, the association of retinal abnormalities with Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) is explained. Structural and functional abnormalities in retina as a predictive marker may facilitate early diagnosis of diseases. Although not all retinal abnormalities are predictive of neurologic diseases, changes in the retinal layers including retinal pigment epithelium and plexiform layers should suggest the risk of PD, MS, ALS, and AD., (© 2024 Wiley Periodicals LLC.)

Background: Hyperreflective retinal foci (HRF) visualized by optical coherence tomography (OCT) potentially represent clusters of microglia. We compared HRF frequencies and their association with retinal neurodegeneration between people with clinically isolated syndrome (pwCIS), multiple sclerosis (pwMS), aquaporin 4-IgG positive neuromyelitis optica spectrum disorder (pwNMOSD), and healthy controls (HC)-as well as between eyes with (ON + eyes) and without a history of optic neuritis (ON - eyes)., Methods: Cross-sectional data of pwCIS, pwMS, and pwNMOSD with previous ON and HC were acquired at Charité-Universitätsmedizin Berlin. HRF analysis was performed manually on the central macular OCT scan. Semi-manual OCT segmentation was performed to acquire the combined ganglion cell and inner plexiform layer (GCIPL), inner nuclear layer (INL), and peripapillary retinal nerve fiber layer (pRNFL) thickness. Group comparisons were performed by linear mixed models., Results: In total, 227 eyes from 88 patients (21 pwCIS, 32 pwMS, and 35 pwNMOSD) and 35 HCs were included. HRF in GCIPL and INL were more frequently detected in pwCIS, pwMS, and pwNMOSD than HCs (p < 0.001 for all comparisons) with pwCIS exhibiting the greatest numbers. ON + eyes of pwMS had less HRF in GCIPL than ON - eyes (p = 0.036), but no difference was seen in pwCIS and pwNMOSD. HRF GCIPL were correlated to GCIPL thickness in ON + eyes in pwMS (p = 0.040) and pwNMOSD (p = 0.031)., Conclusion: HRF occur in ON + eyes and ON - eyes across neuroinflammatory diseases. In pwMS and pwNMOSD, HRF frequency was positively associated with GCIPL thickness indicating that HRF formation might be dependent on retinal ganglion cells., (© 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)