Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. B cell-depleting therapy is highly efficient in treating patients with relapsing-remitting MS (RRMS), although the mechanisms behind reducing disease progression with this type of therapy is unknown. Virus infections are associated with the onset of MS and antibodies to these have previously been suggested to supplement MS diagnostics. Based on this, we aimed to investigate the effect of Ocrevus (OCR) (B cell depletion therapy) on selected virus antibody levels. Blood samples were collected from RRMS patients before (n = 13) and during OCR treatment (n = 29) and from healthy controls (HCs) (n = 15). Serum antibodies to virus antigens from Epstein-Barr virus (EBV), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), Rubella virus, Measles virus, John Cunningham polyomavirus, Mumps virus, Merkel cell polyomavirus, Varicella zoster virus, Influenza A virus, Human herpes virus 6, and Cytomegalovirus were analyzed by enzyme-linked immunosorbent assay. EBV nuclear antigen 1 (EBNA1) IgG levels were elevated in RRMS patients compared to HCs independent of OCR treatment. However, no significant difference in virus antibody levels was observed following OCR treatment. Only SARS-CoV-2 spike protein IgG levels were significantly reduced following OCR treatment. The effect of OCR treatment on antibody levels may correlate with the time of infection. Only EBV EBNA1 IgG levels were significantly elevated RRMS patients at baseline compared to HCs, supporting that EBV infection is involved in the development of MS and confirming the diagnostic value of EBNA1 IgG.

Multiple sclerosis is a chronic autoimmune disease in which the immune system attacks the protective sheath or myelin that covers nerve fibers, impacting the brain's ability to communicate with other areas of the body. This abnormal immune response recruits inflammatory substances, which appear as lesions on the brain and spinal cord. A stroke is characterized by a sudden impairment of neurological function resulting from the loss or restriction of blood flow due to acute damage to a localized area of the central nervous system, including the brain, retina, or spinal cord. While strokes, both ischemic and hemorrhagic, are different in terms of their pathogenesis to MS, mechanisms such as neuroinflammation and neurodegeneration are common denominators among these conditions. Recent studies highlight the involvement of the sphingosine-1-phosphate receptor in the treatment of strokes and how fingolimod, an S1P receptor modulator employed in MS treatment, may play a role in the treatment of stroke-like symptoms. This review aims to explore the potential link between stroke and MS, providing a comprehensive analysis of the existing evidence. It will also shed light on the role of S1P receptors in the pathophysiology of stroke, offering insights into their mechanistic contributions. Furthermore, the review will examine recent studies investigating the therapeutic potential of the S1P modulator, fingolimod, in acute stroke patients, highlighting its efficacy and potential clinical applications. Through this multifaceted approach, we hope to contribute to the development of a deeper understanding of these interconnected neurological conditions and their treatment strategies.

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by immune-mediated demyelination of the central nervous system, resulting in extensive neurological deficit and remyelination impairment. We have previously found that interleukin-four induced one (IL4I1) protein modulates CNS inflammation and enhances remyelination in mouse models of experimental demyelination. However, it remained unclear if IL4I1 regulates lymphocyte activity in MS. To assess the therapeutic potential of IL4I1 in MS, we investigated the impact of IL4I1 treatment on human lymphocytes from peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals and MS patients. We found that IL4I1 increased the relative densities of Th2 and regulatory T-cells, while reducing Th17 cell density in healthy control (HC) samples. Furthermore, IL4I1-treated lymphocytes promoted CNS remyelination when grafted into demyelinated spinal cord lesions in mice. We found that baseline endogenous IL4I1 expression was reduced in people with MS. However, unlike HCs, IL4I1 treatment had no significant effect on IL17 or TOB1 expression in lymphocytes derived from MS patients. These results suggest that IL4I1 skews CD4+ T-cells to a regulatory state in healthy human lymphocytes, which may be essential for promoting remyelination. However, IL4I1 appears unable to exert its influence on lymphocytes in MS, indicating that impaired IL4I1-mediated activity may underlie MS pathology.

Blood-brain barrier dysfunction (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We have previously shown that blocking microglial proliferation using GW2580, a selective inhibitor of CSF1R (Colony stimulating factor 1 receptor), reduced disease progression and severity and prevented the relapse phase. However, whether this was due to effects of GW2580 on the functional integrity of the BBB was not determined. Therefore, here, we examine BBB properties in rats during EAE under GW2580 treatment. Our data suggest that blocking early microglial proliferation through selective targeting of CSF1R signaling has a therapeutic effect in EAE by protecting BBB integrity and reducing peripheral immune cell infiltration. Taken together, our results identify a novel mechanism underlying the effects of GW2580, which could offer a novel therapy for MS.

Multiple sclerosis (MS) is a chronic, and potentially disabling, inflammatory disease of the central nervous system (CNS). MS is generally characterized by recurrent, and self-limited, episodes of neurological dysfunction, which occur unpredictably and often result in multifocal tissue injury within the CNS. Currently, women are affected two to three times as often as men although this may not have been the case during earlier Time-Periods. The pathogenesis of MS is known to involve both critical genetic and environmental mechanisms. Nevertheless, in addition to these two mechanisms, disease-pathogenesis also involves a "truly" random event. Indeed, it is this random mechanism, which is responsible for the currently-observed (and increasing) excess of women among patients with MS. This review summarizes the current state of knowledge regarding the pathogenesis of MS (includong its epidemiology, pathology, and genetics) and considers the therapeutic implications that these pathogenetic mechanisms have both for our currently available therapies as well as for the possible therapeutic approaches to the management of this potentially disabling condition in the future.

Immune reconstitution therapies (IRT) are highly effective therapies for multiple sclerosis (MS). Among IRT, we can distinguish partially selective therapies such as cladribine in tablets (CLAD) and non-selective therapies, which include alemtuzumab (ALEM). Today, it is known that these therapies are effective in controlling the relapse activity of the disease and the progression of clinical disability, which has been proven both in clinical trials and in real world evidence (RWE). However, there is a lack of data assessing the effect of IRT on the neurodegenerative process, which is intensified in patients with MS. The aim of the study was to assess the effect of IRT treatment on the degree and pattern of brain atrophy in patients with MS during 3 years of observation.

Patients with relapsing-remitting MS (RRMS) treated with CLAD and ALEM were retrospectively recruited for the study. Demographic, clinical, and magnetic resonance imaging (MRI) data were collected at 4 time points: before the treatment and one, two, and three years after the treatment. MRI examinations were analyzed volumetrically using Freesurfer software. Global and regional changes in atrophy were assessed by calculating percentage changes in volume between time points. Results of drug groups were compared with each other.

After 3 years of follow-up, statistically significant differences between groups were observed in hippocampus [p < 0.01] and amygdala volume changes [p < 0.01]. Ventral diencephalon atrophy was noted in both groups. On the other hand, in both groups, no significant atrophy of white and grey matter was noted. In addition, an increase in the thalamus volume was observed.

In the studied groups, IRT therapies were shown to slow down the atrophy process in MS patients to a similar extent. These therapies may play a neuroprotective role by increasing the volume of the thalamus and hippocampus. The study was limited by the small number of both groups. Therefore, further studies are needed to fully assess the effect of reconstitution therapies on neurodegenerative processes in patients with RRMS.

Observational studies have suggested a link between leukocyte telomere length (LTL) and multiple sclerosis (MS) progression, but the causal relationship remains uncertain. This study investigates the causal association between LTL and MS progression using a bidirectional two-sample Mendelian randomization (MR) approach. We analyzed genome-wide association summary statistics data from 472,174 individuals for LTL and 12,584 MS patients for disease progression. The primary method was the inverse variance weighted (IVW) approach, supported by sensitivity analyses to ensure robustness. The forward analysis revealed a significant positive causal relationship between LTL and MS progression (β = 0.107, 95 % CI = 0.006 to 0.209, P = 0.037). Conversely, the reverse analysis indicated a negative causal relationship (β = -0.010, 95 % CI = -0.020 to -0.001, P = 0.037). No heterogeneity or horizontal pleiotropy was found, and the sensitivity analyses confirmed consistent results. These findings suggest that telomere dynamics play a complex role in MS progression and highlight their potential as therapeutic targets. Further research is essential to uncover the biological mechanisms underlying the influence of telomeres on MS progression.

Multiple sclerosis (MS) is a demyelinating disease in which the insulating cover (myelin sheath) of the brain and spinal cord is damaged. Demyelination results in a decreased signal transmission in the nervous system. Symptoms include double vision, muscle weakness, and difficulty with coordination. Genetic and viral infections have been proposed as plausible factors responsible for MS. Although there is no cure for MS, treatment prevents future attacks. At present, chemotherapy and monoclonal antibodies are the available treatments for MS. Heterocyclic compounds are currently being tested clinically for their efficacy. Some heterocyclic scaffolds have been found to be promising for the treatment of MS. In view of this, research has been conducted towards the design and discovery of chemical agents for MS. Hence, the literature relevant to drug design for MS in the last decade has been collated and described comprehensively so that it would be helpful for efficient drug design for MS in the future. Additionally, through the structure-activity relationship, the importance of crucial structural features was emphasized. The classification was primarily based on the type of heterocycle.

Multiple sclerosis (MS) unfavorably affects working capacity. The Comprehensive International Classification of Functioning, Disability and Health Core Set for MS (cICF-MS), issued by the World Health Organization, has not yet been extended to evaluate working capacity level (WCL). To evaluate the relative importance of cICF-MS categories in relation to WCL. Persons with MS (PwMS), N = 129, who had been referred to Lithuania's Disability and Working Capacity Assessment Office for WCL determination, were divided into three groups according to the percentage of remaining WCL (WCL1 had 0-25%, WCL2 had 30-40%, and WCL3 had 45-55%). Data regarding the cICF-MS categories were collected through telephone interviews and patient documentation. Using the fractional ranking method, the mean values of cICF-MS impairment were ranked from the most severely affected to the least affected (rank 1-93). Ranks with the 10 highest mean values of impairment severity in each WCL group were included in a descriptive analysis. In the WCL1 and WCL2 groups, the most-affected cICF-MS categories reflected disability related to gait and motor function. The WCL3 group presented with pain, fatigue, and impairments to visual acuity, psychic stability, urination, and memory. This study has identified specific cICF-MS impairment profiles based on remaining WCL.

Recent scientific interest has focused on exploring the potential relationships between fatigue, respiratory function and balance in multiple sclerosis (MS) subjects. While some studies suggest that fatigue may impact respiratory function and postural stability, the exact nature of these associations remains under investigation. Ultrasound imaging is increasingly being used to examine the structural and functional characteristics of core muscles, aiming to better understand how these variables might be interconnected. Understanding these associations is crucial for developing targeted interventions to enhance overall physical performance in this population. This study examines the relationship between fatigue, respiratory function, balance, and ultrasound variables of abdominal musculature in MS.

A cross-sectional study was conducted involving 27 subjects diagnosed with MS, comprising 17 females and 10 males. Study variables were: fatigue (Modified Fatigue Impact Scale-MFIS); respiratory function (Forced Vital Capacity-FVC and Forced Expiratory Volume in the first second-FEV1); balance (Berg Balance Scale-BBS and Trunk Impairment Scale Dynamic-TIS DYN); and ultrasound measurements of abdominal and diaphragmatic musculature. Correlations were analyzed using Spearman's correlation, with a statistical significance level of p < 0.05.

Significant correlations were found between respiratory function and balance scores. FVC showed a moderate correlation with BBS (r = 0.443), while FEV1 had a high correlation with BBS (r = 0.500) and a moderate correlation with TIS DYN (r = 0.427). MFIS showed a moderate negative correlation with BBS (r = -0.402). The strength and function of the central abdominal musculature, particularly the internal oblique, were crucial for trunk stability and postural control.

These findings highlight the interplay between respiratory function, balance, fatigue, and abdominal muscle morphology in MS, emphasizing the potential benefits of interventions targeting respiratory function to improve balance and reduce fatigue, ultimately enhancing quality of life in this population.

Real-world studies in the USA report that 41-56% of patients with multiple sclerosis (MS) are ≥ 50 years old, yet data on their response to disease-modifying therapies (DMTs) is limited. Dimethyl fumarate (DMF) is an oral DMT approved for treating relapsing MS. This analysis evaluated the safety, efficacy, and immunophenotype changes of DMF in patients ≥ 50 years compared with patients < 50 years.

ESTEEM, a 5-year, real-world, observational phase 4 study, assessed the safety and effectiveness of DMF, including treatment-emergent serious adverse events (SAEs) and adverse events (AEs) leading to treatment discontinuation. Absolute lymphocyte counts (ALCs) were recorded from a subset of patients. The PROCLAIM study, a phase 3b interventional study, reported safety outcomes and lymphocyte subset changes in patients with relapsing-remitting MS (RRMS) treated with DMF. The study evaluated safety outcomes by analyzing the incidence of SAEs and detailed changes in CD4+ and CD8+ T cell compartments over 96 weeks of DMF treatment.

ESTEEM included 4020 patients aged < 50 years and 1069 aged ≥ 50 years. AEs leading to discontinuation were reported by 19.6% patients < 50 years and 29.6% of patients ≥ 50 years, with gastrointestinal disorders being the most common. SAEs were reported by 5.2% of patients < 50 years and 8.9% those ≥ 50 years. In PROCLAIM, SAEs were reported in 13% of patients < 50 years and 10% of those ≥ 50 years. Median ALC decreased by 35% in patients < 50 years and 50% in those ≥ 50 years in ESTEEM, with similar patterns observed in PROCLAIM.

ESTEEM found no unexpected safety signals in older patients and annualized relapse rates (ARRs) were significantly reduced in both age groups. Both studies indicated that DMF is efficacious and has a favorable safety profile in patients with RRMS aged ≥ 50 years.

ESTEEM (NCT02047097), PROCLAIM (NCT02525874).

Different definitions of disability progression by Expanded Disability Status Scale (EDSS) may influence frequency and/or time to event.

In this multicenter cohort study, we included PPMS patients with follow-up ≥24 months and ≥3 available EDSS scores overall (≥1 per year). We applied 672 definitions of disability progression including different minimal EDSS increase, required confirmation and fixed/roving-baseline score.

We analyzed follow-up periods from 131 PPMS patients (median age at baseline 53.0 years [45.0 - 63.0], 51.9 % female, median follow-up 3.9 years [2.6 - 6.0], median baseline EDSS 4.0 [2.5 - 6.0]). The most sensitive definition of a progression event was an unconfirmed increase of ≥0.5 points with a roving baseline (81.8 % event rate). The least sensitive definition was an increase of ≥1.0 points with a fixed baseline, minimal distance to reference 48 weeks, and confirmed at ≥48 weeks (28.4 % event rate). Comparing roving vs. fixed baseline over all cutoffs and confirmation definitions, average time to progression was 227 days shorter applying the roving baseline (1405 days [550 - 2653] vs. 1632 days [760 - 2653]).

Different definitions of disability progression result in significantly differing rates of disability progression, which may influence study results and create confusion in clinical practice.

Multiple sclerosis (MS) is an immune-mediated, chronic, inflammatory demyelinating disease of the central nervous system, impacting around 2.8 million people worldwide. Characterised by recurrent relapses or progression, or both, it represents a substantial global health burden, affecting people, predominantly women, at a young age (the mean age of diagnosis is 32 years). Azathioprine is used to treat chronic inflammatory and autoimmune diseases, and it is used in clinical practice as an off-label intervention for MS, especially where access to on-label disease-modifying treatments (DMTs) for MS is limited. Given this, a review of azathioprine's benefits and harms would be timely and valuable to inform shared healthcare decisions.

To evaluate the benefits and harms of azathioprine (AZA) for relapsing and progressive multiple sclerosis (MS), compared to other disease-modifying treatments (DMTs), placebo or no treatment. Specifically, we will assess the following comparisons. AZA compared with other DMTs or placebo as first-choice treatment for relapsing forms of multiple sclerosis AZA compared with other DMTs or placebo for relapsing forms of MS when switching from another DMT AZA compared with other DMTs or placebo as first-choice treatment for progressive forms of MS AZA compared with other DMTs or placebo for progressive forms of MS when switching from another DMT SEARCH METHODS: We conducted an extensive search for relevant literature using standard Cochrane search methods. The most recent search date was 9 August 2023.

We included randomised controlled trials (RCTs) lasting 12 months or more that compared azathioprine versus DMTs, placebo or no intervention in adults with MS. We considered evidence from non-randomised studies of interventions (NRSIs) as these studies may provide additional evidence not available from RCTS. We excluded cluster-randomised trials, cross-over trials, interrupted time series, case reports and studies of within-group design with no control group.

We followed standard Cochrane methodology. There were three outcomes we considered to be critical: disability, relapse and serious adverse events (SAEs, as defined in the studies). We were also interested in other important outcomes: quality-of-life (QoL) impairment (mental score), short-term adverse events (gastrointestinal disorders), long-term adverse events (neoplasms) and mortality.

We included 14 studies: eight RCTs (1076 participants included in meta-analyses) and six NRSIs (1029 participants). These studies involved people with relapsing and progressive MS. Most studies included more women (57 to 83%) than men, with participants' average age at the onset of MS being between 29.4 and 33.4 years. Five RCTs and all six NRSIs were conducted in Europe (1793 participants); two RCTs were conducted in the USA (126 participants) and one in Iran (94 participants). The RCTs lasted two to three years, while NRSIs looked back up to 10 years. Four studies received some funding or support from commercial interests and five were funded by government or philanthropy; the other five provided no information about funding. There are three ongoing studies. Comparison groups included other DMTs (interferon beta and cyclosporine A), placebo or no treatment. Below, we report on azathioprine as a 'first choice' treatment compared to interferon beta for people with relapsing MS. None of the studies reported on any critical or important outcome for this comparison for progressive MS. No study was retrieved comparing azathioprine to placebo or other DMTs for either relapsing or progressive MS. Furthermore, the NRSIs did not provide information not already covered in the RCTs. Azathioprine as a first-choice treatment compared to other DMTs (specifically, interferon beta) for relapsing MS - The evidence is very uncertain about the effect of azathioprine on the number of people with disability progression over two years compared to interferon beta (risk ratio (RR) 0.19, 95% confidence interval (CI) 0.02 to 1.58; 1 RCT, 148 participants; very low certainty evidence). - Azathioprine may decrease the number of people with relapses over a one- to two-year follow-up compared to interferon beta (RR 0.61, 95% CI 0.43 to 0.86; 2 RCTs, 242 participants; low-certainty evidence). - Azathioprine may result in a possible increase in the number of people with SAEs over two years in comparison with interferon beta (RR 6.64, 95% CI 0.35 to 126.27; 1 RCT, 148 participants; low-certainty evidence). - The evidence is very uncertain about the effect of azathioprine on the number of people with the short-term adverse event of gastrointestinal disorders over two years compared to interferon beta (RR 5.30, 95% CI 0.15 to 185.57; 2 RCTs, 242 participants; very low certainty evidence). We found no evidence comparing azathioprine to other DMTs for QoL impairment (mental score), long-term adverse events (neoplasms) or mortality.

Azathioprine has been proposed as an alternative treatment for MS when access to approved, on-label DMTs is limited, especially in resource-limited settings. The limited evidence available suggests that azathioprine may result in a modest benefit in terms of relapse frequency, with a possible increase in SAEs, when compared to interferon beta-1b, for people with relapsing-remitting multiple sclerosis. The evidence for the effect on disability progression and short-term adverse events is very uncertain. Caution is required in interpreting the conclusions of this review since our certainty in the available evidence on the benefits and harms of azathioprine in multiple sclerosis is low to very low, implying that further evidence is likely to change our conclusions. An important limitation we noted in the available evidence is the lack of long-term comparison with other treatments and the failure of most studies to measure outcomes that are important to people with multiple sclerosis, such as quality of life and cognitive decline. This is especially the case in the evidence relevant to people with progressive forms of multiple sclerosis.

The rapidly evolving landscape of effective treatment options in multiple sclerosis has led to a shift of treatment objectives towards a treat-to-target approach aiming to suppress disease activity below the level of detectability early during the disease. To enable treat-to-target, a thorough reappraisal of available outcome measures with respect to their ability in this regard is required.

To that end, we conducted a comprehensive systematic literature review of more than 1000 studies using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 methodology focusing on underlying evidence as well as utility and implementability in clinical practice.

From there, we propose a set of measurable outcomes for everyday routine clinical practice as well as advanced/aspirational measurables requiring additional resources. We also outline remaining knowledge/technology gaps that need to be overcome to enable a treat-to-target approach.

This work provides the basis for an evidence-based definition of outcome targets for relevant stakeholders and regulatory authorities.

Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.

Multiple sclerosis (MS) is a chronic central nervous system (CNS) disease, which is diagnosed by a combination of clinical symptoms and magnetic resonance imaging and measurement of an increased intrathecal antibody synthesis. Genetic as well as environmental factors influence onset of the disease, where especially Epstein-Barr virus (EBV) infection is directly involved in MS development. In this open retrospective study, we aimed to elaborate whether various serum and cerebrospinal fluid (CSF)-based EBV antibody indices may aid in the diagnosis of MS.

Epstein-Barr nuclear antigen (EBNA)1 IgG concentrations in serum and CSF of relapsing-remitting (RR)MS patients (n=61) (M:F 28:33, average 40 years), optic neuritis patients (n=26) (M:F 9:17, average 47 years) and healthy controls (HCs) (n=15) (M:F 8:7, average 43 years) were determined by enzyme-linked immunosorbent assay. The obtained EBNA1 IgG levels were compared to factors such as total IgG, albumin concentrations, specific antibody index, and various serum- and CSF-based indices.

Significantly elevated EBNA1 IgG levels were detected in serum and CSF of RRMS patients compared to HCs. CSF EBNA1 IgG and indices based on specific CSF EBNA1 IgG associated with CSF albumin or serum EBNA1 IgG associated with total serum IgG obtained the highest sensitivities and complemented the IgG index and oligoclonal bands.

These findings indicate that aforementioned indices may supplement existing indices and aid in the diagnosis of MS.

Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT1A) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.

There is scant data regarding the use of oral disease-modifying treatments (oDMT) in patients with relapsing-remitting multiple sclerosis (PwRRMS) from Saudi Arabia.

This study aimed to identify the response rate to oDMT in PwRRMS compared to interferon (IFN) in terms of achieving no evidence of disease activity-3 (NEDA-3).

This retrospective study was conducted at a tertiary care hospital in Saudi Arabia and included all adult PwRRMS over a 2-year period who were on oDMTs or IFN for <1 year. The achievement of overall NEDA-3 and its components (namely, relapse, disability progression, and focal MRI activity) were assessed for each treatment.

A total of 231 patients were included for the analysis of NEDA-3 status, of which 78 (33.8%) were on oDMTs (namely, dimethyl fumarate, teriflunomide, and fingolimod). NEDA-3 status was achieved in 51.3% (OR: 1.86, 95% CI: 1.28-2.71) of patients on oDMTs and in 32% of patients on IFN (OR: 0.72, 95% CI: 0.58-0.89) (P < 0.001). Compared to the IFN group, the oDMT group had significantly lower rates of clinical relapse (P < 0.001), disability progression (P = 0.004), and new focal MRI activity (P = 0.01). Patients on dimethyl-fumarate had higher odds of achieving NEDA-3 (OR: 2.18, 95% CI = 1.09-4.34; P =0.02) compared with those on fingolimod (OR 2.15, 95% CI = 0.70-6.58; P =0.16) and teriflunomide (OR: 1.53, 95% CI = 0.81-2.91; P =0.18).

More than half of the patients with relapsing-remitting multiple sclerosis on oral DMTs achieved NEDA-3 status in this study. Significant differences were observed in NEDA-3 status parameters and achievement between patients on oral DMTs and interferon, with the likeliness being highest among patients treated with dimethyl-fumarate.

Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome.

Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses.

A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%.

In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred.

This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

In recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials.

To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS.

We searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP.

Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS.

Two review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE.

We included 23 studies involving a total of 10,167 participants. The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains. The common comparator for network analysis was placebo. Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo.

The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.

Research shows that persons with mild to moderate multiple sclerosis are less physically active than healthy controls even though they would benefit from it. This study focusses on the feasibility testing and process evaluation of the pilot study of Activity Matters, a twelve-week web-based program, from Ireland, to increase physical activity in this population.

The intervention was adapted to local circumstances in Hamburg, Germany and consists of eleven modules incorporating behavior change techniques. After feasibility had been confirmed, 43 persons with multiple sclerosis participated in a pilot study with a pre-post, single-group intervention design. Qualitative data was collected with questionnaires and semi structured interviews. Physical activity level and stage of change was measured quantitatively.

Participants had a mean age of 49.5 years (SD 9.29) and an average Patient Determined Disease Step Score of 2.2 (SD 1.47). Thirty-six participants answered the follow-up questionnaire. On average 9.8 modules were processed within 13 weeks. Each tool for behavior change was perceived as helpful except the chat group. Physical activity levels increased significantly from pre- to post intervention (p-value 0.042, Cohen's d = 0.35).

The results indicate that Activity Matters is feasible and satisfactory and may change activity levels.

Multiple sclerosis (MS) is a severe neurological disorder that involves inflammation in the brain, spinal cord and optic nerve with key disabling neuropathological outcomes being axonal damage and demyelination. When degeneration of the axo-glial union occurs, a consequence of inflammatory damage to central nervous system (CNS) myelin, dystrophy and death can lead to large membranous structures from dead oligodendrocytes and degenerative myelin deposited in the extracellular milieu. For the first time, this review covers mitochondrial mechanisms that may be operative during MS-related neurodegenerative changes directly activated during accumulating extracellular deposits of myelin associated inhibitory factors (MAIFs), that include the potent inhibitor of neurite outgrowth, Nogo-A. Axonal damage may occur when Nogo-A binds to and signals through its cognate receptor, NgR1, a multimeric complex, to initially stall axonal transport and limit the delivery of important growth-dependent cargo and subcellular organelles such as mitochondria for metabolic efficiency at sites of axo-glial disintegration as a consequence of inflammation. Metabolic efficiency in axons fails during active demyelination and progressive neurodegeneration, preceded by stalled transport of functional mitochondria to fuel axo-glial integrity.

Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.

The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.

During neuroinflammation, monocytes that infiltrate the central nervous system (CNS) may contribute to regenerative processes depending on their activation status. However, the extent and mechanisms of monocyte-induced CNS repair in patients with neuroinflammatory diseases remain largely unknown, partly due to the lack of a fully human assay platform that can recapitulate monocyte-neural stem cell interactions within the CNS microenvironment. We therefore developed a human model system to assess the impact of monocytic factors on neural stem cells, establishing a high-content compatible assay for screening monocyte-induced neural stem cell proliferation and differentiation. The model combined monocytes isolated from healthy donors and human embryonic stem cell derived neural stem cells and integrated both cell-intrinsic and -extrinsic properties. We identified CNS-mimicking culture media options that induced a monocytic phenotype resembling CNS infiltrating monocytes, while allowing adequate monocyte survival. Monocyte-induced proliferation, gliogenic fate and neurogenic fate of neural stem cells were affected by the conditions of monocytic priming and basal neural stem cell culture as extrinsic factors as well as the neural stem cell passage number as an intrinsic neural stem cell property. We developed a high-content compatible human in vitro assay for the integrated analysis of monocyte-derived factors on CNS repair.

Multiple sclerosis (MS) is a chronic inflammatory condition that causes demyelination of the central nervous system accompanied by a wide range of symptoms. The high prevalence of falls among patients diagnosed with MS within the initial six months highlights the importance of this issue. The objective of this study is to identify factors associated with falls in MS patients in order to increase awareness and reduce the risk of falls. This scoping review used specific Mesh terms to formulate the literature search around falls and MS using Medline, Google Scholar, Scopus, and Embase search engines. English papers published between 2012 and 2022, studies with a clear definition of falls, McDonald's diagnostic criteria for MS, and those with Expanded Disability Status Scale (EDSS) or Patient Determined Disease Steps (PDDS) scores were included. Critical data from the selected articles were extracted and classified according to the different factors associated with falls in MS patients. Eighteen articles were included in this review. The most important factors associated with falls in MS patients identified were the severity and progression of the disease, mobility and balance problems, bladder dysfunction, fear of falling, fatigue, and cognitive dysfunction. In conclusion, this scoping review yielded the most common factors associated with falls in patients with MS. Study findings can be used to develop future interventions focusing on improving mobility, proprioception, and balance to decrease fall risk and injury amongst MS patients.

The Comprehensive assessment of Acceptance and Commitment Therapy (CompACT) is a 23-item questionnaire measuring psychological flexibility, a quality of life protective factor. An 18-item version was recently produced. We assessed validity and reliability of CompACT, and equivalence of paper and electronic (eCompACT) versions in people with multiple sclerosis (PwMS) in Italy, Germany and Spain.

We used confirmatory factor analysis and assessed CompACT-23 and CompACT-18 measurement invariance between the three language versions. We assessed construct validity (Spearman's correlations) and internal consistency (Cronbach's alpha). Test-retest reliability (intraclass correlation coefficient, ICC) and equivalence of paper and eCompACT (ICC and linear regression model for repeated measures) were assessed in subsamples of PwMS.

A total of 725 PwMS completed the study. The three-factor structure of the CompACT-23 showed poor fit (RMSEA 0.07; CFI 0.82; SRMR 0.08), while the fit of the CompACT-18 was good (RMSEA 0.05; CFI 0.93; SRMR 0.05). Configural and partial metric invariance were confirmed, as well as partial scalar invariance (reached when five items were allowed to vary freely). The CompACT-18 showed good internal consistency (all alpha ≥ 0.78); and test-retest reliability (all ICCs ≥ 0.86). Equivalence between paper and eCompACT was excellent (all ICCs ≥ 0.86), with no mode, order, or interaction effects.

Results support using the refined CompACT-18 as a three-factor measure of psychological flexibility in PwMS. Paper and eCompACT-18 versions are equivalent. CompACT-18 can be used cross-culturally, but sub-optimal scalar invariance suggests that direct comparison between the three language versions should be interpreted with caution.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

Eye movements can reflect brain alterations and inform on the presence of motor disabilities and cognitive impairments in people with multiple sclerosis (pwMS).

The aim of the study was to determine the correlation between motor and cognitive measurements and eye movement parameters when performing the n-back task (NBKT).

This was a cross-sectional study carried out at Ramos Mejía Hospital, a center specialized in demyelinating diseases in Buenos Aires, Argentina. The study population consisted of 66 patients with relapsing-remitting multiple sclerosis (RRMS) and 5 patients with secondary progressive multiple sclerosis (SPMS). pwMS performed the n-back test while using a device head mounted display (HMD) with eyetracking capabilities in order to capture eye movement. Clinical motor and cognitive measures were assessed with Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (NHPT), Timed 25-Foot Walk (T25FW), and Symbol Digit Modalities Test (SDMT).

pwMS showed strong and statistically significant correlations between gaze duration; number of fixations, saccade amplitude and motor disabilities and cognitive impairments as measured by EDSS, NHPT, T25FW, and SDMT.

This study found significant correlations between eye movement behavior and motor and cognitive disability in pwMS. These findings suggest that eye movements have the potential to be used as a surrogate biomarker in MS progression.

Body fluid markers could be helpful to predict the conversion into clinically definite multiple sclerosis (MS) in people with a first demyelinating event of the central nervous system (CNS). Consequently, biomarkers such as oligoclonal bands, which are integrated in the current MS diagnostic criteria, could assist early MS diagnosis.

This review examines existing knowledge on a broad spectrum of body fluid markers in people with a first CNS demyelinating event, explores their potential to predict conversion to MS, to assess MS disease activity, as well as their utility to differentiate MS from atypical demyelinating disorders such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein associated disease.

This field of research has shown a dramatic increase of evidence, especially in the last decade. Some biomarkers are already established in clinical routine (e.g. oligoclonal bands) while others are currently implemented (e.g. kappa free light chains) or considered as breakthroughs (e.g. neurofilament light). Determination of biomarkers poses challenges for continuous monitoring, especially if exclusively detectable in cerebrospinal fluid. A handful of biomarkers are measurable in blood which holds a significant potential.

Theory of Mind (ToM) is understanding others' minds. Empathy is an insight into emotions and feelings of others. Persons with multiple sclerosis (pwMS) may experience impairment in ToM and empathy. To investigate ToM, empathy, and their relationship with neuroimaging, neuropsychological, and neuropsychiatric data. 41 pwMS and 41 HC were assessed using RMET for ToM, EQ, BICAMS, HADS. Cortical and subcortical gray matter volumes were calculated with Freesurfer from 3T MRI scans. pwMS showed lower EQ scores (44.82 ± 11.9 vs 51.29 ± 9.18, p = 0.02) and worse RMET performance (22.37 ± 4.09 vs 24,47 ± 2.93, p = 0.011). Anxiety and depression were higher in pwMS. EQ correlated with subcortical (amygdala) and cortical (anterior cingulate) volumes. RMET correlated with cortical volumes (posterior cingulate, lingual). In regression analysis, amygdala volume was the single predictor of empathy performance (p = 0.041). There were no significant correlations between social cognitive tests and general cognition. A weak negative correlation was found between EQ and the level of anxiety (r = -0.342, p = 0.038) The present study indicates that pwMS have impairment on ToM and empathy. The performance of ToM and empathy in MS is linked to the volumes of critical brain areas involved in social cognition.

Multiple sclerosis, and its murine model experimental autoimmune encephalomyelitis (EAE), is a neurodegenerative autoimmune disease of the CNS characterized by T cell influx and demyelination. Similar to other autoimmune diseases, therapies can alleviate symptoms but often come with side effects, necessitating the exploration of new treatments. We recently demonstrated that the Cullin-RING E3 ubiquitin ligase 4b (CRL4b) aided in maintaining genome stability in proliferating T cells. In this study, we examined whether CRL4b was required for T cells to expand and drive EAE. Mice lacking Cul4b (Cullin 4b) in T cells had reduced EAE symptoms and decreased inflammation during the peak of the disease. Significantly fewer CD4+ and CD8+ T cells were found in the CNS, particularly among the CD4+ T cell population producing IL-17A, IFN-γ, GM-CSF, and TNF-α. Additionally, Cul4b-deficient CD4+ T cells cultured in vitro with their wild-type counterparts were less likely to expand and differentiate into IL-17A- or IFN-γ-producing effector cells. When wild-type CD4+ T cells were activated in vitro in the presence of the recently developed CRL4 inhibitor KH-4-43, they exhibited increased apoptosis and DNA damage. Treatment of mice with KH-4-43 following EAE induction resulted in stabilized clinical scores and significantly reduced numbers of T cells and innate immune cells in the CNS compared with control mice. Furthermore, KH-4-43 treatment resulted in elevated expression of p21 and cyclin E2 in T cells. These studies support that therapeutic inhibition of CRL4 and/or CRL4-related pathways could be used to treat autoimmune disease.

Disease-modifying therapies (DMTs) have led to improved health and work productivity among people with multiple sclerosis (PwMS).

To describe trajectories of recent DMT use and their association with sickness absence and/or disability pension (SADP) among PwMS in Sweden.

A longitudinal register-based study was conducted among 1395 PwMS with treatment start in 2014/2015. While DMT use over 5 years was assessed using sequence analysis resulting in four clusters, a 7-year (Y-2 toY4) trend of SADP was analyzed using zero-inflated negative binomial regression.

Four clusters of DMT use trajectories were identified: long-term non-high-efficacy (483, 34.6%), long-term high-efficacy (572, 41%), escalation (221, 15.8%), and discontinuation (119, 8.5%). Progressive MS and higher expanded disability status scale scores were associated with the escalation, long-term high-efficacy, or discontinuation clusters. PwMS in the long-term high-efficacy and escalation clusters had higher likelihood of being on SADP. However, PwMS initiating high-efficacy DMTs demonstrated steeper decline in SADP than others.

Using sequence analysis, this study showed recent DMT use trajectories among PwMS where initiation of high-efficacy DMTs has become more common. The trend of SADP was stable and lower in those using non-high-efficacy DMTs and larger improvements were shown in those initiating high-efficacy DMTs.

We evaluate the potential clinical and cost impacts of discontinuing disease-modifying therapy (DMT) in people with multiple sclerosis (PwMS) when age-related immunosenescence can reduce DMT efficacy while increasing associated risks.

A Markov model simulated clinical and cost impacts to the patient and payers when a proportion of eligible patients with relapsing remitting multiple sclerosis (RRMS) discontinue DMT. Eligibility was defined as age >55 years, an RRMS diagnosis of >5 years, and no history of relapses for 5 years. Increasing the proportion of eligible patients willing to discontinue therapy was also modeled. Clinical and cost inputs were from published literature.

Difference in EDSS progression between eligible patients who did and did not attempt discontinuation was not significant. After 1 year of eligibility, per-patient costs were $96k lower in the cohort that attempted discontinuation; however a higher proportion of relapses were seen in this group. When the proportion of patients willing to discontinue DMT increased, clinical findings remained consistent while the average cost per patient decreased.

While there are increased clinical and cost benefits as more eligible patients attempt discontinuation, the risk of relapses can increase. Timely disease monitoring is required to manage safe DMT discontinuation.

Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329A ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management.

We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes.

We were unable to detect any association between rs10191329A and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329A . However, we were able to replicate the association of two suggestive SNVs (rs7289446G and rs868824C ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset.

Identification of rs10191329A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.