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The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side effects, highlighting the importance of adjusted treatment considerations. MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immunopathological and MRI aspects of ageing in the CNS in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed. [ABSTRACT FROM AUTHOR]

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering‐associated‐worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus‐based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts. ANN NEUROL 2024;96:826–845 [ABSTRACT FROM AUTHOR]

A large number of disease-modifying immunotherapies are available for the treatment of people with multiple sclerosis. Many disease-modifying immunotherapies show scarce or no safety data in pregnancy and breastfeeding and are labeled as being contraindicated during these periods in the Swiss summary of product characteristics. Some disease-modifying immunotherapies also have restrictions for male patients. Hence, family planning should always be considered in treatment decisions. If clinically necessary, the continuation of immunotherapy during pregnancy can be considered for some substances. In these situations, the "Good Off-Label Use Practice", careful consideration of the benefit–risk profile, and interprofessional cooperation between the treating neurologist, obstetrician–gynecologist, and pharmacist/pharmacologist, ideally with the involvement of experienced centers, is necessary. Here, we present an update on disease-modifying immunotherapies in multiple sclerosis with a focus on family planning, pregnancy, and breastfeeding and provide consensus recommendations of the Medico-Scientific Advisory Board of the Swiss Multiple Sclerosis Society, the Swiss Neurological Society, and the Swiss Society for Gynecology and Obstetrics (represented by the Academy of Fetomaternal Medicine). These unified national recommendations are necessary, as guidelines from other countries differ and because of separate approval/reimbursement situations in Switzerland. [ABSTRACT FROM AUTHOR]

The presence of central nervous system lesions fulfilling the criteria of dissemination in space and time on MRI leads to the diagnosis of a radiologically isolated syndrome (RIS), which may be an early sign of multiple sclerosis (MS). However, some patients who do not fulfill the necessary criteria for RIS still evolve to MS, and some T2 hyperintensities that resemble demyelinating lesions may originate from mimics. In light of the recent recognition of the efficacy of disease-modifying therapy (DMT) in RIS, it is relevant to consider additional imaging features that are more specific of MS. We performed a narrative review on cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL) in patients with RIS. In previous RIS studies, the reported prevalence of CLs ranges between 20.0 and 40.0%, CVS + white matter lesions (WMLs) between 87.0 and 93.0% and PRLs between 26.7 and 63.0%. Overall, these imaging findings appear to be frequent in RIS cohorts, although not consistently taken into account in previous studies. The search for CLs, CVS + WML and PRLs in RIS patients could lead to earlier identification of patients who will evolve to MS and benefit from DMTs. [ABSTRACT FROM AUTHOR]

Background and purpose: In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator‐independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA‐derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS. Methods: A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age‐ and sex‐matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two‐dimensional axial rAMIRA imaging at the inter‐vertebral disc levels C2/3–C5/C6 and the lumbar enlargement level Tmax. ALS Functional Rating Scale–revised (ALSFRS‐R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed. Results: Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax. Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax. SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS‐R (p < 0.001) and SNIP (p = 0.0016). Conclusion: Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted. [ABSTRACT FROM AUTHOR]

Background: Increasingly, patients, clinicians, and regulators call for more evidence on the impact of innovative medicines on quality of life (QoL). We assessed the effects of disease-modifying therapies (DMTs) on QoL in people with multiple sclerosis (PwMS). Methods: Randomized trials assessing approved DMTs in PwMS with results for at least one outcome referred to as "quality of life" were searched in PubMed and ClinicalTrials.gov. Results: We identified 38 trials published between 1999 and 2023 with a median of 531 participants (interquartile range (IQR) 202 to 941; total 23,225). The evaluated DMTs were mostly interferon-beta (n = 10; 26%), fingolimod (n = 7; 18%), natalizumab (n = 5; 13%), and glatiramer acetate (n = 4; 11%). The 38 trials used 18 different QoL instruments, with up to 11 QoL subscale measures per trial (median 2; IQR 1–3). QoL was never the single primary outcome. We identified quantitative QoL results in 24 trials (63%), and narrative statements in 15 trials (39%). In 16 trials (42%), at least one of the multiple QoL results was statistically significant. The effect sizes of the significant quantitative QoL results were large (median Cohen's d 1.02; IQR 0.3–1.7; median Hedges' g 1.01; IQR 0.3–1.69) and ranged between d 0.14 and 2.91. Conclusions: Certain DMTs have the potential to positively impact QoL of PwMS, and the assessment and reporting of QoL is suboptimal with a multitude of diverse instruments being used. There is an urgent need that design and reporting of clinical trials reflect the critical importance of QoL for PwMS. [ABSTRACT FROM AUTHOR]

Background: Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. Objective: The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). Methods: Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. Results: We identified 48 pragmatic trials published 1967–2022 that included a median of 82 participants (interquartile range (IQR) = 42–160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). Conclusion: Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence. [ABSTRACT FROM AUTHOR]

Intrathecal IgM production in multiple sclerosis is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in multiple sclerosis, CSF from two independent cohorts, including multiple sclerosis patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS-related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of multiple sclerosis donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterization and antigen identification. We produced five cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR + plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an experimental autoimmune encephalomyelitis (EAE) model. CSF IgM might contribute to CNS inflammation in multiple sclerosis by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies showed that the myelin of the brain changes in the life span, and demyelination contributes to the loss of brain plasticity during normal aging. Diffusion-weighted magnetic resonance imaging (dMRI) allows studying brain connectivity in vivo by mapping axons in white matter with tractography algorithms. However, dMRI does not provide insight into myelin; thus, combining tractography with myelin-sensitive maps is necessary to investigate myelin-weighted brain connectivity. Tractometry is designated for this purpose, but it suffers from some serious limitations. Our study assessed the effectiveness of the recently proposed Myelin Streamlines Decomposition (MySD) method in estimating myelinweighted connectomes and its capacity to detect changes in myelin network architecture during the process of normal aging. This approach opens up new possibilities compared to traditional Tractometry. Methods: In a group of 85 healthy controls aged between 18 and 68  years, we estimated myelin-weighted connectomes using Tractometry and MySD, and compared their modulation with age by means of three well-known global network metrics. Results: Following the literature, our results show that myelin development continues until brain maturation (40  years old), after which degeneration begins. In particular, mean connectivity strength and efficiency show an increasing trend up to 40  years, after which the process reverses. Both Tractometry and MySD are sensitive to these changes, but MySD turned out to be more accurate. Conclusion: After regressing the known predictors, MySD results in lower residual error, indicating that MySD provides more accurate estimates of myelin-weighted connectivity than Tractometry. [ABSTRACT FROM AUTHOR]

Background and purpose: In relapsing–remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real‐world setting, where both drugs are licensed as first‐line therapies for RRMS. Methods: We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12‐month confirmed EDSS worsening were compared using Cox proportional hazard models. Results: In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). Conclusion: Analysis of real‐world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT) is a biomarker of neuroaxonal loss in multiple sclerosis (MS). Objective: The objective was to assess the relative role of OCT, next to magnetic resonance imaging (MRI) and serum markers of disability in MS. Methods: A total of 100 patients and 52 controls underwent OCT to determine peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layers (GCIPL). Serum neurofilament light chain (sNfL), total lesion volume (TLV), and brain parenchymal fraction (BPF) were also assessed. The associations of OCT with disability were examined in linear regression models with correction for age, vision, and education. Results: In patients, pRNFL was associated with the Symbol Digit Modalities Test (SDMT; p = 0.030). In the multivariate analysis including sNfL and MRI measures, pRNFL (β = 0.19, p = 0.044) and TLV (β = −0.24, p = 0.023) were the only markers associated with the SDMT. pRNFL (p < 0.001) and GCIPL (p < 0.001) showed associations with the Expanded Disability Status Scale (EDSS). In the multivariate analysis, GCIPL showed the strongest association with the EDSS (β = −0.32, p < 0.001) followed by sNfL (β = 0.18, p = 0.024). Conclusion: The associations of OCT measures with cognitive and physical disability were independent of serum and brain MRI markers of neuroaxonal loss. OCT can be an important tool for stratification in MS, while longitudinal studies using combinations of biomarkers are warranted. [ABSTRACT FROM AUTHOR]

Quantitative MRI (qMRI) probes the microstructural properties of the central nervous system (CNS) by providing biophysical measures of tissue characteristics. In this work, we aimed to (i) identify qMRI measures that distinguish histological lesion types in postmortem multiple sclerosis (MS) brains, especially the remyelinated ones; and to (ii) investigate the relationship between those measures and quantitative histological markers of myelin, axons, and astrocytes in the same experimental setting. Three fixed MS whole brains were imaged with qMRI at 3T to obtain magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative T1 (qT1), quantitative susceptibility mapping (QSM), fractional anisotropy (FA) and radial diffusivity (RD) maps. The identification of lesion types (active, inactive, chronic active, or remyelinated) and quantification of tissue components were performed using histological staining methods as well as immunohistochemistry and immunofluorescence. Pairwise logistic and LASSO regression models were used to identify the best qMRI discriminators of lesion types. The association between qMRI and quantitative histological measures was performed using Spearman's correlations and linear mixed‐effect models. We identified a total of 65 lesions. MTR and MWF best predicted the chance of a lesion to be remyelinated, whereas RD and QSM were useful in the discrimination of active lesions. The measurement of microstructural properties through qMRI did not show any difference between chronic active and inactive lesions. MWF and RD were associated with myelin content in both lesions and normal‐appearing white matter (NAWM), FA was the measure most associated with axon content in both locations, while MWF was associated with astrocyte immunoreactivity only in lesions. Moreover, we provided evidence of extensive astrogliosis in remyelinated lesions. Our study provides new information on the discriminative power of qMRI in differentiating MS lesions ‐especially remyelinated ones‐ as well as on the relative association between multiple qMRI measures and myelin, axon and astrocytes. [ABSTRACT FROM AUTHOR]

Axon radius is a potential biomarker for brain diseases and a crucial tissue microstructure parameter that determines the speed of action potentials. Diffusion MRI (dMRI) allows non-invasive estimation of axon radius, but accurately estimating the radius of axons in the human brain is challenging. Most axons in the brain have a radius below one micrometer, which falls below the sensitivity limit of dMRI signals even when using the most advanced human MRI scanners. Therefore, new MRI methods that are sensitive to small axon radii are needed. In this proof-of-concept investigation, we examine whether a surface-based axonal relaxation process could mediate a relationship between intra-axonal T2 and T1 times and inner axon radius, as measured using postmortem histology. A unique in vivo human diffusion-T1-T2 relaxation dataset was acquired on a 3T MRI scanner with ultra-strong diffusion gradients, using a strong diffusion-weighting (i.e., b = 6,000 s/mm²) and multiple inversion and echo times. A second reduced diffusion-T2 dataset was collected at various echo times to evaluate the model further. The intra-axonal relaxation times were estimated by fitting a diffusionrelaxation model to the orientation-averaged spherical mean signals. Our analysis revealed that the proposed surface-based relaxation model effectively explains the relationship between the estimated relaxation times and the histological axon radius measured in various corpus callosum regions. Using these histological values, we developed a novel calibration approach to predict axon radius in other areas of the corpus callosum. Notably, the predicted radii and those determined from histological measurements were in close agreement. [ABSTRACT FROM AUTHOR]