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Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome. [ABSTRACT FROM AUTHOR]

Background and purpose: The validity, reliability, and longitudinal performance of the Patient‐Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. Methods: We included relapsing–remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test–retest reliability was examined. Longitudinal data were analysed with mixed‐effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). Results: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient‐reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test–retest reliability was good to excellent (concordance correlation coefficient = 0.73–0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. Conclusion: The PDDS has greater correlation with other PROs but less correlation with other MS‐related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS. [ABSTRACT FROM AUTHOR]

Background and purpose: Understanding predictors of changes in employment status among people living with multiple sclerosis (MS) can assist health care providers to develop appropriate work retention/rehabilitation programs. We aimed to model longitudinal transitions of employment status in MS and estimate the probabilities of retaining employment status or losing or gaining employment over time in individuals with a first clinical diagnosis of central nervous system demyelination (FCD). Methods: This prospective cohort study comprised adults (aged 18–59 years) diagnosed with FCD (n = 237) who were followed for more than 11 years. At each review, participants were assigned to one of three states: unemployed, part‐time, or full‐time employed. A Markov multistate model was used to examine the rate of state‐to‐state transitions. Results: At the time of FCD, participants with full‐time employment had an 89% chance of being in the same state over a 1‐year period, but this decreased to 42% over the 10‐year follow‐up period. For unemployed participants, there was a 92% likelihood of remaining unemployed after 1 year, but this probability decreased to 53% over 10 years. Females, those who progressed to clinically definite MS, those with a higher relapse count, and those with a greater level of disability were at increased risk of transitioning to a deteriorated employment state. In addition, those who experienced clinically significant fatigue over the follow‐up period were less likely to gain employment after being unemployed. Conclusions: In our FCD cohort, we found a considerable rate of employment transition during the early years post‐diagnosis. Over more than a decade of follow‐up post‐FCD, we found that females and individuals with a greater disability and a higher relapse count are at higher risk of losing employment. [ABSTRACT FROM AUTHOR]

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case–control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications. [ABSTRACT FROM AUTHOR]

Background: Microglia, an immune cell found exclusively within the CNS, initially develop from haematopoietic stem cell precursors in the yolk sac and colonise all regions of the CNS early in development. Microglia have been demonstrated to play an important role in the development of oligodendrocytes, the myelin producing cells in the CNS, as well as in myelination. Mertk is a receptor expressed on microglia that mediates immunoregulatory functions, including myelin efferocytosis. Findings: Here we demonstrate an unexpected role for Mertk-expressing microglia in both oligodendrogenesis and myelination. The selective depletion of Mertk from microglia resulted in reduced oligodendrocyte production in early development and the generation of pathological myelin. During demyelination, mice deficient in microglial Mertk had thinner myelin and showed signs of impaired OPC differentiation. We established that Mertk signalling inhibition impairs oligodendrocyte repopulation in Xenopus tadpoles following demyelination. Conclusion: These data highlight the importance of microglia in myelination and are the first to identify Mertk as a regulator of oligodendrogenesis and myelin ultrastructure. [ABSTRACT FROM AUTHOR]

Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone's tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone's effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses. [ABSTRACT FROM AUTHOR]

Background and purpose: Epstein–Barr virus (EBV) is implicated in multiple sclerosis (MS) risk; evidence for other herpesviruses is inconsistent. Here, we test blood markers of infection with human herpesvirus 6 (HHV‐6), varicella zoster virus (VZV), and cytomegalovirus (CMV) as risk factors for a first clinical diagnosis of central nervous system demyelination (FCD) in the context of markers of EBV infection. Methods: In the Ausimmune case–control study, cases had an FCD, and population controls were matched on age, sex, and study region. We quantified HHV‐6‐ and VZV‐DNA load in whole blood and HHV‐6, VZV, and CMV antibodies in serum. Conditional logistic regression tested associations with FCD risk, adjusting for Epstein–Barr nuclear antigen (EBNA) IgG, EBV‐DNA load, and other covariates. Results: In 204 FCD cases and 215 matched controls, only HHV‐6‐DNA load (positive vs. negative) was associated with FCD risk (adjusted odds ratio = 2.20, 95% confidence interval = 1.08–4.46, p = 0.03). Only EBNA IgG and HHV‐6‐DNA positivity were retained in a predictive model of FCD risk; the combination had a stronger association than either alone. CMV‐specific IgG concentration modified the association between an MS risk‐related human leucocyte antigen gene and FCD risk. Six cases and one control had very high HHV‐6‐DNA load (>1.0 × 106 copies/mL). Conclusions: HHV‐6‐DNA positivity and high load (possibly due to inherited HHV‐6 chromosomal integration) were associated with increased FCD risk, particularly in association with markers of EBV infection. With growing interest in prevention/management of MS through EBV‐related pathways, there should be additional consideration of the role of HHV‐6 infection. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS. [ABSTRACT FROM AUTHOR]

Background: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. Objective: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. Methods: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. Results: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = −1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (β = 0.38, 95% CI = 0.04, 0.72, p = 0.03). Conclusion: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS. [ABSTRACT FROM AUTHOR]

Introduction: Multiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors. DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFNb), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNb reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNb treatment on methylation. Methods: The objective of this study was to determine the changes in DNAm associated with INFβ use, using methylation arrays and statistical deconvolutions on two separate datasets (total ntreated = 64, nuntreated = 285). Results: We show that IFNb treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFNb treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNb treatment recruits the endogenous anti-viral molecular machinery. Finally, statisticaldeconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNβ induced methylation changes. Discussion: In conclusion, our study shows that IFNβ treatment is a potent and targeted epigenetic modifier in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale =0.8289, P = 3.52 × 10-08), the other in males (rs698805; βmale = -1.5395, P = 4.35 × 10-08), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in central nervous system compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and g-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change. [ABSTRACT FROM AUTHOR]

Microglia regulate multiple processes in the central nervous system, exhibiting a considerable level of cellular plasticity which is facilitated by an equally dynamic transcriptional environment. While many gene networks that regulate microglial functions have been characterised, the influence of epigenetic regulators such as small non-coding microRNAs (miRNAs) is less well defined. We have sequenced the miRNAome and mRNAome of mouse microglia during brain development and adult homeostasis, identifying unique profiles of known and novel miRNAs. Microglia express both a consistently enriched miRNA signature as well as temporally distinctive subsets of miRNAs. We generated robust miRNA-mRNA networks related to fundamental developmental processes, in addition to networks associated with immune function and dysregulated disease states. There was no apparent influence of sex on miRNA expression. This study reveals a unique developmental trajectory of miRNA expression in microglia during critical stages of CNS development, establishing miRNAs as important modulators of microglial phenotype. Microglial miRNA signatures are characterised in the developing mouse brain, with specific miRNA-mRNA networks being associated with CNS development, immune function and dysregulated disease states. [ABSTRACT FROM AUTHOR]

Background: Consumption of ultra-processed foods (UPFs) has been linked to risk of chronic diseases, with scant evidence in relation to multiple sclerosis (MS). Methods: We tested associations between UPF consumption and likelihood of a first clinical diagnosis of central nervous system demyelination (FCD) (267 cases, 508 controls), a common precursor to MS. We used data from the 2003–2006 Ausimmune Study and logistic regression with full propensity score matching for age, sex, region of residence, education, smoking history, body mass index, physical activity, history of infectious mononucleosis, dietary misreporting, and total energy intake. Results: Higher UPF consumption was statistically significantly associated with an increased likelihood of FCD (adjusted odds ratio = 1.08; 95% confidence interval = 1.0,1.15; p = 0.039), representing an 8% increase in likelihood of FCD per one energy-adjusted serving/day of UPFs. Conclusion: Higher intakes of UPF were associated with increased likelihood of FCD in this Australian cohort. Nutrition education and awareness of healthy eating patterns may benefit those at high risk of FCD. [ABSTRACT FROM AUTHOR]

Background: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. Results: We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5–44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. Conclusion: Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: Gait in people with multiple sclerosis (PwMS) is affected even when no changes can be observed on clinical examination. A sensitive measure of gait deterioration is stability; however, its correlation with motor tract damage has not yet been established. Objective: To compare stability between PwMS and healthy controls (HCs) and determine associations between stability and diffusion magnetic resonance image (MRI) measures of axonal damage in selected sensorimotor tracts. Methods: Twenty-five PwMS (Expanded Disability Status Scale (EDSS) < 2.5) and 15 HCs walked on a treadmill. Stability from sacrum (LDESAC), shoulder (LDESHO) and cervical (LDECER) was calculated using the local divergence exponent (LDE). Participants underwent a 7T-MRI brain scan to obtain fibre-specific measures of axonal loss within the corticospinal tract (CST), interhemispheric sensorimotor tract (IHST) and cerebellothalamic tract (CTT). Correlation analyses between LDE and fibre density (FD) within tracts, fibre cross-section (FC) and FD modulated by FC (FDC) were conducted. Between-groups LDE differences were analysed using analysis of variance (ANOVA). Results: Correlations between all stability measures with CSTFD, between CSTFDC with LDESAC and LDECER, and LDECER with IHSTFD and IHSTFDC were significant yet moderate (R < −0.4). Stability was significantly different between groups. Conclusions: Poorer gait stability is associated with corticospinal tract (CST) axonal loss in PwMS with no-to-low disability and is a sensitive indicator of neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: People with multiple sclerosis face significant employment-related challenges, with little known of the drivers of these outcomes. Objective: We examined prospective trajectories of employment-related outcomes up to 11 years following a first episode of central nervous system (CNS) demyelination (FCD). Methods: Participants were aged 18–59 years, at FCD, with at least two observations and were employed at study entry or anytime during follow-up (n = 207). Outcomes were employment status (full-time, part-time and unemployed), average workhours per week and disability support pension (DSP; receiving/not receiving). We used group-based trajectory modelling to identify groups with common trajectories. Factors associated with trajectory membership were explored using log-multinomial regression. Results: Distinct trajectories were identified for employment (4), workhours (4) and DSP (2). Compared with stable full-time, female sex was strongly associated with being in the stable part-time trajectory (risk ratio (RR): 5.35; 95% confidence interval (CI) = 2.56–11.20; p < 0.001). A greater level of disability at 5-year review (RR: 1.35; 95% CI = 1.19–1.53) and having more than two comorbidities at baseline (RR: 2.77; 95% CI = 1.37–5.64) were associated with being in early and late deteriorated employment trajectories, respectively. Compared with the increased part-time trajectory, every additional relapse during the 5 years post-FCD was associated with a 10% increased risk of being in the reduced part-time trajectory (RR = 1.10; 95%CI = 1.00–1.22). For every additional EDSS point at 5-year review, the risk of being in the DSP trajectory increased (RR = 1.21; 95% CI = 1.05–1.41). Conclusion: These trajectories indicate substantial heterogeneity and the complex impact of MS on employment from its earliest timepoints. Understanding these trends could enable better targeting of interventions to facilitate workforce retention, particularly for females, those with a higher number of comorbidities, more frequent relapses and greater rate of disability accrual. [ABSTRACT FROM AUTHOR]

Background: Predicting long-term visual outcomes and axonal loss following acute optic neuritis (ON) is critical for choosing treatment. Predictive models including all clinical and paraclinical measures of optic nerve dysfunction following ON are lacking. Objectives: Using a prospective study method, to identify 1 and 3 months predictors of 6 and 12 months visual outcome (low contrast letter acuity 2.5%) and axonal loss [retinal nerve fiber layer thickness and multifocal evoked potential (mfVEP) amplitude] following acute ON. Methods: In total, 37 patients of acuteON onset were evaluated within 14 days using between-eye asymmetry of visual acuity, color vision (Ishihara plates), optical coherence tomography, mfVEP, and optic nerve magnetic resonance imaging [magnetic transfer ratio (MTR) and diffusion tensor imaging (DTI)]. Results: Visual outcome at 6 and 12 months was best predicted by Ishihara asymmetry at 1 and 3 months following ON onset. Axonal loss at 6 and 12 months was reliably predicted by Ishihara asymmetry at 1 month. Optic nerve MTR and DTI at 3 months post-acute ON could predict axonal loss at 6 and 12 months. Conclusions: Simple Ishihara asymmetry testing 1month after acuteON onset can best predict visual outcome and axonal loss at 6 and 12months in a clinical or research setting. [ABSTRACT FROM AUTHOR]

Myelination within the central nervous system (CNS) is crucial for the conduction of action potentials by neurons. Variation in compact myelin morphology and the structure of the paranode are hypothesised to have significant impact on the speed of action potentials. There are, however, limited experimental data investigating the impact of changes in myelin structure upon conductivity in the central nervous system. We have used a genetic model in which myelin thickness is reduced to investigate the effect of myelin alterations upon action potential velocity. A detailed examination of the myelin ultrastructure of mice in which the receptor tyrosine kinase Tyro3 has been deleted showed that, in addition to thinner myelin, these mice have significantly disrupted paranodes. Despite these alterations to myelin and paranodal structure, we did not identify a reduction in conductivity in either the corpus callosum or the optic nerve. Exploration of these results using a mathematical model of neuronal conductivity predicts that the absence of Tyro3 would lead to reduced conductivity in single fibres, but would not affect the compound action potential of multiple myelinated neurons as seen in neuronal tracts. Our data highlight the importance of experimental assessment of conductivity and suggests that simple assessment of structural changes to myelin is a poor predictor of neural functional outcomes. [ABSTRACT FROM AUTHOR]

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS. [ABSTRACT FROM AUTHOR]

Anti-N-methyl-D-aspartate (NMDA) receptor antibody (anti-NMDAR Ab)-mediated encephalitis is an autoimmune disorder involving the production of antibodies against NMDARs in the central nervous system that leads to neurological or psychiatric dysfunction. Initially described as a paraneoplastic syndrome in young women with teratomas, increased testing has found it to be a heterogeneous condition that affects both the sexes with varying clinical manifestations, severity, and aetiology. This case report describes a 67-year-old man with a 40-year history of relapsing, severe, treatment-refractory schizophrenia. Due to the worsening of his condition during a prolonged inpatient admission for presumed relapse of psychosis, a revisit of the original diagnosis was considered with extensive investigations performed including an autoimmune panel. This revealed anti-NMDAR Abs in both the serum and cerebrospinal fluid on two occasions. Following treatment with intravenous immunoglobulin and methylprednisolone, he demonstrated rapid symptom improvement. This is a rare case of a long-standing psychiatric presentation with a preexisting diagnosis of schizophrenia subsequently found to have anti-NMDAR Ab-mediated encephalitis. Whether the case is one of initial NMDAR encephalitis vs. overlap syndrome is unknown. Most importantly, this case highlights the need for vigilance and balanced consideration for treatment in cases of long-standing psychiatric presentation where the case remains treatment refractory to antipsychotics or when atypical features including seizures and autonomic dysfunction or focal neurology are observed. [ABSTRACT FROM AUTHOR]

Background: Myelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction. Establishing the proper pattern of myelin in neural circuits requires communicative axo-glial interactions, however, the molecular interactions that occur between oligodendrocytes and axons during developmental myelination and myelin maintenance remain to be fully elucidated. Our previous work identified G protein-coupled receptor 62 (Gpr62), an uncharacterized orphan g-protein coupled receptor, as being selectively expressed by mature oligodendrocytes within the CNS, suggesting a potential role in myelination or axoglial interactions. However, no studies to date have assessed the functional requirement for Gpr62 in oligodendrocyte development or CNS myelination. Methods: To address this, we generated a knockout mouse strain lacking the Gpr62 gene. We assessed CNS myelination during both postnatal development and adulthood using immunohistochemistry, electron microscopy and western blot. In addition, we utilized AAV-mediated expression of a tagged Gpr62 in oligodendrocytes to determine the subcellular localization of the protein in vivo. Results: We find that virally expressed Gpr62 protein is selectively expressed on the adaxonal myelin layer, suggestive of a potential role for Gpr62 in axo-myelinic signaling. Nevertheless, Gpr62 knockout mice display normal oligodendrocyte numbers and apparently normal myelination within the CNS during both postnatal development and adulthood. Conclusions: We conclude that in spite of being well-placed to mediate neuronal-oligodendrocyte communications, Gpr62 is overall dispensable for CNS myelination. [ABSTRACT FROM AUTHOR]

Background: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. Objective: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. Methods: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. Results: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25–0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88–0.99), higher serum IgA (OR 0.37, 95% CI 0.17–0.80) and higher serum IgG (OR 0.81, 95% CI 0.67–0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75–0.96) and higher serum IgA (OR 0.23, 95% CI 0.07–0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06–1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02–3.86) were associated with increased odds of antimicrobial use. Conclusions: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy. [ABSTRACT FROM AUTHOR]

Background: Dietary patterns and their association with subsequent clinical course have not been well studied in early multiple sclerosis (MS). Objectives: To describe dietary patterns in people in 5 years following first clinical demyelination and assess associations with MS conversion and relapse. Methods: This study included baseline food frequency questionnaire dietary intake (entry to the Ausimmune Study) and 5-year follow-up; iterated principal factor analysis was applied. MS conversion and relapse risks were assessed by Cox proportional hazards models, adjusted for age, sex, study site, education, body mass index (BMI), smoking and omega-3 supplement use. Results: In cases with a first clinical diagnosis of central nervous system (CNS) demyelination, we identified three major dietary patterns, 'Prudent', 'High-Vegetable' and 'Mixed', explaining 43%, 37% and 24% of diet variance in dietary intake, respectively. Fruits, vegetables, fish, wholegrains and nuts loaded highly on the Prudent pattern, starchy vegetables and legumes on the High-Vegetable pattern, and meats and alcohol on the Mixed pattern. Diet factor scores were not associated with MS conversion risk. Those with baseline Prudent scores above the median had significantly lower relapse risk (adjusted hazard ratio = 0.54, 95% confidence interval (CI) 0.37, 0.81) with some evidence of a plateau effect. Conclusion: Prudent diet factor score above the median was prospectively associated with lower relapse risk in the 5 years following the first clinical demyelinating event. [ABSTRACT FROM AUTHOR]

Upper and lower limb impairments are common in people with multiple sclerosis (pwMS), yet difficult to clinically identify in early stages of disease progression. Tasks involving complex motor control can potentially reveal more subtle deficits in early stages, and can be performed during functional MRI (fMRI) acquisition, to investigate underlying neural mechanisms, providing markers for early motor progression. We investigated brain activation during visually guided force matching of hand or foot in 28 minimally disabled pwMS (Expanded Disability Status Scale (EDSS) < 4 and pyramidal and cerebellar Kurtzke Functional Systems Scores ≤ 2) and 17 healthy controls (HC) using ultra‐high field 7‐Tesla fMRI, allowing us to visualise sensorimotor network activity in high detail. Task activations and performance (tracking lag and error) were compared between groups, and correlations were performed. PwMS showed delayed (+124 s, p =.002) and more erroneous (+0.15 N, p =.001) lower limb tracking, together with lower cerebellar, occipital and superior parietal cortical activation compared to HC. Lower activity within these regions correlated with worse EDSS (p =.034), lower force error (p =.006) and higher lesion load (p <.05). Despite no differences in upper limb task performance, pwMS displayed lower inferior occipital cortical activation. These results demonstrate that ultra‐high field fMRI during complex hand and foot tracking can identify subtle impairments in lower limb movements and upper and lower limb brain activity, and differentiates upper and lower limb impairments in minimally disabled pwMS. [ABSTRACT FROM AUTHOR]

We propose that multiple sclerosis (MS) is best characterized as a syndrome rather than a single disease because different pathogenetic mechanisms can result in the constellation of symptoms and signs by which MS is clinically characterized. We describe several cellular mechanisms that could generate inflammatory demyelination through disruption of homeostatic interactions between immune and neural cells. We illustrate that genomics is important in identifying phenocopies, in particular for primary progressive MS. We posit that molecular profiling, rather than traditional clinical phenotyping, will facilitate meaningful patient stratification, as illustrated by interactions between HLA and a regulator of homeostatic phagocytosis, MERTK. We envisage a personalized approach to MS management where genetic, molecular, and cellular information guides management. [ABSTRACT FROM AUTHOR]

Retinal ganglion cells (RGCs) are the only output neurons of the vertebrate retina, integrating signals from other retinal neurons and transmitting information to the visual centers of the brain. The death of RGCs is a common outcome in many optic neuropathies, such as glaucoma, demyelinating optic neuritis and ischemic optic neuropathy, resulting in visual defects and blindness. There are currently no therapies in clinical use which can prevent RGC death in optic neuropathies; therefore, the identification of new targets for supporting RGC survival is crucial in the development of novel treatments for eye diseases. In this study we identify that the receptor tyrosine kinase, Tyro3, is critical for normal neuronal function in the adult mouse retina. The loss of Tyro3 results in a reduction in photoreceptor and RGC function as measured using electroretinography. The reduction in RGC function was associated with a thinner retinal nerve fiber layer and fewer RGCs. In the central retina, independent of the loss of RGCs, Tyro3 deficiency resulted in a dramatic reduction in the number of RGC dendrites in the inner plexiform layer. Our results show that Tyro3 has a novel, previously unidentified role in retinal function, RGC survival and RGC morphology. The Tyro3 pathway could therefore provide an alternative, targetable pathway for RGC protective therapeutics. [ABSTRACT FROM AUTHOR]

The white matter is highly vascularised by the cerebral venous system. In this paper, we describe a unique blood oxygen-level dependent (BOLD) signal within the white matter using functional MRI and spatial independent components analysis. The signal is characterized by a narrow peak frequency band between 0.05 and 0.1 Hz. Hypercapnia, induced transient increases in white matter venous BOLD that disrupted the oscillation indicative of a vasocontractile mechanism. Comparison of the white matter venous BOLD oscillations between 14 healthy subjects and 18 people with perivenular inflammation due to multiple sclerosis (MS), revealed loss of power in the white matter venous BOLD signal in the peak frequency band (patients = 6.70 ± 0.94 dB/Hz vs. controls = 7.64 ± 0.71 dB/Hz; p = 0.006). In MS, lower power was associated with greater levels of neuroinflammatory activity (R = −0.64, p = 0.006). Using a signal modeling technique, we assessed the anatomical distribution of white matter venous BOLD signal abnormalities and detected reduced power in the periventricular white matter, a region of known venous damage in MS. These results demonstrate a novel link between neuroinflammation and vascular physiological dysfunction in the cerebral white matter, and could indicate enduring loss of vascular compliance associated with imperfect repair of blood-brain barrier damage after resolution of acute neuroinflammation. [ABSTRACT FROM AUTHOR]

Background/objectives: The evidence for diet as a risk factor for multiple sclerosis (MS) is inconclusive. We examined the associations between fish consumption and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS.Methods: The 2003-2006 Ausimmune Study was a case-control study examining environmental risk factors for FCD, with participants recruited from four regions of Australia and matched on age, sex, and study region. Dietary intake data were collected using a food frequency questionnaire. We used conditional logistic regression models to test associations between fish consumption (total, tinned, grilled, and fried) and risk of FCD (249 cases and 438 controls), adjusting for history of infectious mononucleosis, smoking, serum 25-hydroxyvitamin D concentrations, socio-economic status, omega-3 supplement use, dietary under-reporting, and total energy intake.Results: Higher total fish consumption (per 30 g/day, equivalent to two serves/week) was associated with an 18% reduced risk of FCD (AOR 0.82; 95% CI 0.70, 0.97). While we found no statistically significant associations between grilled and fried fish consumption and risk of FCD, higher tinned fish consumption (per 30 g/day) was associated with a 41% reduced risk of FCD (AOR 0.59; 95% CI 0.39, 0.89).Conclusions: Tinned fish is predominantly oily, whereas grilled and fried fish are likely to be a combination of oily and white types. Oily fish is high in vitamin D and very long chain polyunsaturated omega-3 fatty acids, both of which may be beneficial in relation to MS. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is an unpredictable, chronic neurological disease accompanied with high rates of depression and anxiety, particularly in the early stages of diagnosis. There is evidence to suggest that cognitive behavioural therapy (CBT) is effective for the treatment of depression amongst individuals with MS; however, there is a paucity of tailored CBT interventions designed to be offered in the newly diagnosed period. This trial is the first to assess the effectiveness and cost-effectiveness of a tailored CBT intervention compared to a supportive listening (SL) intervention amongst individuals with MS who are depressed.Methods: ACTION-MS is a two-arm parallel group, assessor-blinded, active comparator, randomised controlled trial which will test whether a tailored CBT-based intervention compared to an SL intervention can reduce depression and related factors such as anxiety, fatigue, pain and sleep problems in those newly diagnosed with MS. Sixty participants who are within 5 years of having received a diagnosis of MS and scored within the mild to moderate range of depression on the Beck Depression Inventory (BDI-II) will be recruited from MS clinics located across three hospital sites in Melbourne, Australia. The primary outcome is depression severity using the BDI-II at post-assessment. Intervention satisfaction and acceptability will be assessed. A cost-effectiveness analysis will also be conducted. Data will be analysed on an intention-to-treat basis.Discussion: There is a scarcity of psychological interventions for depression targeting the newly diagnosed period. However, interventions during this time point have the potential to have a major impact on the mental and physical wellbeing of those newly diagnosed with MS. The current trial will provide data on the effectiveness of a tailored CBT intervention for the treatment of depression in those newly diagnosed with MS. Findings will also provide effect size estimates that can be used to power a later-stage multi-centre trial of treatment efficacy, and will provide information on the mechanisms underlying any treatment effects and cost-effectiveness data for delivering this intervention in outpatient MS clinics.Trial Registration: ISRCTN trials registry, ISRCTN63987586. Current controlled trials. Retrospectively registered on 20 October 2017. [ABSTRACT FROM AUTHOR]

The evidence associating red meat consumption and risk of multiple sclerosis is inconclusive. We tested associations between red meat consumption and risk of a first clinical diagnosis of central nervous system demyelination (FCD), often presaging a diagnosis of multiple sclerosis. We used food frequency questionnaire data from the 2003–2006 Ausimmune Study, an incident, matched, case-control study examining environmental risk factors for FCD. We calculated non-processed and processed red meat density (g/1,000 kcal/day). Conditional logistic regression models (with participants matched on age, sex, and study region) were used to estimate odds ratios (ORs), 95% confidence intervals (95% CI) and p- values for associations between non-processed (n = 689, 250 cases, 439 controls) and processed (n = 683, 248 cases, 435 controls) red meat density and risk of FCD. Models were adjusted for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, race, education, body mass index and dietary misreporting. A one standard deviation increase in non-processed red meat density (22 g/1,000 kcal/day) was associated with a 19% reduced risk of FCD (AOR = 0.81; 95%CI 0.68, 0.97; p = 0.02). When stratified by sex, higher non-processed red meat density (per 22 g/1,000 kcal/day) was associated with a 26% reduced risk of FCD in females (n = 519; AOR = 0.74; 95%CI 0.60, 0.92; p = 0.01). There was no statistically significant association between non-processed red meat density and risk of FCD in males (n = 170). We found no statistically significant association between processed red meat density and risk of FCD. Further investigation is warranted to understand the important components of a diet that includes non-processed red meat for lower FCD risk. [ABSTRACT FROM AUTHOR]

Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63. [ABSTRACT FROM AUTHOR]

We present a case of monocytopaenia and mycobacteria related infection (MonoMac) syndrome in a 30-year-old man of Indian origin. The clinical diagnosis of GATA2 haploinsufficiency was suspected after an unusual neurological presentation on a background of myelodysplastic syndrome and childhood pulmonary tuberculosis. The patient had a longitudinally extensive spinal cord lesion and a lesion in the medulla. No obvious infective cause for the spinal cord MrI abnormality was found, and the lesions were presumed to be inflammatory in nature. The family history consisted of autosomal dominant clinical features suggestive of GATA2 haploinsufficiency. Genetic testing in peripheral leucocytes revealed a pathogenic mutation in GATA2. this is the first-ever published case of possible MonoMac syndrome with a neurological presentation. The case highlights the rarity and complexity of the diagnosis and the clinical sequelae that ensued with the patient dying of gram-negative septicaemia while receiving intravenous steroid therapy for the spinal cord lesion. [ABSTRACT FROM AUTHOR]

Background/objectives: Although the current evidence is insufficient to recommend a special diet for people with multiple sclerosis (MS), dietary advice for people with MS is prolific online and in the media. This study aimed to describe dietary changes made in the year following a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. subjects/methods: We used follow-up data from the Ausimmune Study, a multicentre matched case-control study examining the environmental risk factors for a FCD. A total of 244 cases (60 male, 184 female) completed a 1-year follow-up interview, which included a question about dietary changes. We described the number and proportion (%) of participants who reported making dietary changes and the type of change made. We investigated independent predictors of making a dietary change using a multivariable logistic regression model. results: A total of 38% (n = 92) of participants at the 1-year follow-up reported making at least one dietary change over the last year. There were no statistically significant independent associations between any participant characteristic and odds of making a dietary change. Of those who made at least one dietary change, the most common changes were increasing fruit and/or vegetable intake (27%, n = 25) and following a low-fat diet (25%, n = 23). conclusion: A considerable proportion of the study population reported making at least one dietary change in the year following a FCD, with the majority of changes being toward a healthier diet. Further research is warranted to investigate the reasons behind any dietary changes adopted by people with a FCD or with MS, and whether making a dietary change has benefits for the progression of demyelinating diseases, e.g., to a diagnosis of MS, as well as for general health and well-being. [ABSTRACT FROM AUTHOR]

Subtle gait and balance dysfunction is a precursor to loss of mobility in multiple sclerosis (MS). Biomechanical assessments using advanced gait and balance analysis technologies can identify these subtle changes and could be used to predict mobility loss early in the disease. This update critically evaluates advanced gait and balance analysis technologies and their applicability to identifying early lower limb dysfunction in people with MS. Non-wearable (motion capture systems, force platforms, and sensor-embedded walkways) and wearable (pressure and inertial sensors) biomechanical analysis systems have been developed to provide quantitative gait and balance assessments. Non-wearable systems are highly accurate, reliable and provide detailed outcomes, but require cumbersome and expensive equipment. Wearable systems provide less detail but can be used in community settings and can provide real-time feedback to patients and clinicians. Biomechanical analysis using advanced gait and balance analysis technologies can identify changes in gait and balance in early MS and consequently have the potential to significantly improve monitoring of mobility changes in MS. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study). Methods: Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR) "load" estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review. results: Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose-response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard. conclusion: We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposure demonstrated a reduced MS conversion and relapse hazard, suggesting beneficial effects of sun exposure on clinical course. [ABSTRACT FROM AUTHOR]

Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the individual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of individual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS. [ABSTRACT FROM AUTHOR]

Background: There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis. Objective: To examine the association between stressful life events and risk of first demyelinating event (FDE). Methods: This was a multicentre incident case–control study. Cases (n = 282 with first diagnosis of central nervous system (CNS) demyelination, including n = 216 with ‘classic FDE’) were aged 18–59 years. Controls without CNS demyelination (n = 558) were matched to cases on age, sex and study region. Stressful life events were assessed using a questionnaire based on the Social Readjustment Rating Scale. Results: Those who suffered from a serious illness in the previous 12 months were more likely to have an FDE (odds ratio (OR) = 2.35 (1.36, 4.06), p = 0.002), and when we limited our reference group to those who had no stressful life events, the magnitude of effect became stronger (OR = 5.41 (1.80, 16.28)). The total stress number and stress load were not convincingly associated with the risk of an FDE. Conclusion: Cases were more likely to report a serious illness in the previous 12 months, which could suggest that a non-specific illness provides an additional strain to an already predisposed immune system. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: It is not currently known whether gait and balance measures are responsive to deterioration of motor function in multiple sclerosis (MS) patients with low EDSS scores (≤3.0). The aim of this study was to quantify MS-related gait and balance deterioration over a 12-month period. METHODS: Thirty-eight participants with MS (33 female, mean age: 41.1±8.3 years), mean time since diagnosis 2.2± 4.1 years, EDSS score≤3.0 and without clinical evidence of gait deterioration, were recruited. Participants performedwalking trials and Functional and Lateral Reach Tests. Kinematics of the ankle and knee, and electromyography of the tibialis anterior and medial gastrocnemius muscles were also measured. RESULTS: Three participants reported relapses with worsening EDSS scores and 4 non-relapsing participants had worse EDSS scores at 12 months. There were significant decreases in mean gait speed, stride length and balance scores, and a significant increase in double support. Marked changes in ankle kinematics, with decreased medial gastrocnemius activity were observed. CONCLUSION: Gait and balance performance of non-disabled RRMS participants may progressively decline, even in the absence of both acute clinical relapse and change in clinical status measured by the EDSS. [ABSTRACT FROM AUTHOR]

Background: To examine the effectiveness and acceptability of an 8-week individual tailored cognitive behavioural therapy (CBT) intervention for the treatment of depressive symptoms in those newly diagnosed with multiple sclerosis. Methods: The current study presents a pilot, parallel group randomized controlled trial (RCT) with an allocation ratio of 1:1 conducted in a large research and teaching hospital in Melbourne, Australia. 30 individuals with a mean age of 36.93 years (SD = 9.63) who were newly diagnosed with multiple sclerosis (MS) (X = 24.87 months, SD = 15. 61) were randomized to the CBT intervention (n = 15) or treatment as usual (TAU) (n = 15). The primary outcome was level of depressive symptoms using the Beck Depression Inventory-II (BDI-II). Secondary outcomes were level of anxiety, fatigue and pain impact, sleep quality, coping, acceptance of MS illness, MS related quality of life, social support, and resilience. Tertiary outcomes were acceptability and adherence to the intervention. Results: Large between group treatment effects were found for level of depressive symptoms at post and at 20 weeks follow-up (d = 1.66-1.34). There were also small to large group treatment effects for level of anxiety, fatigue and pain impact, sleep quality, MS related quality of life, resilience, and social support at post and at 20 weeks follow-up (d = 0.17-1.63). There were no drop-outs and participants completed all treatment modules. All participants reported the treatment as 'very useful', and most (73.4%) reported that the intervention had addressed their problems 'completely'. Conclusions: These data suggest that the tailored early intervention is appropriate and clinically effective for the treatment of depressive symptoms in those newly diagnosed with MS. A larger RCT comparing the CBT intervention with an active comparative treatment with longer term follow-up and cost effectiveness analyses is warranted. The pilot trial has been retrospectively registered on 28/04/2016 with the ISRCTN registry (trial ID ISRCTN10423371). [ABSTRACT FROM AUTHOR]

Previous studies have reported diffusion tensor imaging (DTI) changes within the optic radiations of patients after optic neuritis (ON). We aimed to study optic radiation DTI changes over 12 months following acute ON and to study correlations between DTI parameters and damage to the optic nerve and primary visual cortex (V1). We measured DTI parameters [fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD)] from the optic radiations of 38 acute ON patients at presentation and 6 and 12 months after acute ON. In addition, we measured retinal nerve fibre layer thickness, visual evoked potential amplitude, optic radiation lesion load, and V1 thickness. At baseline, FA was reduced and RD and MD were increased compared to control. Over 12 months, FA reduced in patients at an average rate of −2.6% per annum (control = −0.51%; p=0.006). Change in FA, RD, and MD correlated with V1 thinning over 12 months (FA: R=0.450, p=0.006; RD: R=-0.428, p=0.009; MD: R=-0.365, p=0.029). In patients with no optic radiation lesions, AD significantly correlated with RNFL thinning at 12 months (R=0.489, p=0.039). In conclusion, DTI can detect optic radiation changes over 12 months following acute ON that correlate with optic nerve and V1 damage. [ABSTRACT FROM AUTHOR]