To assess messenger RNA (mRNA) expression of POU2AF1 and Spi-B and their potential regulatory microRNAs (miRNAs) in natalizumab-treated patients with multiple sclerosis and in therapy-associated progressive multifocal leukoencephalopathy (PML).

To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563).

Cognitive decline in multiple sclerosis (MS) negatively impacts patients' everyday functioning and quality of life. Since symptomatic pharmacological treatment is not yet available alternative treatment strategies such as cognitive rehabilitation are of particular interest.

Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.

MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression. We compared the expression of 1059 miRNAs in B lymphocytes from untreated and natalizumab treated relapsing-remitting multiple sclerosis (RRMS) patients and healthy volunteers (HV). Forty nine miRNAs were down-regulated in untreated MS patients compared with HV. A distinct pattern of 10 differentially expressed miRNAs was found in natalizumab treated patients compared with untreated patients. Two clusters, i.e. miR-106b-25 and miR-17-92, were particularly deregulated. MiRNA-mRNA interaction analysis revealed B cell receptor, phosphatidyl-inositol-3-kinase (PI3K) and phosphatase and tensin homology (PTEN) signaling being the key affected pathways. We discovered deregulated viral miRNAs in untreated patients as compared with HV and natalizumab treated patients, a novel finding that may be related to latency and activation of viruses in MS. Our findings provide first insights into miRNA dependent regulation of B cell function in MS and the impact of a therapy not primarily targeting B cells on this regulation.

Neuroimaging measures hold promise for enhancing the detection of disease-related genetic variants. In this study, we use advanced multivariate regression methods to assess the predictive value of single nucleotide polymorphisms (SNPs) on several brain volumetric- and lesion-related neuroimaging measures in a well-characterized cohort of 326 patients with multiple sclerosis (MS). SNP selection was constrained to key epigenetic regulatory genes to further explore the emerging role of epigenetics in MS. Regression models consistently identified rs2522129, rs2675231, and rs2389963 as having among the highest predictive values for explaining differences related to brain volume measures. These SNPs are all contained in genes from the same superfamily, histone deacetylases, which have biological functions that are relevant to MS, neurodegeneration, and aging. Our preliminary findings generate hypotheses for testing in future independent MS data sets as well as other neurodegenerative conditions.

To diagnose multiple sclerosis (MS), evidence for dissemination in space and time is required. There is no clear definition on how symptoms and signs of a patient indicate clinical dissemination in space. To provide a uniform approach on this subject, a clinical classification system was described recently differentiating patients with mono- and multifocal clinical presentation. Here we assess the predictive value of clinically defined dissemination in space at first presentation for time to clinically definite MS (CDMS).

Cerebellar symptoms in multiple sclerosis (MS) are well described; however, the exact contribution of cerebellar damage to MS disability has not been fully explored. Longer-term observational periods are necessary to better understand the dynamics of pathological changes within the cerebellum and their clinical consequences. Cerebellar lobe and single lobule volumes were automatically segmented on 664 3D-T1-weighted MPRAGE scans (acquired at a single 1.5 T scanner) of 163 MS patients (111 women; mean age: 47.1 years; 125 relapsing-remitting (RR) and 38 secondary progressive (SP) MS, median EDSS: 3.0) imaged annually over 4 years. Clinical scores (EDSS, 9HPT, 25FWT, PASAT, SDMT) were determined per patient per year with a maximum clinical follow-up of 11 years. Linear mixed-effect models were applied to assess the association between cerebellar volumes and clinical scores and whether cerebellar atrophy measures may predict future disability progression. SPMS patients exhibited faster posterior superior lobe volume loss over time compared to RRMS, which was related to increase of EDSS over time. In RRMS, cerebellar volumes were significant predictors of motor scores (e.g. average EDSS, T25FWT and 9HPT) and SDMT. Atrophy of motor-associated lobules (IV-VI + VIII) was a significant predictor of future deterioration of the 9HPT of the non-dominant hand. In SPMS, the atrophy rate of the posterior superior lobe (VI + Crus I) was a significant predictor of future PASAT performance deterioration. Regional cerebellar volume reduction is associated with motor and cognitive disability in MS and may serve as a predictor for future disease progression, especially of dexterity and impaired processing speed.

Background: Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. Aim: To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. Method: One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1-C2; C2/3) on SC and brain images and the entire cervical cord (C1-C7) on SC images only. Results: CSA estimates were significantly smaller using SCT compared to NQL and ASM (p < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1-C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all p ≤ 0.006 at the C1-C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. Conclusion: For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches.

Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging-and almost exclusively performed at 7 T field strength-depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (1) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3 T MRI system; and (2) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3 T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete/complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.

Symptom-related adverse events associated with perioperative chemotherapy in patients with breast cancer include short-term adverse events such as nausea and vomiting. However, changes in the severity and duration of prolonged symptom-related adverse events have not been fully investigated. We present a protocol of a study that aims to clarify the prevalence of symptom-related adverse events in patients with breast cancer 1 year after neoadjuvant or adjuvant chemotherapy using an electronic patient-reported outcomes (ePRO) system.

The phase 3 TERIKIDS study demonstrated efficacy and manageable safety for teriflunomide versus placebo in children with relapsing multiple sclerosis (RMS).

Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS).

A change in MRI hardware impacts brain volume measurements. The aim of this study was to use MRI data from multiple sclerosis (MS) patients and healthy control subjects (HCs) to statistically model how to adjust brain atrophy measures in MS patients after a major scanner upgrade.

Myasthenia gravis is an autoimmune disorder defined by muscle weakness and fatigability associated with antibodies against proteins of the neuromuscular junction (NMJ). The most common autoantibody target is the acetylcholine receptor (AChR). Three mechanisms have been postulated by which autoantibodies might interfere with neurotransmission: direct antagonism of the receptor, complement-mediated destruction of the postsynaptic membrane, and enhanced internalization of the receptor. It is very likely that more than one of these mechanisms act in parallel. Dissecting the mechanisms of autoantibody-mediated pathology requires patient-derived, monoclonal antibodies. Using membrane antigen capture activated cell sorting (MACACS), we isolated AChR-specific B cells from patients with myasthenia gravis, and produced six recombinant antibodies. All AChR-specific antibodies were hypermutated, including isotypes IgG1, IgG3, and IgG4, and recognized different subunits of the AChR. Despite clear binding, none of the individual antibodies showed significant antagonism of the AChR measured in an in vitro neuromuscular synapse model, or AChR-dependent complement activation, and they did not induce myasthenic signs in vivo. However, combinations of antibodies induced strong complement activation in vitro, and severe weakness in a passive transfer myasthenia gravis rat model, associated with NMJ destruction and complement activation in muscle. The strongest complement activation was mediated by combinations of antibodies targeting disparate subunits of the AChR, and such combinations also induced the formation of large clusters of AChR on the surface of live cells in vitro. We propose that synergy between antibodies of different epitope specificities is a fundamental feature of this disease, and possibly a general feature of complement-mediated autoimmune diseases. The importance of synergistic interaction between antibodies targeting different subunits of the receptor can explain the well-known discrepancy between serum anti-AChR titers and clinical severity, and has implications for therapeutic strategies currently under investigation.

Wearable sensor technologies have the potential to improve monitoring in people with multiple sclerosis (MS) and inform timely disease management decisions. Evidence of the utility of wearable sensor technologies in people with MS is accumulating but is generally limited to specific subgroups of patients, clinical or laboratory settings, and functional domains.

Previous studies have demonstrated that white matter (WM) lesions bias automated brain tissue classifications and cerebral volume measurements. However, filling WM lesions using the intensity of neighbouring normal-appearing WM has been shown to increase the accuracy of automated volume measurements in the brain. In the present study, we investigate the influence of WM lesions on cortical thickness (CTh) measures and assessed the impact of lesion filling on both cross-sectional/longitudinal and global/regional measurements of CTh in multiple sclerosis (MS) patients.

Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. The present study evaluated the effect of atorvastatin added to interferon beta-1b in multiple sclerosis (MS) in a multicenter, randomized, parallel-group, rater-blinded study performed in eight Swiss hospitals. Seventy-seven patients with relapsing-remitting MS started interferon beta-1b every other day. After 3 months, they were randomized 1:1 to receive atorvastatin 40 mg/day or not in addition to interferon beta-1b until month 15. The primary endpoint was the proportion of patients with new lesions on T2-weighted images at month 15 compared to baseline at month three. At study end, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.14; 95 % CI 0.36-3.56; p = 0.81). All predefined secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of new Gd-enhancing lesions on T1-weighted images, total brain volume, volume of grey matter, volume of white matter, EDSS, MSFC, relapse rate, time to first relapse, number of relapse-free patients and neutralizing antibodies did not show any significant differences (all p values >0.1). Transient elevations of liver enzymes were more frequent with atorvastatin (p = 0.02). In conclusion, atorvastatin 40 mg/day in addition to interferon beta-1b did not have a beneficial effect on relapsing-remitting MS compared to interferon beta-1b monotherapy over a 12-month period.

RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.

Prevention of global gray matter (GM) volume changes in multiple sclerosis (MS) are an objective in clinical trials, but the effect of immunomodulatory medication on regional GM atrophy progression is unclear. MRIs from 86 patients with relapsing-remitting MS (RRMS) followed up for 24 months were analyzed using voxel-based morphometry. An analysis of covariance model (cluster threshold, corrected p<0.05) was used to compare GM volumes between baseline and follow-up while stratified by immunomodulatory medication (IM): Interferone INF-beta-1a (n=34), INF-beta-1b (n=16), glatiramer acetate (GA) (n=15), and no-immunomodulatory treatment (n=21). In the INF-beta-1a/1b group (n=50), significant GM volume reductions were observed during follow-up in fronto-temporal, cingulate and cerebellar cortical brain regions, without significant differences between the INF-beta-1a and INF-beta-1b patients. In the GA group and in unmedicated patients, no significant regional GM volume reductions were observed. In contrast to GA, INF-beta-1a/1b treatment was associated with GM volume reductions in hippocampal/parahippocampal and anterior cingulate cortex. This is the first longitudinal study investigating the effects of IMs on GM in RRMS. Results suggest differences in the dynamics of regional GM volume atrophy in differentially treated or untreated RRMS patients.