IL-21 and IL-21 Receptor Expression in Lymphocytes and Neurons in Multiple Sclerosis Brain

IL-17–producing CD4+ T cells (Th-17) contribute to the pathogenesis of experimental autoimmune encephalomyelitis and are associated with active disease in multiple sclerosis (MS). In addition to IL-17, Th-17 cells can also express IL-21, IL-22, and IL-6 under Th-17–polarizing conditions (IL-6 and transforming growth factor-β). In this study we investigated IL-21 and IL-21 receptor (IL-21R) expression in MS lesions by in situ hybridization and immunohistochemistry. We detected strongly IL-21+ infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4+ cells. In contrast, IL-21R was much more broadly distributed on CD4+, CD19+, and CD8+ lymphocytes but not major histocompatibility complex class-II+ macrophages/microglia. Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons. These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk

An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue

Highlights NAAG likely contributes to the total NAA differences between multiple sclerosis lesion and normal appearing brain tissue. myo-Inositol was not shown to be different between chronic AQP4Ab-NMOSD brain lesions and normal appearing brain tissue. An optimised MRS methodology is described, using 7T field strength and correcting for tissue T2 water relaxion differences. 7-tesla MRS profiles of chronic brain lesions and normal appearing white matter are presented for MS and AQP4Ab-NMOSD. Abstract Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS

Sodium channel Nav1.6 accumulates at the site of infraorbital nerve injury

<p>Abstract</p> <p>Background</p> <p>Sodium channel (NaCh) expressions change following nerve and inflammatory lesions and this change may contribute to the activation of pain pathways. In a previous study we found a dramatic increase in the size and density of NaCh accumulations, and a remodeling of NaChs at intact and altered myelinated sites at a location just proximal to a combined partial axotomy and chromic suture lesion of the rat infraorbital nerve (ION) with the use of an antibody that identifies all NaCh isoforms. Here we evaluate the contribution of the major nodal NaCh isoform, Na_v1.6, to this remodeling of NaChs following the same lesion. Sections of the ION from normal and ION lesioned subjects were double-stained with antibodies against Na_v1.6 and caspr (contactin-associated protein; a paranodal protein to identify nodes of Ranvier) and then z-series of optically sectioned images were captured with a confocal microscope. ImageJ (NIH) software was used to quantify the average size and density of Na_v1.6 accumulations, while additional single fiber analyses measured the axial length of the nodal gap, and the immunofluorescence intensity of Na_v1.6 in nodes and of caspr in the paranodal region.</p> <p>Results</p> <p>The findings showed a significant increase in the average size and density of Na_v1.6 accumulations in lesioned IONs when compared to normal IONs. The results of the single fiber analyses in caspr-identified typical nodes showed an increased axial length of the nodal gap, an increased immunofluorescence intensity of nodal Na_v1.6 and a decreased immunofluorescence intensity of paranodal caspr in lesioned IONs when compared to normal IONs. In the lesioned IONs, Na_v1.6 accumulations were also seen in association with altered caspr-relationships, such as heminodes.</p> <p>Conclusion</p> <p>The results of the present study identify Na_v1.6 as one isoform involved in the augmentation and remodeling of NaChs at nodal sites following a combined partial axotomy and chromic suture ION lesion. The augmentation of Na_v1.6 may result from an alteration in axon-Schwann cell signaling mechanisms as suggested by changes in caspr expression. The changes identified in this study suggest that the participation of Na_v1.6 should be considered when examining changes in the excitability of myelinated axons in neuropathic pain models.</p

Setting a national consensus for managing mild and blast traumatic brain injury: post-meeting consensus report

A meeting was held on Wednesday 15 January 2020 to examine the current evidence for non-routine imaging and for neuroendocrine screening in the management of military personnel with brain injury and overlapping symptom domains. The Summit aimed to specifically address the relative utility of magnetoencephalography (MEG), diffusion tensor imaging (DTI) and susceptibility weighted imaging (SWI) in the UK context. This Consensus Report discusses points of consensus, points for further discussion/points of equipoise and recommendations that arose during, and following, the meeting

OPTIMISE: MS study protocol: a pragmatic, prospective observational study to address the need for, and challenges with, real world pharmacovigilance in multiple sclerosis

IntroductionThe power of ‘real world’ data to improve our understanding of the clinical aspects of multiple sclerosis (MS) is starting to be realised. Disease modifying therapy (DMT) use across the UK is driven by national prescribing guidelines. As such, the UK provides an ideal country in which to gather MS outcomes data. A rigorously conducted observational study with a focus on pharmacovigilance has the potential to provide important data to inform clinicians and patients while testing the reliability of estimates from pivotal trials when applied to patients in the UK.Methods and analysisThe primary aim of this study is to characterise the incidence and compare the risk of serious adverse events in people with MS treated with DMTs. The OPTIMISE:MS database enables electronic data capture and secure data transfer. Selected clinical data, clinical histories and patient-reported outcomes are collected in a harmonised fashion across sites at the time of routine clinical visits. The first patient was recruited to the study on 24 May 2019. As of January 2021, 1615 individuals have baseline data recorded; follow-up data are being captured and will be reported in due course.Ethics and disseminationThis study has ethical permission (London City and East; Ref 19/LO/0064). Potential concerns around data storage and sharing are mitigated by the separation of identifiable data from all other clinical data, and limiting access to any identifiable data. The results of this study will be disseminated via publication. Participants provide consent for anonymised data to be shared for further research use, further enhancing the value of the study.</jats:sec

Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART):a phase 2b, multiarm, double-blind, randomised placebo-controlled trial

Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2Akita/+ mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2Akita/+ and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2Akita/+ mice and sex-matched littermate controls. Our phenotypic analysis of Ins2Akita/+ mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM

Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol

Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access

Local Translation in Primary Afferent Fibers Regulates Nociception

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states