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Objectives Characterise telehealth use in MS clinics during the COVID–19 pandemic. Assess patient and clinician attitudes towards telehealth. Compare telehealth–based and physical EDSS obtained during period of telehealth implementation. Methods Clinic records from Mar-Dec 2020 were reviewed. Patients and clinicians completed questionnaires about experiences using Telehealth. The iMed database was searched for EDSS recorded via face-to-face and telehealth appointments during and compared to face-to-face EDSS preceding and following the study period. T-test and Chi-square test were used for between-group comparisons. Results 2023 appointments (27% face-to-face, 35% video, 37% telephone) were conducted. New referrals were predominantly face-to-face (66%). 89% of patients were satisfied with telehealth. 58% felt they were as good as face-to-face visits, whilst only 11% of clinicians agreed. Many patients favoured a hybrid model. Safety during the COVID-19 pandemic was important to both groups. EDSS increase from the preceding visit was recorded in a significantly higher proportion of face-to-face than telehealth appointments (p=0.027), with the increase driven by patients with baseline EDSS≤4.0. Amongst patients with EDSS increases, similar numbers of suspected relapses were seen via both modalities. Absolute increase in EDSS was also significantly greater amongst patients seen face-to-face (p Conclusion Patient satisfaction with telehealth was high, whilst clinicians preferred face-to-face consultations. EDSS increase was more frequently recorded via face-to-face than telehealth appointments, which may underestimate lower EDSS. Future clinics could combine both modalities.

Objective To examine factors determining risk of self-reported infections and antimicrobial use in patients receiving Ocrelizumab for MS. Methods Retrospective, observational cohort study conducted in Ocrelizumab-treated patients at the Royal Melbourne Hospital. The association of clinical and laboratory factors with self-reported infection rate and antimicrobial use were estimated using univariate and multivariable logistic regression models. Results 185 patients were included in the study, and 176 infections were reported in 89 patients (46.1%), and in 47 patients (25.3%) antimicrobial use was identified. 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 EDSS (OR 1.99, 95% CI 1.02 - 3.86) were associated with increased odds of antimicrobial use. Conclusions Higher serum IgA, IgG and older age were associated with reduced odds of infection. Our findings highlight non-uniformity of infection risk in Ocrelizumab-treated MS patients, and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.

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), The results from this study 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 in minimally disabled people with multiple sclerosis (pwMS). Compared to healthy control, pwMS displayed delayed and more erroneous lower limb tracking, together with lower cerebellar, occipital and superior parietal cortical activation. Despite no differences in upper limb task performance, pwMS displayed lower inferior occipital cortical activation.

Multiple sclerosis is a neuroinflammatory disease of the CNS that is associated with significant irreversible neuro-axonal loss, leading to permanent disability. There is thus an urgent need for in vivo markers of axonal loss for use in patient monitoring or as end-points for trials of neuroprotective agents. Advanced diffusion MRI can provide markers of diffuse loss of axonal fibre density or atrophy within specific white matter pathways. These markers can be interrogated in specific white matter tracts that underpin important functional domains such as sensorimotor function. This study aimed to evaluate advanced diffusion MRI markers of axonal loss within the major sensorimotor tracts of the brain, and to correlate the degree of axonal loss in these tracts to precise kinematic measures of hand and foot motor control and gait in minimally disabled people with multiple sclerosis. Twenty-eight patients (Expanded Disability Status Scale < 4, and Kurtzke Functional System Scores for pyramidal and cerebellar function ≤ 2) and 18 healthy subjects underwent ultra-high field 7 Tesla diffusion MRI for calculation of fibre-specific measures of axonal loss (fibre density, reflecting diffuse axonal loss and fibre cross-section reflecting tract atrophy) within three tracts: cortico-spinal tract, interhemispheric sensorimotor tract and cerebello-thalamic tracts. A visually guided force-matching task involving either the hand or foot was used to assess visuomotor control, and three-dimensional marker-based video tracking was used to assess gait. Fibre-specific axonal markers for each tract were compared between groups and correlated with visuomotor task performance (force error and lag) and gait parameters (stance, stride length, step width, single and double support) in patients. Patients displayed significant regional loss of fibre cross-section with minimal loss of fibre density in all tracts of interest compared to healthy subjects (family-wise error corrected p-value < 0.05), despite relatively few focal lesions within these tracts. In patients, reduced axonal fibre density and cross-section within the corticospinal tracts and interhemispheric sensorimotor tracts were associated with larger force tracking error and gait impairments (shorter stance, smaller step width and longer double support) (family-wise error corrected p-value < 0.05). In conclusion, significant gait and motor control impairments can be detected in minimally disabled people with multiple sclerosis that correlated with axonal loss in major sensorimotor pathways of the brain. Given that axonal loss is irreversible, the combined use of advanced imaging and kinematic markers could be used to identify patients at risk of more severe motor impairments as they emerge for more aggressive therapeutic interventions., Multiple sclerosis is a neuroinflammatory disease of the CNS, associated with irreversible neuro-axonal loss, leading to permanent disability. Strik et al. report that advanced diffusion MRI reveals diffuse axonal loss in major sensorimotor pathways that correlate with subtle impairments in lower limb motor control and gait in minimally disabled patients., Graphical Abstract Graphical Abstract

Highlights • Covid-19 pandemic can have implications for MS and neuroimmunology patients and potentially their adherence to disease modifying therapies (DMTs). • A large proportion of patients receiving DMT's for their MS expressed some degree of concern regarding the COVID-19 pandemic and their therapy in one MS centre in Australia. • The level of concern in most patients was at most mild however. • Patients ascribed similar concern to the risk of a relapse of their disease compared to the risk of contracting COVID-19, perhaps underscoring a willingness to continue their DMT despite the pandemic., Objective: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic. Methods: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making. Results: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making. Conclusions: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild. Patients on B-cell depleting therapies were more inclined to express a higher level of concern. A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19. Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic.

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.

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.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

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.

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.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.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.ISRCTN trials registry, ISRCTN63987586. Current controlled trials. Retrospectively registered on 20 October 2017.

Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross-section, that can be estimated for each fibre direction in each voxel (termed a “fixel”). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 ± 10.2 years, 11 females) and 14 healthy controls (32.7 ± 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS., Highlights • Fibre density is reduced in lesions and normal-appearing white matter in MS • Fibre density detects white matter pathology in regions of crossing fibres • Loss of fibre density and cross-section selectively evident in visual pathways of optic neuritis patients.

Background Neural damage at early stages of multiple sclerosis (MS) can subtly affect gait muscle activation patterns. Detecting these changes using current clinical tools, however, is not possible. We propose using muscle coactivation measures to detect these subtle gait changes. This may also help in identifying people with MS (PwMS) that may benefit from strategies aimed at preventing further mobility impairments. Objective We aimed to determine if coactivation of ankle muscles during gait is greater in PwMS with Expanded Disability Status Scale (EDSS) score

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.

Neuroethics is central to the Australian Brain Initiative’s aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative. Refereed/Peer-reviewed

Remyelination in the CNS is the natural process of damage repair in demyelinating diseases such as multiple sclerosis (MS). However, remyelination becomes inadequate in many people with MS, which results in axonal degeneration and clinical disability. Enhancement of remyelination is a logical therapeutic goal; nevertheless, all currently licensed therapies for MS are immunomodulatory and do not support remyelination directly. Several molecular pathways have been identified as potential therapeutic targets to induce remyelination, and some of these have now been assessed in proof-of-concept clinical trials. However, trial design faces several obstacles: optimal clinical or paraclinical outcome measures to assess remyelination remain ill-defined, and identification of the ideal timing of therapy is also a crucial issue. In addition, realistic expectations are needed concerning the probable benefits of such therapies. Nevertheless, approaches that enhance remyelination are likely to be protective for axons and so could prevent long-term neurodegeneration. Future MS treatment paradigms, therefore, are likely to comprise a combinatorial approach that involves both immunomodulatory and regenerative treatments.

International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients., Author Summary Multiple sclerosis (MS) is the most common neurological disease of young Caucasian adults. Oligodendrocytes are the key cell type damaged in MS, a process that is accompanied by loss of the myelin sheath that these cells produce, resulting in demyelination and ultimately in secondary damage to nerve cells. Susceptibility to MS is strongly influenced by genes, and over 100 genes have now been linked with the risk of developing MS. However, surprisingly little is known about the biological mechanism by which any one of these genes increases the probability of developing MS. In this study we have explored in detail the links between one known MS risk gene, MERTK, and MS susceptibility. We found that a number of different alterations in the MERTK gene are independently associated with the risk of developing MS. One these changes was also linked with changes in the level of expression of MERTK in monocytes, an immune cell type known to be involved in the etiology of MS. In an unexpected result, we found this expression-linked alteration in MERTK was either protective or risk-associated, depending on the genotype of the individual at another well known MS risk gene known as HLA-DRB1. In addition, we found that not only were alterations in MERTK associated with MS susceptibility, but potentially with ongoing disease course, indicating that MERTK may be a good target for the development of novel MS therapeutics.

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.

Introduction Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON. Methods Thirty acute ON patients were studied at 1,3,6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further. Results Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p =

Nanodiamonds (NDs) containing silicon vacancy (SiV) defects were evaluated as a potential biomarker for the labeling and fluorescent imaging of neural precursor cells (NPCs). SiV-containing NDs were synthesized using chemical vapor deposition and silicon ion implantation. Spectrally, SiV-containing NDs exhibited extremely stable fluorescence and narrow bandwidth emission with an excellent signal to noise ratio exceeding that of NDs containing nitrogen-vacancy (NV) centers. NPCs labeled with NDs exhibited normal cell viability and proliferative properties consistent with biocompatibility. We conclude that SiVcontaining NDs are a promising biomedical research tool for cellular labeling and optical imaging in stem cell research., The paper was accepted for publication in Optics letters

Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, namedstretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included theNdrg1gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D) a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. Thestretchermutant mouse is more severely affected than mice in which theNdrg1gene had been knocked out by homologous recombination. Our results demonstrate that theNdrg1strmutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 ofNdrg1encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system.

none 50 si studio multicentrico The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or

Trans‐synaptic degeneration could exacerbate neurodegeneration in multiple sclerosis (MS). We aimed to assess whether anterograde trans‐synaptic degeneration could be identified in the primary visual pathway in vivo. Diffusion tensor imaging (DTI) was used to assess the optic radiations in 15 patients with previous optic nerve inflammation and 9 healthy volunteers. A probabilistic atlas of the optic radiations was created from healthy diffusion tractography data. Lengthwise profiles for DTI parameters (axial [λ(||)], radial [λ(⟂)] and mean diffusivity [MD], fractional anisotropy [FA] and the angle of deviation of the principal eigenvector [α]) were analyzed for patients and controls. Patients also underwent multifocal visual evoked potential (mfVEP) assessments to characterize the latency and amplitude of cortical potentials. Correlations were performed between mfVEP latency and amplitude in the left and right visual hemi‐fields and DTI parameters in the contra‐lateral optic radiations. Patients displayed a significant decrease in λ(||) within the body of both optic radiations, which significantly correlated with loss of mfVEP amplitude. Abnormal λ(⟂) and FA were detected bilaterally throughout the optic radiations in patients but the abnormality was not associated with amplitude reduction or latency prolongation of the mfVEP. An abnormal α value was observed in the left optic radiations of patients, and the α value in the body of the optic radiations also correlated with mfVEP amplitude loss. The assocation between bilateral DTI abnormalities within the optic radiations and loss of afferent electrical activity could indicate anterograde trans‐synaptic degeneration occurs following optic neuritis. Hum Brain Mapp 33:2047–2061, 2012. © 2011 Wiley Periodicals, Inc.

Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination.

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles ofAxl,Mer, andGas6mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression ofTyro3decreased, correlating with the loss of oligodendrocytes. Gas6 both promotedin vitrosurvival of oligodendrocytes (39.3 ± 3.1 vs 11.8 ± 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor α mRNA expression was reduced ∼48%). In Gas6−/−mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-π (glutathioneS-transferase-π)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6−/−mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6−/−mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.

Summary Higher sibling exposure is associated with a reduced risk of asthma and other T helper 2 (Th2)-type disorders, possibly through a beneficial effect of higher infection load. The effect on Th1 disorders such as multiple sclerosis (MS) is less clear. Here we examine the association between asthma and MS, taking into account early life sibling exposure. A population-based case–control study in Tasmania, Australia based on 136 cases of magnetic resonance imaging (MRI)-confirmed MS and 272 community controls, matched on sex and year of birth. Study measures include cumulative exposure to total, older or younger siblings by age 6 years, history of doctor-diagnosed asthma and serological IgG responses to herpes viruses. MS cases were more likely (P = 0·02) than controls to have asthma which began before age of onset of MS symptoms compared to the corresponding age for controls. The absence of younger sibling exposure by age 6 years potentiated (P = 0·04) the association between asthma and MS. Compared to those with younger sibling exposure and no asthma, the adjusted odds ratio for MS for those with asthma and no younger sibling exposure was 7·22 (95% CI: 2·52, 20·65). Early life sibling exposure was associated with altered IgG serological responses to Epstein–Barr virus (EBV) and herpes simplex virus 1 (HSV1) in adulthood. Reduced early life sibling exposure appeared to contribute to the excess of asthma among MS cases by the time of MS onset. MS development may reflect factors that relate to a general immuno-inflammatory up-regulation of immune activity as well as disease specific factors. The link between early life sibling exposure and the immune response to herpes group viral antigens is consistent with a protective role for early life infections.

Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) have both been reported to stimulate precursors in the developing CNS. To clarify these effects, we used clonal analysis to determine the lineage potential of precursors stimulated with each factor, at two stages of development. It was found that in cells isolated from the cerebrum of embryonic day 17 (E17) mice, FGF-2 stimulated both a multipotential precursor, which gave rise to neurons and astrocytes, and a committed glial precursor. In contrast, EGF only stimulated the glial restricted precursor. Thus, it appears that the multipotential cell, previously identified to be present at E10, remains selectively responsive to FGF-2, and that the EGF responsiveness observed at E17 reflects the presence of a new restricted class of precursors, rather than a switch in factor specificity of the multipotential cell.

Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB1*1501-DQB1*0602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB1*1501-DQB1*0602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.

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).