ORCID Profile
0000-0003-3999-085X
Current Organisations
Royal Melbourne Hospital
,
Florey Institute of Neuroscience and Mental Health
,
University of Melbourne
,
Royal Australasian College of Physicians
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Neurogenetics | Central Nervous System | Neurosciences | Clinical Pharmacology And Therapeutics | Medical Biochemistry and Metabolomics | Neurology And Neuromuscular Diseases | Genetics | Diagnostic Applications | Central Nervous System | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Medical Biochemistry and Metabolomics not elsewhere classified | Nanobiotechnology
ANZSRC Socio-Economic Objective (SEO)
Nervous system and disorders | Inherited diseases (incl. gene therapy) | Cardiovascular System and Diseases | Disease distribution and transmission | Nervous System and Disorders | Blood Disorders | Treatments (e.g. chemicals, antibiotics) | Diagnostic methods |
Related Links
Publications
Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Cladribine followed by autologous stem-cell transplantation in progressive multiple sclerosis
Publisher: Wiley
Date: 2004
DOI: 10.1111/J.1444-0903.2004.00516.X
Abstract: Abstract We studied the safety of autologous peripheral blood stem‐cell transplantation (PBSCT) in four patients with progressive multiple sclerosis. Clinical and magnetic resonance imaging outcomes were secondary end‐points. Cladribine administration preceded filgrastim‐primed PBSC collection, aiming for lymphocyte depletion. Conditioning was with antithymocyte globulin and cyclophosphamide. The procedure was well tolerated, but without obvious clinical benefit. The study was terminated when other therapeutic options with lower morbidity became available. (Intern Med J 2004 34: 66−69)
Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation
Publisher: Frontiers Media SA
Date: 16-06-2020
Regulation of the early development of the nervous system by growth factors
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0163-7258(94)00044-1
Abstract: Development of the nervous system, although patterned by intrinsic genetic expression, appears to be dependent on growth factors for many of the differentiation steps that generate the wide variety of neurons and glia found in the both the central and peripheral nervous system. By using in vitro assays, including clonal analysis, the precise function of the various growth factors and the differentiation potential of the various neural populations has begun to be described. This review discusses some of the recent findings and examines how neuronal differentiation may result from the interaction of several growth factors.
Role of Cytokines as Mediators and Regulators of Microglial Activity in Inflammatory Demyelination of the CNS
Publisher: Springer Science and Business Media LLC
Date: 30-03-2010
DOI: 10.1007/S12017-010-8112-Z
Abstract: As the resident innate immune cells of the central nervous system (CNS), microglia fulfil a critical role in maintaining tissue homeostasis and in directing and eliciting molecular responses to CNS damage. The human disease Multiple Sclerosis and animal models of inflammatory demyelination are characterized by a complex interplay between degenerative and regenerative processes, many of which are regulated and mediated by microglia. Cellular communication between microglia and other neural and immune cells is controlled to a large extent by the activity of cytokines. Here we review the role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination, highlighting their importance in potentiating cell damage, promoting neuroprotection and enhancing cellular repair in a context-dependent manner.
Multiple sclerosis: Cognition and saccadic eye movements
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.JNS.2008.10.001
Abstract: Ocular motor abnormalities are frequently reported in Multiple Sclerosis (MS), the most salient of which are well represented by the commonly used clinical measure, the EDSS. However, cognitive function, which is poorly represented by this scale, may also be ascertained from ocular motor measures, suggesting that an analysis of eye movements has the potential to extend and complement this more conventional measure. The generation of single and triple-step memory-guided saccades was investigated in 25 in iduals with MS and a comparable number of neurologically healthy in iduals matched for age and IQ. Experimental measures were correlated with a battery of neuropsychological tests evaluating attentional, working memory and executive processes, the cognitive domains most commonly compromised in MS. For single memory-guided saccades, MS patients were less accurate and generated more erroneous responses to non-target stimuli. Saccadic latencies were also prolonged. For triple-step memory-guided saccades, MS patients were less accurate and more variable. A number of significant correlations were revealed between measures of each of these characteristics and scores on the range of neuropsychological assessments. These ocular motor measures demonstrate considerable sensitivity with respect to evaluating cognitive function in MS, particularly working memory and inhibitory control processes. This suggests that they could represent the foundation of a user-friendly surrogate marker of disease severity and progression in MS.
Chopper, a New Death Domain of the p75 Neurotrophin Receptor That Mediates Rapid Neuronal Cell Death
Publisher: Elsevier BV
Date: 09-2000
Higher Non-processed Red Meat Consumption Is Associated With a Reduced Risk of Central Nervous System Demyelination
Publisher: Frontiers Media SA
Date: 19-02-2019
Dysequilibrium of the PTH-FGF23-vitamin D axis in relapsing remitting multiple sclerosis; a longitudinal study.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2018
A brain-derived neurotrophic factor-based p75NTRpeptide mimetic ameliorates experimental autoimmune neuritis induced axonal pathology and demyelination
Publisher: Society for Neuroscience
Date: 05-2017
DOI: 10.1523/ENEURO.0142-17.2017
Abstract: Axonal damage and demyelination are major determinants of disability in patients with peripheral demyelinating neuropathies. The neurotrophin family of growth factors are essential for the normal development and myelination of the peripheral nervous system (PNS), and as such are potential therapeutic candidates for ameliorating axonal and myelin damage. In particular, BDNF promotes peripheral nerve myelination via p75 neurotrophin receptor (p75 NTR ) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75 NTR (cyclo- d PAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75 NTR is abundantly expressed in affected peripheral nerves. We found that systemic administration of cyclo- d PAKKR ameliorates EAN disease severity and accelerates recovery. Animals treated with cyclo- d PAKKR displayed significantly better motor performance compared to control animals. Histological assessment revealed that cyclo- d PAKKR administration limits the extent of inflammatory demyelination and axonal damage, and protects against the disruption of nodal architecture in affected peripheral nerves. In contrast, a structural control peptide of cyclo- d PAKKR exerted no influence. Moreover, all the beneficial effects of cyclo- d PAKKR in EAN are abrogated in p75 NTR heterozygous mice, strongly suggesting a p75 NTR -dependent effect. Taken together, our data demonstrate that cyclo- d PAKKR ameliorates functional and pathological defects of EAN in a p75 NTR -dependant manner, suggesting that p75 NTR is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75 NTR is a strategy worthy of further investigation.
Extracellular signal‐regulated kinase 1/2 signaling promotes oligodendrocyte myelination in vitro
Publisher: Wiley
Date: 03-08-2012
DOI: 10.1111/J.1471-4159.2012.07871.X
Abstract: Multiple extracellular factors have been implicated in orchestrating myelination of the CNS however, less is known about the intracellular signaling cascades that regulate this process. We have previously shown that brain-derived neurotrophic factor (BDNF) promotes oligodendrocyte myelination. Here, we screened for the activation of candidate signaling pathways in in vitro myelination assays and found that extracellular signal-regulated kinase (Erk) signaling positively correlated with basal levels of oligodendrocyte myelination as well as BDNF-induced myelination in vitro. By selectively manipulating Erk1/2 activation in oligodendrocytes in vitro, we found that constitutive activation of Erk1/2 significantly increased myelination, mimicking the promyelinating effect of BDNF, and also caused myelination to occur earlier. Conversely, selective inhibition of Erk1/2 in oligodendrocytes significantly reduced the basal level of myelination and blocked the promyelinating effect of BDNF. Analysis of myelinating spinal cord and corpus callosum white matter tracts revealed that the majority of mature oligodendrocytes are co-labeled with phospho-Erk1/2, whereas phospho-Erk1/2 was rarely observed in oligodendrocyte progenitor cells. Finally, the total level of phospho-Erk1/2 correlated with myelin formation during the early postnatal period. Collectively, these data identify that Erk1/2 signaling within oligodendrocytes exerts an important and direct effect to promote myelination.
Persistence on Therapy and Propensity Matched Outcome Comparison of Two Subcutaneous Interferon Beta 1a Dosages for Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 21-05-2013
Vitamin D status: Multifactorial contribution of environment, genes and other factors in healthy Australian adults across a latitude gradient
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JSBMB.2013.01.011
Abstract: Vitamin D deficiency is common and implicated in risk of several human diseases. Evidence on the relative quantitative contribution of environmental, genetic and phenotypic factors to vitamin D status (assessed by the serum concentration of 25-hydroxyvitamin D, 25(OH)D) in free-living populations is sparse. We conducted a cross-sectional study of 494 Caucasian adults aged 18-61years, randomly selected from the Australian Electoral Roll according to groups defined by age, sex and region (spanning 27°-43°South). Data collected included personal characteristics, sun exposure behaviour, biomarkers of skin type and past sun exposure, serum 25(OH)D concentration and candidate single nucleotide polymorphisms. Ambient ultraviolet radiation (UVR) levels in the month six weeks before blood s ling best predicted vitamin D status. Serum 25(OH)D concentration increased by 10nmol/L as reported time in the sun doubled. Overall, 54% of the variation in serum 25(OH)D concentration could be accounted for: 36% of the variation was explained by sun exposure-related factors 14% by genetic factors (including epistasis) and 3.5% by direct measures of skin phenotype. Novel findings from this study are demonstration of gene epistasis, and quantification of the relative contribution of a wide range of environmental, constitutional and genetic factors to vitamin D status. Ambient UVR levels and time in the sun were of prime importance but it is nonetheless important to include the contribution of genetic factors when considering sun exposure effects. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Case Report: Confirmation by Metagenomic Sequencing of Visceral Leishmaniasis in an Immunosuppressed Returned Traveler
Publisher: American Society of Tropical Medicine and Hygiene
Date: 04-11-2020
Achievements and obstacles of remyelinating therapies in multiple sclerosis.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2017
DOI: 10.1038/NRNEUROL.2017.139
Abstract: 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.
An adverse lipid profile and increased levels of adiposity significantly predict clinical course after a first demyelinating event
Publisher: BMJ
Date: 20-03-2017
Abstract: To investigate the prospective associations between adiposity and lipid-related variables and conversion to multiple sclerosis (MS), time to subsequent relapse and progression in disability. A cohort of 279 participants with a first clinical diagnosis of central nervous system demyelination was prospectively followed to 5-year review. Height, weight, waist and hip circumference were measured, and serum s les taken for measurement of lipids and apolipoproteins. Survival analysis was used for conversion to MS and time to relapse, and linear regression for annualised change in disability (Expanded Disability Status Scale). Higher body mass index (BMI adjusted HR (aHR): 1.22 (1.04 to 1.44) per 5 kg/m Higher levels of adiposity, non-HDL and TC/HDL ratio were prospectively associated with a higher rate of disability progression, and higher adiposity and triglycerides were associated with relapse but not with conversion to MS. Improving the lipid profile and losing weight into the healthy range could reduce the accumulation of disability.
Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis
Publisher: SAGE Publications
Date: 14-02-2013
Abstract: Gene–environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). In iduals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92–10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79–2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59–2.59 excess risk due to interaction=3.30, 95%CI=0.47–6.12 attributable proportion due to interaction=45%, 95% CI=22–68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene–environment interactions on both a multiplicative and additive scale.
Functional activation changes at ultra-high field related to upper and lower limb impairments in multiple sclerosis
Publisher: Cold Spring Harbor Laboratory
Date: 15-08-2020
DOI: 10.1101/2020.08.13.20174664
Abstract: 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 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 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 =0.002) and more erroneous (+0.15 N, p =0.001) lower limb tracking, together with higher primary motor and premotor cortex activation, and lower cerebellar activation compared to HC. No differences were seen in upper limb performance or activation. Functional activation levels of cerebellar, visual and motor areas correlated with task performance. These results demonstrate that ultra-high field fMRI during complex hand and foot tracking can identify subtle impairments in movement and brain activity, and differentiates upper and lower limb impairments in minimally disabled pwMS.
Diffusion tensor imaging of the optic radiations after optic neuritis
Publisher: Wiley
Date: 13-09-2012
DOI: 10.1002/HBM.21343
Population attributable fractions and joint effects of key risk factors for multiple sclerosis
Publisher: SAGE Publications
Date: 21-07-2016
Abstract: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11–4.03), 4.31 (95% CI, 2.24–8.31), 7.96 (95% CI, 3.84–16.49), and 21.24 (95% CI, 5.48–82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78 p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9–91.4) of FCD onset. High anti-EBNA IgG was another important contributor. A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.
Multidisciplinary rehabilitation for adults with multiple sclerosis
Publisher: Oxford University Press (OUP)
Date: 07-2008
Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study
Publisher: BMJ
Date: 09-08-2003
High Prudent diet factor score predicts lower relapse hazard in early multiple sclerosis
Publisher: SAGE Publications
Date: 23-07-2020
Abstract: Dietary patterns and their association with subsequent clinical course have not been well studied in early multiple sclerosis (MS). To describe dietary patterns in people in 5 years following first clinical demyelination and assess associations with MS conversion and relapse. 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. 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. Prudent diet factor score above the median was prospectively associated with lower relapse risk in the 5 years following the first clinical demyelinating event.
Synergy between TGF-β3 and NT-3 to promote the survival of spiral ganglia neurones in vitro
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0304-3940(97)00928-2
Abstract: Transforming growth factor-betas (TGF-betas) have been implicated in normal inner ear development and in promoting neuronal survival. Early rat post-natal spiral ganglion cells (SGC) in dissociated cell culture were used as a model of auditory innervation to test the trophic factors TGF-beta3 and neurotrophin-3 (NT-3) for their ability, in idually or in combination, to promote neuronal survival. The findings from this study suggest that TGF-beta3 supports neuronal survival in a concentration-dependent manner. Moreover TGF-beta3 and NT-3-potentiated spiral ganglion neuronal survival in a synergistic fashion.
Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JOCN.2014.01.018
Abstract: In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.
Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels
Publisher: Springer Science and Business Media LLC
Date: 03-01-2013
DOI: 10.1038/MP.2011.168
Abstract: The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.
Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 3 Treatment practicalities and recommendations
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JOCN.2014.01.017
Abstract: In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence in idual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing in idual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.
Sex as a determinant of relapse incidence and progressive course of multiple sclerosis
Publisher: Oxford University Press (OUP)
Date: 18-10-2013
DOI: 10.1093/BRAIN/AWT281
Abstract: 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 <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.
Optic nerve diffusion changes and atrophy jointly predict visual dysfunction after optic neuritis
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.NEUROIMAGE.2008.12.047
Abstract: Recently, there has been strong interest in the development of imaging techniques to quantify axonal and myelin pathology in patients with multiple sclerosis (MS). Optic neuritis, a condition characterised by inflammatory demyelination of the optic nerve, is one of the commonest sites of MS relapse, and exhibits similar pathological alterations to MS lesions elsewhere in the central nervous system (CNS). Unlike other regions of the CNS, however, the function of the optic nerve can be accurately assessed using clinical measures, as well as electrophysiological techniques such as visual evoked potential recordings. Therefore, optic neuritis is useful for investigating the relationship between abnormalities in optic nerve structure, assessed using magnetic resonance imaging (MRI), and visual dysfunction, assessed clinically and electrophysiologically. The aims of the present study were to assess optic nerve structural abnormalities in patients with a history of unilateral optic neuritis using MRI, and then to identify correlations between abnormalities in optic nerve MRI and visual dysfunction. Ten controls and sixteen patients underwent high resolution optic nerve diffusion tensor imaging (DTI), T2- and T1-weighted MRI. In addition, Snellen visual acuity and the latency and litude of multifocal visual evoked potentials (mfVEP) were tested in all patients. Diffusion and volumetric MRI indices were correlated to mfVEP functional indices. Significant abnormalities were detected in MRI and mfVEP measures in patients' affected nerves compared to unaffected optic nerves or optic nerves from healthy controls. Reduced mfVEP litude in the affected side significantly correlated with both affected optic nerve atrophy (R=0.58, p=0.02) and reduced fractional anisotropy (FA) (R=0.52, p=0.04). However, atrophy and reduced FA did not correlate with each other. To further investigate this disassociation, we used linear regression analysis with optic nerve atrophy and optic nerve FA as independent variables and mfVEP litude as the dependent variable. The resulting linear regression model was highly significant (R=0.819, p=0.001). These results show that, 4 years after unilateral optic neuritis, MRI-based measures of optic nerve structural abnormalities (decreased anisotropy and volume) independently predict visual dysfunction.
Growth factors: Potential therapeutic applications in neurology
Publisher: BMJ
Date: 12-1994
Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.JOCN.2014.01.016
Abstract: Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using in idual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.
The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
Publisher: Oxford University Press (OUP)
Date: 27-02-2010
DOI: 10.1093/HMG/DDQ090
Abstract: Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these s les. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40 the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
Lineage specification of neuronal precursors in the mouse spinal cord.
Publisher: Proceedings of the National Academy of Sciences
Date: 24-10-1995
Abstract: We have investigated the differentiation potential of precursor cells within the developing spinal cord of mice and have shown that spinal cord cells from embryonic day 10 specifically give rise to neurons when plated onto an astrocytic monolayer, Ast-1. These neurons had the morphology of motor neurons and 83% expressed the motor neuron markers choline acetyltransferase, peripherin, calcitonin gene-related peptide, and L-14. By comparison, 10% of the neurons arising on monolayers of other neural cell lines or 3T3 fibroblasts had motor neuron characteristics. Cells derived from dorsal, intermediate, and ventral regions of the spinal cord all behaved similarly and gave rise to motor neuron-like cells when plated onto Ast-1. By using cells that expressed the lacZ reporter gene, it was shown that 93% of cells present on the Ast-1 monolayers were motor neuron-like. Time-lapse analysis revealed that the precursors on the Ast-1 monolayers gave rise to neurons either directly or following a single cell ision. Together, these results indicate that precursors in the murine spinal cord can be induced to differentiate into the motor neuron phenotype by factors produced by Ast-1 cells, suggesting that a similar factor(s) produced by cells akin to Ast-1 may regulate motor neuron differentiation in vivo.
Onset Symptoms, Tobacco Smoking, and Progressive-Onset Phenotype Are Associated With a Delayed Onset of Multiple Sclerosis, and Marijuana Use With an Earlier Onset
Publisher: Frontiers Media SA
Date: 08-06-2018
Multiple Sclerosis as a Syndrome—Implications for Future Management
Publisher: Frontiers Media SA
Date: 28-08-2020
Antisaccade performance in patients with multiple sclerosis
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.CORTEX.2009.02.016
Abstract: Commonly used measures of disability in patients with Multiple sclerosis (MS) inadequately reflect disease severity and progression. Further, cognitive deficits experienced by up to 70% of patients, are poorly represented by these measures. Saccadic eye movements may provide a powerful tool for the analysis of cognitive changes in MS, providing a surrogate measure of performance that extends more conventional measures. The cognitive control of eye movements has not previously been investigated in patients with MS. We studied antisaccade (AS) performance in 25 patients with MS and compared the results with 25 age matched healthy controls, to evaluate the resolution of response conflict between volitional and automatic processes. Experimental measures were also correlated with a battery of neuropsychological tests evaluating attention, working memory and executive processes, the most commonly reported cognitive deficits in MS. Compared to controls, patients with MS generated significantly more prosaccade errors, and AS latencies were prolonged and more variable. Error rates correlated significantly with scores on the commonly used PASAT. MS patients also exhibited poor spatial accuracy, with mean absolute error significantly larger and more variable than control subjects. The sensitivity of this task in dissociating function in MS, as well as clear correlation with a key measure of cognition, suggests that eye movements, may provide a surrogate measure of cognitive function in MS, with the potential to sensitively assess disease severity and progression.
Serial Diffusion Tensor Imaging of the Optic Radiations after Acute Optic Neuritis
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/2764538
Abstract: 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 litude, 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.
Neuroglial responses to CNS injury: prospects for novel therapeutics.
Publisher: Informa UK Limited
Date: 09-2004
Abstract: Immune-mediated therapies can reduce the relapse rate in multiple sclerosis. However, there is no clear-cut evidence that any of these therapies substantially alter the long-term outcome for patients with progressive multiple sclerosis. The neurological disability that all too frequently accompanies multiple sclerosis is ultimately due to injury to target cells, principally oligodendroglia, within the nervous system. Recent data suggest that activation of leukemia inhibitory factor-receptor signaling is an important component of a neurobiological response that serves to limit the extent of immune-mediated injury. Therefore, inactivation of this pathway could provide a novel approach to the treatment of demyelinating disease.
Neurotrophin receptor homolog‐2 regulates nerve growth factor signaling
Publisher: Wiley
Date: 08-2008
DOI: 10.1111/J.1471-4159.2008.05539.X
Abstract: The neurotrophin receptor homolog (NRH2) is closely related to the p75 neurotrophin receptor (p75NTR) however, its function and role in neurotrophin signaling are unclear. NRH2 does not bind to nerve growth factor (NGF), however, is able to form a receptor complex with tropomyosin-related kinase receptor A (TrkA) and to generate high-affinity NGF binding sites. Despite this, the mechanisms underpinning the interaction between NRH2 and TrkA remain unknown. Here, we identify that the intracellular domain of NRH2 is required to form an association with TrkA. Our data suggest extensive intracellular interaction between NRH2 and TrkA, as either the juxtamembrane or death domain regions of NRH2 are sufficient for interaction with TrkA. In addition, we demonstrate that TrkA signaling is dramatically influenced by the co-expression of NRH2. Importantly, NRH2 did not influence all downstream TrkA signaling pathways, but rather exerted a specific effect, enhancing src homology 2 domain-containing transforming protein (Shc) activation. Moreover, downstream of Shc, the co-expression of NRH2 resulted in TrkA specifically modulating mitogen-activated protein kinase pathway activation, but not the phosphatidylinositol 3-kinase/Akt pathway. These results indicate that NRH2 utilizes intracellular mechanisms to not only regulate NGF binding to TrkA, but also specifically modulate TrkA receptor signaling, thus adding further layers of complexity and specificity to neurotrophin signaling.
Neural transplantation for Parkinson's disease: a critical appraisal.
Publisher: Wiley
Date: 08-1991
DOI: 10.1111/J.1445-5994.1991.TB01357.X
Abstract: The medical treatment of severe Parkinson's disease is presently problematical and neural transplantation has been proposed as an additional therapy. While functional improvement in animal models of Parkinson's disease has been reported following neural grafting, the treatment of human Parkinsonian patients by adrenal medulla autografting into the neostriatum has produced little clinical improvement overall, and is associated with significant morbidity. Although recent grafting of human foetal dopaminergic neurons has shown more promise, many of the case reports lack rigorous assessment and long term follow-up. Further laboratory experimentation in animal models, particularly primates, to ascertain the mechanism of action of the grafts, the optimal sites for grafting, and the immunological responses to grafting, is essential. The future success of neural transplantation for Parkinson's disease may depend on the development of novel strategies such as the use of growth factors to aid cell survival, regulate neurotransmitter levels and promote connectivity. However, at present, the clinical application of neural transplantation for Parkinson's disease is premature.
Molecular mechanisms regulating motor neuron development and degeneration
Publisher: Elsevier
Date: 2004
Neurotrophin receptor expression and responsiveness by postnatal cerebral oligodendroglia
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2001
DOI: 10.1097/00001756-200112210-00044
Abstract: The low affinity neurotrophin receptor (p75(NTR)) is implicated in promoting oligodendrocytic death after nerve growth factor (NGF) stimulation but NGF and neurotrophin-3 (NT-3) can also potentiate oligodendrocytic survival. We show regional variability in p75(NTR) expression within the central nervous system of the postnatal rat expression is readily detectable by immunohistochemistry upon a subset of CNPase-positive oligodendroglia in optic nerve but not within the cerebrum. Nevertheless, oligodendroglia isolated from the cerebrum and cultured for 16 hours express p75(NTR) as well as the trkC but not the TrkA gene. Viability was not, however, influenced by exposure to either NGF or NT-3. Cells overexpressing p75(NTR) remained unresponsive to NGF but exhibited potentiated survival with NT-3, correlating with the differential expression profile of their high affinity receptors.
Method for optic nerve intensity characterization in mice from Mn2+ enhanced MR images
Publisher: SPIE
Date: 26-02-2009
DOI: 10.1117/12.813351
The differentiation and survival of murine neurons in vitro is promoted by soluble factors produced by an astrocytic cell line
Publisher: Wiley
Date: 06-1993
Abstract: The influence of accessory cells on the generation of neurons and neuronal survival has been studied in vitro using an immortalised, cloned cell line, Ast-1, which has many of the functional and phenotypic characteristics of cells of the astrocytic lineage. It was found that monolayers of Ast-1 cells were equivalent to monolayers of primary astrocytes in their ability to promote the generation of neurofilament positive neurons from neuroepithelial cells obtained from embryonic day 10 (E10) mice and both were superior to NIH 3T3 cells. Ast-1 cell monolayers were also found to provide a suitable substrate for the prolonged survival (at least 3 days in vitro) of neurofilament positive neurons obtained from E17 mice, whereas neurons plated onto NIH 3T3 cells were all dead after 2 days. Medium conditioned by Ast-1 cells displayed similar biological activities to that of the monolayers: it increased the number of neurons generated from the E10 neuroepithelial cells, whether they were plated directly onto glass coverslips or onto monolayers of NIH 3T3 cells and it increased the survival of E17 neurons plated directly onto glass coverslips. In addition, the Ast-1 conditioned medium was shown to promote the survival of the neuroepithelial cells. These results confirm that one of the mechanisms by which astrocytes or their precursors may regulate neuronal development is by secreting soluble growth factors, as has been previously documented in the case of fibroblast growth factor (FGF) (Hatten et al., 1988 Drago et al., 1991a). However, it appears in this system that FGF is not responsible for the demonstrated biological activities, and the Ast-1 action appears to be mediated by putatively novel factor(s).
A role for galanin in human and experimental inflammatory demyelination
Publisher: Proceedings of the National Academy of Sciences
Date: 08-09-2009
Abstract: The neuropeptide galanin is widely expressed by many differing subsets of neurons in the nervous system. There is a marked upregulation in the levels of the peptide in a variety of nerve injury models and in the basal forebrain of humans with Alzheimer's disease. Here we demonstrate that galanin expression is specifically and markedly upregulated in microglia both in multiple sclerosis (MS) lesions and shadow plaques. Galanin expression is also upregulated in the experimental autoimmune encephalomyelitis (EAE) model of MS, although solely in oligodendrocytes. To study whether the observed increase in expression of galanin in inflammatory demyelination might modulate disease activity, we applied the EAE model to a panel of galanin transgenic lines. Over-expression of galanin in transgenic mice (Gal-OE) abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or galanin receptor-2 (GalR2) increase disease severity. The pronounced effects of altered endogenous galanin or GalR2 expression on EAE disease activity may reflect a direct neuroprotective effect of the neuropeptide via activation of GalR2, similar to that previously described in a number of neuronal injury paradigms. Irrespective of the mechanism(s) by which galanin alters EAE disease activity, our findings imply that galanin/GalR2 agonists may have future therapeutic implications for MS.
A Functional and Neuropathological Testing Paradigm Reveals New Disability-Based Parameters and Histological Features for P0180–190-Induced Experimental Autoimmune Neuritis in C57BL/6 Mice
Publisher: Oxford University Press (OUP)
Date: 12-01-2017
DOI: 10.1093/JNEN/NLW110
Abstract: We assessed novel disability-based parameters and neuropathological features of the P0180-190 peptide-induced model of experimental autoimmune neuritis (EAN) in C57BL/6 mice. We show that functional assessments such as running capacity provide a more sensitive method for detecting alterations in disease severity than a classical clinical scoring paradigm. We performed detailed ultrastructural analysis and show for the first time that tomaculous neuropathy is a neuropathological feature of this disease model. In addition, we demonstrate that ultrastructural assessments of myelin pathology are sufficiently sensitive to detect significant differences in both mean G-ratio and mean axon diameter between mice with EAN induced with different doses of pertussis toxin. In summary, we have established a comprehensive assessment paradigm for discriminating variations in disease severity and the extent of myelin pathology in this model. Our findings indicate that this model is a powerful tool to study the pathogenesis of human peripheral demyelinating neuropathies and that this assessment paradigm could be used to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritides.
The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude
Publisher: SAGE Publications
Date: 20-12-2011
Abstract: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) statusfor the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude ( p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change ( p 0.001). The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.
Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2-independent pathway.
Publisher: Society for Neuroscience
Date: 15-06-1999
DOI: 10.1523/JNEUROSCI.19-12-04828.1999
Abstract: Apoptosis is involved in the regulation of Schwann cell numbers during normal development and after axonal damage, but the molecular regulation of Schwann cell death remains unknown. We have used stably transfected rat Schwann cell lines to study the potential roles of nerve growth factor (NGF), the antiapoptotic protein Bcl-2 and the cytokine response modifier A (CrmA) in modulating Schwann cell death in vitro . Bcl-2 inhibited Schwann cell apoptosis induced by survival factor withdrawal, whereas CrmA did not. In contrast, Bcl-2-transfected Schwann cells were susceptible to apoptosis in response to exogenous NGF, whereas CrmA-expressing cell lines were resistant. Demonstration of high levels of the low-affinity neurotrophin receptor p75 but not the high-affinity TrkA receptor on the Bcl-2-transfected cell lines suggested that the NGF-induced killing was mediated by p75. This was confirmed by resistance of Schwann cells isolated from p75 knockout mice to the NGF-induced cell death. Nerve growth factor also promoted the death of wild-type mouse and rat Schwann cells in the absence of survival factor withdrawal. Endogenous Bcl-2 mRNA was expressed by wild-type Schwann cells in all conditions that promoted survival but was downregulated to undetectable levels after survival factor withdrawal. In conclusion, our results demonstrate the existence of two separate pathways that expedite apoptosis in Schwann cells: a Bcl-2-blockable pathway initiated on loss of trophic support, and a Bcl-2-independent, CrmA-blockable pathway mediated via the p75 receptor.
The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells
Publisher: Oxford University Press (OUP)
Date: 08-04-2031
DOI: 10.1093/HMG/DDT529
Abstract: Genome-wide association studies have identified a linkage disequilibrium (LD) block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyzes the conversion of 25 vitamin D3 (VitD3) to 1,25VitD3. Fine-mapping analysis has failed to identify which of the 17 genes in this block is most associated with MS. We have previously used a functional approach to identify the causal gene. We showed that the expression of several genes in this block in whole blood is highly associated with the MS risk allele, but not CYP27B1. Here, we show that CYP27B1 is predominantly expressed in dendritic cells (DCs). Its expression in these cells is necessary for their response to VitD, which is known to upregulate pathways involved in generating a tolerogenic DC phenotype. Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by the genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolizes 1,25 VitD3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced VitD pathway gene upregulation in DC2s of carriers of the risk haplotype of CYP27B1 contributes to autoimmune diseases. These data support therapeutic approaches aimed at targeting VitD effects on DCs.
Diffusion tensor imaging correlates of visual impairment in multiple sclerosis and chronic optic neuritis
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 21-02-2012
DOI: 10.1167/IOVS.11-8864
Abstract: To compare white matter (WM) injuries associated with vision loss in multiple sclerosis (MS) and optic neuritis (ON). Twenty-three patients with clinically definite relapsing-remitting MS and chronic unilateral ON and 14 neurologically healthy volunteers were monocularly tested with Sloan 100%, 2.5%, and 1.25% contrast visual acuity charts. Primary visual pathway and whole-brain WM injury were assessed with optical coherence tomography (OCT) and diffusion tensor imaging (DTI). OCT and DTI correlates of high- and low-contrast visual impairment were identified using correlation analyses. The MS patients displayed significantly reduced retinal nerve fiber layer (RNFL) thickness and altered optic nerve and radiation DTI measures compared with the controls. In the patients, 2.5% and 1.25% contrast letter acuity in the unaffected eye correlated significantly and independently with optic nerve and optic radiation DTI measures. Visual acuity in affected eyes did not correlate with optic nerve or optic radiation DTI measures, but did correlate with DTI measures in prefrontal and temporal brain regions that were shown to connect structurally to visual cortices. In unaffected eyes, visual impairment was associated with WM injury in the visual pathway. In contrast, irrecoverable visual impairment after ON was associated with injury to frontal WM, which potentially impairs the capacity for remapping visual processing.
The role of latitude, ultraviolet radiation exposure and vitamin D in childhood asthma and hayfever: an Australian multicenter study
Publisher: Wiley
Date: 30-09-2011
DOI: 10.1111/J.1399-3038.2010.01099.X
Abstract: Observations of increasing allergy prevalence with decreasing distance from the Equator and positive associations with ambient ultraviolet radiation have contributed to a growing interest in the possible role of vitamin D in the etiology of allergy. The aims of this study were to describe any latitudinal variation in the prevalence of childhood allergy in Australia and to evaluate, in parallel, the in idual associations between ultraviolet radiation (UVR)- and vitamin D-related measures and hayfever asthma and both conditions. Participants were population-based controls who took part in a multicenter case-control study, aged 18-61 yr and resident in one of four study regions ranging in latitude from 27°S to 43°S. Data were derived from a self-administered questionnaire, interview and examination by a research officer and biologic s ling. Latitude and longitude coordinates were geocoded from participants' residential locations and climatic data were linked to postcodes of current residence. Stored serum was analyzed for 25-hydroxyvitamin D concentrations and silicone rubber casts of the skin were used as an objective measure of cumulative actinic damage. There was an inverse latitude gradient for asthma (a 9% decrease per increasing degree of latitude) however, this pattern did not persist after adjusting for average daily temperature. There was no association between any of the UVR- or vitamin D-related measures and childhood asthma, but greater time in the sun in winter between the ages 6-15 yr was associated with an increase in the odds of having hayfever [adjusted odds ratios (OR) 1.29 95% CI 1.01-1.63]. Oral supplementation with cod liver oil in childhood increased the odds of a history of having both asthma and hayfever (2.87 1.00-8.32). Further investigation of the possible role of early vitamin D supplementation in the development of allergy is warranted. Our results also suggest that solar exposure during childhood may be important in allergic sensitization. Plausible explanations, including biologic mechanisms, exist for both observations.
The regulation of neural precursor cells within the mammalian brain
Publisher: Elsevier BV
Date: 02-1995
Optic nerve diffusion tensor imaging after acute optic neuritis predicts axonal and visual outcomes
Publisher: Public Library of Science (PLoS)
Date: 26-12-2013
The clinical profile of NMOSD in Australia and New Zealand
Publisher: Springer Science and Business Media LLC
Date: 31-01-2020
LIF receptor signaling modulates neural stem cell renewal
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.MCN.2004.07.004
Abstract: Activation of the leukemia inhibitory factor (LIF) receptor has been reported to promote gliogenesis and also to support neural stem cell (NSC) renewal. To investigate this paradox, we isolated NSCs and generated neurospheres from embryonic mice either wild-type, heterozygous, or homozygous null for LIF receptor (LIFR)-beta. Exogenous LIF abrogated neurosphere formation and promoted expression of GFAP by all cells in wild-type and heterozygous cultures. LIF also stimulated a twofold increase in the number of multipotential clones generated from these cultures in comparison with those pretreated with EGF and FGF-2 (E+F) alone. In contrast, the clonogenicity of low-density cultures of LIFR knockout cells was reduced in comparison with that of wild-type cells grown in E+F and was unaffected by LIF. Thus, although LIFR signaling is not necessary for NSC self-renewal, it enhances both the clonogenicity and the expression of GFAP by these multipotential cells.
Leukemia Inhibitory Factor Is an Autocrine Survival Factor for Schwann Cells
Publisher: Wiley
Date: 07-1999
DOI: 10.1046/J.1471-4159.1999.0730096.X
Abstract: Schwann cells play a major role in promoting nerve survival and regeneration after injury. Their activities include providing neurotrophic factors and increasing the production of extracellular matrix components and cell surface adhesion molecules to promote axon regeneration. Following nerve transection, leukemia inhibitory factor (LIF) is up-regulated by Schwann cells at the injury site. LIF receptors are also up-regulated at the nerve injury site, but their cellular localization and function have not been fully characterized. We demonstrate that Schwann cells express mRNAs for LIF and the LIF receptor components LIF receptor subunit beta and glycoprotein 130 in vitro. We also show that although LIF is not required for the genesis of Schwann cells, it can potentiate the survival of differentiated Schwann cells in the context of neuregulin support. Not only does exogenous LIF promote survival under these conditions, but addition of the soluble LIF receptor (LIF binding protein) and anti-LIF antibodies significantly reduced cell survival, suggesting that LIF exerts autocrine effects. These results suggest that Schwann cell survival following nerve injury is potentially modulated by LIF.
Sun exposure and vitamin D are independent risk factors for CNS demyelination
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-02-2011
Inhibitory saccadic dysfunction is associated with cerebellar injury in multiple sclerosis
Publisher: Wiley
Date: 03-09-2014
DOI: 10.1002/HBM.22329
Multiple sclerosis: disability profile and quality of life in an Australian community cohort
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2006
Multiple Sclerosis Severity Score: Using disability and disease duration to rate disease severity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-04-2005
Schwann cell apoptosis in the postnatal axotomized sciatic nerve is mediated via NGF through the low-affinity neurotrophin receptor.
Publisher: Oxford University Press (OUP)
Date: 04-2003
Abstract: Schwann cell death is a developmentally regulated phenomenon and is also induced after peripheral nerve axotomy in neonatal rodents. In this study, we explored whether ligand-induced activation of the low-affinity neurotrophin receptor (p75(NTR)) is responsible for inducing Schwann cell death in vivo. Administration of exogenous nerve growth factor (NGF) to the axotomized nerve site in wild-type animals resulted in a 2.6-fold increase in Schwann cell apoptosis in the distal nerve stumps compared to axotomy alone. No increase in apoptosis, above baseline levels, was seen in p75(NTR)-mutant mice either with or without NGF When anti-NGF antibodies were administered to the site of the peripheral nerve lesion in wild-type mice there was a reduction in the percentage of Schwann cell apoptosis to levels seen in both the quiescent state and in the axotomized nerves of the p75(NTR)-mutant mice. These results demonstrate that apoptosis of Schwann cells in axotomized peripheral nerve is mediated predominantly through p75(NTR) signaling and initiated via endogenously produced NGF.
Higher intake of omega-3 polyunsaturated fatty acids is associated with a decreased risk of a first clinical diagnosis of central nervous system demyelination: Results from the Ausimmune Study
Publisher: SAGE Publications
Date: 11-09-2016
Abstract: There is contradictory evidence for a role of dietary fat in risk of multiple sclerosis (MS). To examine the association between usual fat intake (total, saturated, monounsaturated (MUFA), polyunsaturated (PUFA), omega-3 and omega-6) and risk of a first clinical diagnosis of CNS demyelination (FCD). Multi-centre incident case-control study in four regions of Australia during 2003–2006. Cases were aged 18–59 years and had a FCD controls were matched to a case on age, sex and location. Dietary data were collected using a validated food frequency questionnaire. In 267 cases and 517 controls with dietary data, higher intake (per g/day) of omega-3 PUFA (adjusted odds ratio, AOR=0.61 (95% CI 0.40–0.93)), and particularly that derived from fish (AOR=0.54 (95% CI 0.31–0.93)) rather than from plants (AOR=0.75 (95% CI 0.39–1.43)) was associated with a decreased risk of FCD. Total fat intake and intake of other types of fat were not associated with FCD risk. There was a significant decrease in FCD risk with higher intake of omega-3 PUFA, particularly that originating from fish. There was no evidence to indicate that the intake of other types of dietary fat or fat quantity in the previous 12 months was associated with an altered risk of FCD.
Pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases.
Publisher: Wiley
Date: 09-2000
DOI: 10.1034/J.1600-0560.2000.027008381.X
Abstract: Invasive pigmented squamous cell carcinoma (PSCC) of the skin is reportedly rare. Herein, we evaluate an additional five cases and compare their relative frequency with non-pigmented squamous cell carcinoma (SCC). Of 46,791 archived cases of SCC, a total of five cases of PSCC were discovered for a relative frequency of approximately 0.01%. Grossly, each tumor presented as a rapidly growing crusted papule on actinic damaged skin of the face. Microscopically, all were composed of a mixture of keratininized squamous cells and melanin-producing dendritic melanocytes. The squamous cells stained for epithelial membrane antigen, and both low and high molecular keratins. The melanocytes stained for S-100 and HMB-45. A matched series of 31 SCCs were subjected to an identical immunohistochemical battery of stains to determine if a histologically subtle and unsuspected number of intratumoral melanocytes existed in SCC. Each of the cases failed to show intratumoral melanocytes. The differential diagnosis and possible histogenesis of PSCC is discussed and the importance of extensive pathologic examination to prevent misdiagnosis is emphasized. Despite the histologic dissimilarity, the long-term prognosis of the reported cases was similar to conventional SCC.
Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice
Publisher: Wiley
Date: 30-08-2004
DOI: 10.1002/JNR.20256
Abstract: Neurotrophin level imbalances and altered p75 neurotrophin receptor (p75(NTR)) expression are implicated in spinal motor neuron degeneration in human and mouse models of amyotrophic lateral sclerosis (ALS). Recently, elevated reactive astrocyte-derived nerve growth factor (NGF) was linked to p75(NTR)-expressing motor neuron death in adult transgenic ALS mice. To test the role of NGF-dependent p75(NTR)-mediated signalling in ALS, we examined the effects of a cyclic decapeptide antagonist of p75(NTR) ligand binding by using neurotrophin-stimulated cell death assays and transgenic ALS mice. Murine motor neuron-like (NSC-34) cell cultures expressed full-length and truncated p75(NTR), tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog-2 (NHR2) but were TrkA deficient. Accordingly, treatment of cells with NGF induced dose-dependent cell death, which was significantly blocked by the cyclic decapeptide p75(NTR) antagonist. Application of brain-derived neurotrophic factor, neurotrophin-3, or neurotrophin-4 to cultures increased cell proliferation, and such trophic effects were abolished by pretreatment with the tyrosine kinase inhibitor K-252a. Systemic administration of a modified cyclic decapeptide p75(NTR) antagonist conjugated to the TAT4 cell permeabilization sequence to presymptomatic transgenic SOD1(G93A) mice affected neither disease onset nor disease progression, as determined by hindlimb locomotor, grip strength, and survival analyses. These studies suggest that disrupting NGF-p75(NTR) interactions by using this approach is insufficient to alter the disease course in transgenic ALS mice. Thus, alternate ligand-independent pathways of p75(NTR) activation or additional NGF receptor targets may contribute to motor neuron degeneration in ALS mice.
Occupational Exposure and Risk of Central Nervous System Demyelination
Publisher: Oxford University Press (OUP)
Date: 12-04-2013
DOI: 10.1093/AJE/KWS361
Abstract: Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003-2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25 also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered.
An Experimental Investigation of White Matter Venous Hemodynamics: Basic Physiology and Disruption in Neuroinflammatory Disease
Publisher: Frontiers Media SA
Date: 02-06-2020
Higher fish consumption and lower risk of central nervous system demyelination
Publisher: Springer Science and Business Media LLC
Date: 08-08-2020
DOI: 10.1038/S41430-019-0476-Z
Abstract: 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. 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. 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). 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.
Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41467-017-02719-2
Abstract: 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 in idual 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 in idual 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.
A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis
Publisher: Oxford University Press (OUP)
Date: 17-07-2015
DOI: 10.1093/HMG/DDV278
Abstract: Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.
Stressful life events and the risk of initial central nervous system demyelination
Publisher: SAGE Publications
Date: 06-09-2016
Abstract: There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis. To examine the association between stressful life events and risk of first demyelinating event (FDE). 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. 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. 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.
Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
Publisher: Public Library of Science (PLoS)
Date: 18-03-2016
The physical anthropometry, lifestyle habits and blood pressure of people presenting with a first clinical demyelinating event compared to controls: The Ausimmune study
Publisher: SAGE Publications
Date: 13-05-2013
Abstract: Lifestyle factors prior to a first clinical demyelinating event (FCD), a disorder often preceding the development of clinically definite multiple sclerosis (MS), have not previously been examined in detail. Past tobacco smoking has been consistently associated with MS. This was a multicentre incident case-control study. Cases ( n = 282) were aged 18–59 years with an FCD and resident within one of four Australian centres (from latitudes 27°S to 43°S), from 1 November 2003 to 31 December 2006. Controls ( n = 558) were matched to cases on age, sex and study region, without CNS demyelination. Exposures measured included current and past tobacco and marijuana, alcohol and beverage use, physical activity patterns, blood pressure and physical anthropometry. A history of smoking ever was associated with FCD risk (AOR 1.89 (95%CL 1.82, 3.52)). Marijuana use was not associated with FCD risk after adjusting for confounders such as smoking ever but the estimates were imprecise because of a low prevalence of use. Alcohol consumption was common and not associated with FCD risk. No case-control differences in blood pressure or physical anthropometry were observed. Past tobacco smoking was positively associated with a risk of FCD but most other lifestyle factors were not. Prevention efforts against type 2 diabetes and cardiovascular disease by increasing physical activity and reducing obesity are unlikely to alter MS incidence, and more targeted c aigns will be required.
Oligodendrocytes exhibit selective expression of suppressor of cytokine signaling genes and signal transducer and activator of transcription 1 independent inhibition of interferon-gamma-induced toxicity in response to leukemia inhibitory factor
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.NEUROSCIENCE.2005.09.022
Abstract: Multiple sclerosis is an autoimmune disease of the CNS that results in the death of oligodendrocytes, the myelinating cells of the CNS. Previous studies have indicated that the cytokine leukemia inhibitory factor prevents the cytotoxic effects of interferon-gamma on oligodendrocytes in vitro, and the death of oligodendrocytes in an animal model of multiple sclerosis. Members of a recently characterized family of proteins, the suppressors of cytokine signaling, have been demonstrated to mediate negative cross-talk between cytokines, with induction of suppressors of cytokine signaling proteins by one cytokine inhibiting the activity of a second. Here, we assess whether induction of members of the suppressors of cytokine signaling family could explain the antagonistic biological effects of leukemia inhibitory factor and interferon-gamma upon oligodendrocytes. It is found that leukemia inhibitory factor rapidly and strongly induces the expression of suppressors of cytokine signaling-3 in cultured rat oligodendrocytes, whereas interferon-gamma weakly induces the expression of both suppressor of cytokine signaling-1 and 3. Pre-treatment of oligodendrocytes with leukemia inhibitory factor does not prevent the subsequent phosphorylation of signal transducer and activator of transcription-1 by interferon-gamma indicating that the leukemia inhibitory factor inhibition of interferon-gamma toxicity in oligodendrocytes is mediated by a suppressor of cytokine signaling-3 independent mechanism.
EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract
Publisher: Proceedings of the National Academy of Sciences
Date: 27-10-1998
Abstract: Members of the Eph family of tyrosine kinase receptors have been implicated in the regulation of developmental processes and, in particular, axon guidance in the developing nervous system. The function of the EphA4 (Sek1) receptor was explored through creation of a null mutant mouse. Mice with a null mutation in the EphA4 gene are viable and fertile but have a gross motor dysfunction, which is evidenced by a loss of coordination of limb movement and a resultant hopping, kangaroo-like gait. Consistent with the observed phenotype, anatomical studies and anterograde tracing experiments reveal major disruptions of the corticospinal tract within the medulla and spinal cord in the null mutant animals. These results demonstrate a critical role for EphA4 in establishing the corticospinal projection.
Treatment of experimental autoimmune encephalomyelitis with antisense oligonucleotides against the low affinity neurotrophin receptor
Publisher: Wiley
Date: 15-03-2000
DOI: 10.1002/(SICI)1097-4547(20000315)59:6<712::AID-JNR3>3.0.CO;2-L
A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-10-2011
Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis
Publisher: MDPI AG
Date: 22-10-2012
Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (−597 G A and −174 G C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (−572 G C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different −597 or −174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of in iduals with MS who carried a C allele at position −572, although this was not significant after correction for multiple comparisons. Interestingly, however, the −572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression.
Diffusion tensor imaging of acute inflammatory lesion evolution in multiple sclerosis
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.JOCN.2012.03.022
Abstract: The initiating events in multiple sclerosis (MS) plaque formation are poorly understood. Retrospective analysis of serial imaging data can improve the understanding of tissue changes characterising acute MS lesion evolution. This study aimed to assess lesion evolution using diffusion tensor imaging data from serially acquired scans from 22 patients with MS. Mean diffusivity (MD) and fractional anisotropy (FA) were measured from 13 suitable plaques from five patients and carefully matched regions of contralateral normal-appearing white matter. Measurement times were on average: 5 months and 1 month prior to, during, and 1 month and 2 months post gadolinium-enhancement. A significant increase in MD (7.25%) but no change in FA was observed in white matter areas that exhibited enhancement 5 months later. The pre-lesional MD increase was significantly correlated with the MD increase 2 months subsequent to enhancement (R=0.73, p=0.04) but not to the MD increase during enhancement (R=0.11). These results suggest that MD is sensitive to tissue changes that precede blood-brain barrier (BBB) breakdown by at least 5 months and that MD assessments may predict injury following BBB restoration.
Increased proliferation of precursor cells in the adult rat brain after targeted lesioning
Publisher: Elsevier BV
Date: 12-1996
DOI: 10.1016/S0006-8993(96)00979-1
Abstract: There have been a number of reports on the proliferation of a subset of precursor cells in the subventricular zone of the lateral ventricles in the adult mammalian brain. Here we report on studies that sought to ascertain whether these cells could respond to a targeted lesion of the adult brain by increasing their proliferative rate. We have lesioned the fimbria fornix, a major pathway of septal cholinergic fibers. Previous reports demonstrated that such a lesion results in the loss of neurons in both the basal forebrain and in the CA1 field of hippoc us, without direct injury to either tissue. Ten days after making such a lesion in adult rats, the animals were given serial injections of [3H]thymidine and sacrificed after a final injection. The brains were processed for both immunocytochemistry and autoradiography. Our data demonstrate a two-fold increase over the basal proliferative rate in animals that had received such a lesion. We used a panel of antibodies to ascertain the identity of the proliferating cells. The only clearly identifiable cells that were [3H]thymidine-positive were astrocytes, based on GFAP staining. The remainder of the cells were of a null phenotype.
A small peptide mimetic of brain‐derived neurotrophic factor promotes peripheral myelination
Publisher: Wiley
Date: 24-02-2013
DOI: 10.1111/JNC.12168
Abstract: The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination in vitro - promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo-dPAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo-dPAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo-dPAKKR promoted myelination of nerve growth factor-dependent neurons in vitro, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo-dPAKKR also significantly promoted the myelination of tropomyosin-related kinase receptor B-expressing neurons in vitro, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons in vitro, cyclo-dPAKKR uniformly promoted their myelination. Local injection of cyclo-dPAKKR adjacent to the developing sciatic nerve in vivo significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo-dPAKKR promotes peripheral myelination in vitro and in vivo, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases.
Endogenous leukemia inhibitory factor production limits autoimmune demyelination and oligodendrocyte loss.
Publisher: Wiley
Date: 23-02-2006
DOI: 10.1002/GLIA.20321
Abstract: Autoimmune injury to oligodendrocytes evokes an endogenous response in the central nervous system, which initially limits the acute injury to oligodendrocytes and myelin, and subsequently promotes remyelination. The key molecular and cellular events responsible for this beneficial outcome are incompletely understood. In this article, we utilize murine autoimmune encephalomyelitis (EAE) to focus on the effect of endogenously produced leukemia inhibitory factor (LIF) upon mature oligodendrocyte survival after demyelinating injury. We show that the mRNA for LIF is markedly upregulated in the spinal cord in the context of acute inflammatory demyelination. After clinical disease onset, administration of neutralizing anti-LIF antibodies over a four day period significantly worsens disease severity in two different murine EAE models. We also show that administration of neutralizing antibodies results in reduced activation of the cognate LIF receptor components in the spinal cord. Histologically, anti-LIF antibody administration increases the extent of acute demyelination (P < 0.01) and doubles the oligodendrocyte loss already induced by EAE (P < 0.05), without altering the extent of inflammatory infiltration into the spinal cord. Although acute EAE induces a rapid, three-fold increase in the proliferation of NG2 positive oligodendrocyte progenitors (P < 0.001), this response is not diminished by antagonism of endogenous LIF. We conclude that endogenous LIF is induced in response to autoimmune demyelination in the spinal cord and protects mature oligodendrocytes from demyelinating injury and cell death, thereby resulting in attenuation of clinical disease severity.
Measurement of Epstein-Barr virus DNA load using a novel quantification standard containing two EBV DNA targets and SYBR Green I dye
Publisher: Springer Science and Business Media LLC
Date: 22-09-2010
A Neuroethics Framework for the Australian Brain Initiative
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEURON.2019.01.004
Abstract: 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.
Variation within MBP gene predicts disease course in multiple sclerosis
Publisher: Wiley
Date: 09-03-2017
DOI: 10.1002/BRB3.670
Serial MRI in multiple sclerosis: a prospective pilot study of lesion load, whole brain volume and thalamic atrophy
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/S0967-5868(03)00145-0
Abstract: Using serial magnetic resonance imaging (MRI), we investigated the relationship between diffuse cerebral atrophy, T1 and T2 lesion volumes, mean thalamic volumes and clinical progression in patients with established multiple sclerosis (MS). Eleven patients were included in this prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, and T2 hyperintense lesion volumes at baseline and at up to 3 years follow-up were assessed on MRI brain scans. As a putative measure of cerebral atrophy mean thalamic volumes were also obtained. The outcome measures were the MRI parameters and disability on Kurtzke's expanded disability status scale (EDSS). Of the 11 patients 6 worsened clinically as measured by an increase of 0.5 or more on the EDSS. Cerebral atrophy occurred in 91% of patients and was independent of changes in lesion volumes and was not associated with disease progression as determined by the EDSS.
Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 05-03-2013
A randomised controlled trial: Outcomes of bladder rehabilitation in persons with multiple sclerosis
Publisher: BMJ
Date: 11-06-2010
Abstract: A stratified, randomised, waitlist controlled study over 12 months assessed the effectiveness of a 6 week bladder rehabilitation programme in persons with multiple sclerosis (pwMS) in an Australian community cohort. Patients with definite MS and bladder issues (n=74) recruited from a tertiary hospital database were randomised to a treatment group (n=40) for an in idualised bladder rehabilitation programme or to a control waitlist group (n=34). The Urogenital Distress Inventory (UDI6), Neurological Disability Scale (NDS) and the American Urological Association Symptom Index (AUA) assessed bladder impairment and 'activity limitation' a single Quality of life (QoL) item in the AUA and the Incontinence Impact Questionnaire (IIQ7) measured restriction in 'participation'. Primary outcome measures were assessed at baseline and at 12 months. Analysis of per protocol data from 58 patients (treatment n=24, control n=34) showed reduced disability in the treatment group, with significant differences (p 0.5) in post-treatment UDI6, NDS, AUA total, AUA QoL and IIQ7 scores for the two groups. The treatment group compared with the control group showed improvement: 78% versus 27% for UDI6 and 59% versus 17% improved for IIQ7. More patients in the control group deteriorated over the study period on the UDI6 (30% vs 0% p<0.001) and IIQ7 (39 vs 0% p=0.001). A multifaceted, in idualised bladder rehabilitation programme reduces disability and improves QoL in pwMS compared with no intervention after 12 months of follow-up. Information on specific interventions in different bladder types in MS and the impact on QoL need further evaluation. Australian Clinical trials Registry ACTRNO12605000676617.
Optic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes
Publisher: Public Library of Science (PLoS)
Date: 18-12-2012
Erratum: A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))
Publisher: Elsevier BV
Date: 2020
The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function
Publisher: Public Library of Science (PLoS)
Date: 11-06-2015
White matter haemodynamics: Basic physiology and disruption in neuroinflammatory disease
Publisher: Cold Spring Harbor Laboratory
Date: 25-10-2017
DOI: 10.1101/208751
Abstract: The white matter is highly vascularised by the cerebral venous system. The neuroinflammatory disease multiple sclerosis is associated with infiltration of peripheral immune cells into the brain via these vessels. Understanding venous pathophysiology in multiple sclerosis is thus critical for understanding early disease aetiology. 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, a blind signal source separation method. The signal was characterised by a narrow peak frequency band between 0.05 and 0.1 Hz. Hypercapnia (transient breath holds), known to alter venous calibre in cortex, induced transient increases in white matter BOLD that disrupted the oscillation indicative of a vasodilatory/contractile mechanism. Comparison of the white matter BOLD oscillations between age and sex matched groups of 18 multiple sclerosis and 14 healthy participants revealed a loss of power in the white matter 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 multiple sclerosis patients, lower power was associated with greater levels of neuroinflammatory activity (R=−0.64, p=0.006) but not neurodegenerative disease markers. Using a signal modelling technique, we assessed the anatomical distribution of white matter BOLD signal abnormalities and detected reduced power in the periventricular white matter, a region of known venous damage in multiple sclerosis patients. 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.
Latitudinal variation in incidence and type of first central nervous system demyelinating events
Publisher: SAGE Publications
Date: 18-02-2010
Abstract: Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18—59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27° south to 43° south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55% (95% confidence interval (CI) 7.37—11.78, p 0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69% (95% CI 9.68—19.94, p 0.001) female 8.13% (95% CI 5.69—10.62, p 0.001)) and also by the presenting FDE type: optic neuritis 11.39% (95% CI 7.15—15.80, p 0.001) brainstem/cerebellar syndrome 9.47% (95% CI 5.18—13.93, p 0.001) and spinal cord syndrome 5.36% (95% CI 1.78—9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females ( p = 0.02) and between optic neuritis and spinal cord syndrome ( p = 0.04). The male to female ratio varied from 1 : 6.7 at 27° south to 1 : 2.5 at 43° south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis.
Gait and balance impairment in early multiple sclerosis in the absence of clinical disability
Publisher: SAGE Publications
Date: 09-2006
Abstract: This study evaluated the gait and balance performance of two clinically distinct groups of recently diagnosed and minimally impaired multiple sclerosis (MS) patients (Expanded Disability Status Scale range 0- 2.5), compared to control subjects. Ten MS patients with mild pyramidal signs (Pyramidal Functional Systems 1.0), 10 MS patients with no pyramidal signs (Pyramidal Functional Systems 0) and 20 age- and gender-matched control subjects were assessed using laboratory-based gait analysis and clinical balance measures. Both MS groups demonstrated reduced speed and stride length ( P 0.001), and prolonged double limb support ( P .02), compared to the control group, along with alterations in the timing of ankle muscle activity, and the pattern of ankle motion during walking, which occurred independent of gait speed. The pyramidal MS group walked with reduced speed ( P=0.03) and stride length ( P=0.04), and prolonged double limb support ( P=0.01), compared to the non-pyramidal group. Both MS groups demonstrated concomitant balance impairment, performing poorly on the Functional Reach Test compared to the control group ( P .05). The identification of incipient gait and balance impairment in MS patients with recent disease onset suggests that motor function may begin to deteriorate in the early stages of the disease, even in the absence of clinical signs of pyramidal dysfunction.
Asthma onset prior to multiple sclerosis and the contribution of sibling exposure in early life
Publisher: Oxford University Press (OUP)
Date: 13-10-2006
DOI: 10.1111/J.1365-2249.2006.03235.X
Abstract: 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.
Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve
Publisher: SAGE Publications
Date: 2016
Abstract: Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.
Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia
Publisher: Springer Science and Business Media LLC
Date: 11-04-2007
DOI: 10.1007/S00415-006-0315-8
Abstract: Adequate 25(OH)D levels are required to prevent adverse effects on bone health. Population-based data on factors associated with 25(OH)D levels of people with MS have been lacking. To examine the prevalence and determinants of vitamin D insufficiency in a population-based s le of MS cases and controls, and to compare 25(OH)D status between MS cases and controls, taking into account case disability. We conducted a population based case-control study in Tasmania, Australia (latitude 41-43 degrees S) on 136 prevalent cases with MS confirmed by magnetic resonance imaging and 272 community controls, matched on sex and year of birth. Measurements included serum 25(OH)D, sun exposure, skin type, dietary vitamin D intake and disability including EDSS. A high prevalence of vitamin D insufficiency was found in MS cases and controls. Among MS cases, increasing disability was strongly associated with lower levels of 25(OH)D and with reduced sun exposure. Cases with higher disability (EDSS > 3) were more likely to have vitamin D insufficiency than controls (OR = 3.07 (1.37, 6.90) for 25(OH)D </= 40 nmol/l), but cases with low disability were not (OR = 0.87 (0.41, 1.86)). The strong associations between disability, sun exposure and vitamin D status indicate that reduced exposure to the sun, related to higher disability, may contribute to the high prevalence of vitamin D insufficiency found in this population-based MS case s le. Active detection of vitamin D insufficiency among people with MS and intervention to restore vitamin D status to adequate levels should be considered as part of the clinical management of MS.
Common genetic variation within miR-146a predicts disease onset and relapse in multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 10-11-2018
DOI: 10.1007/S10072-017-3177-1
Abstract: Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 08-2011
DOI: 10.1038/NATURE10251
Measurement of intracellular cytokines in MS patients treated with β-interferon and association of a β-interferon induced exacerbation with increased expression of γ-interferon by monocytes
Publisher: Elsevier BV
Date: 09-2001
New treatments for multiple sclerosis.
Publisher: Wiley
Date: 12-1999
Oligodendroglial Expression of TrkB Independently Regulates Myelination and Progenitor Cell Proliferation
Publisher: Society for Neuroscience
Date: 13-03-2013
DOI: 10.1523/JNEUROSCI.3990-12.2013
Abstract: The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in regulating CNS myelination. BDNF mutant mice exhibit a hypomyelinating phenotype, and BDNF exerts distinct effects upon oligodendroglial proliferation, differentiation, and myelination in vitro . To investigate the precise influence that BDNF exerts in regulating CNS myelination in vivo , we have generated conditional knock-out mice in which TrkB has been deleted specifically in oligodendrocytes. Deletion of TrkB disrupted normal oligodendrocyte myelination, resulting in a significant reduction in myelin protein expression and myelination of CNS white matter tracts during development. Importantly, conditional knock-out mice exhibited normal numbers of mature oligodendrocytes and normal numbers of myelinated axons however, myelin thickness was significantly reduced during development. These data indicate that while TrkB expression in oligodendrocytes plays no role in the initial contact with axons, it exerts an important influence in subsequent stages to promote myelin ensheathment. The conditional knock-out mice also exhibited an increased density of oligodendrocyte progenitor cells (OPCs) in CNS white matter tracts. Concordant with these results, in vitro analyses using OPCs subjected to TrkB knockdown also revealed increased OPC proliferation. Our data suggested this effect was dependent upon TrkC and p75 expression. Thus, our data demonstrate that TrkB expression in oligodendroglia exerts a direct effect on oligodendrocytes to promote myelination and an indirect effect upon the OPC population, modifying their proliferative potential.
Closing the case of APOE in multiple sclerosis: No association with disease risk in over 29 000 subjects
Publisher: BMJ
Date: 09-2012
DOI: 10.1136/JMEDGENET-2012-101175
Abstract: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Given the large s le size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
Association of plasma levels of Protein S with disease severity in multiple sclerosis
Publisher: SAGE Publications
Date: 24-07-2015
Abstract: The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) play important roles in modulating innate immune responses and central demyelination. The TAM receptor ligand Protein S (PROS) has also been shown to modulate innate immune cell responses. We assessed whether plasma levels of PROS are changed in multiple sclerosis (MS) patients and whether changes are associated with disease severity. Plasma levels of total and free PROS were measured using enzyme-linked immunosorbent assay in a discovery cohort (MS: 65, control: 14) and an independent replication cohort (MS: 29, control: 29). The Multiple Sclerosis Severity Score (MSSS) was used to evaluate associations between plasma PROS levels and disease severity. We found plasma levels of total, but not free PROS, were decreased in MS patients compared with controls. In female MS patients, we observed decreases in total and free PROS levels compared with controls. In addition, we also observed higher MSSS in patients with very low levels of plasma free PROS. These data suggest PROS may represent a potential marker of disease severity in MS.
Sun Exposure over a Lifetime in Australian Adults from Latitudinally Diverse Regions
Publisher: Wiley
Date: 19-02-2013
DOI: 10.1111/PHP.12044
Abstract: Spatio-temporal patterns in sun exposure underlie variations in skin cancer incidence and vitamin D deficiency, indicate effectiveness of sun protection programs and provide insights into future health risks. From 558 adults across four regions of Australia (Brisbane (27°S), Newcastle (33°S), Geelong and the Western Districts of Victoria (37°S) and Tasmania (43°S)), we collected: self-report data on time-in-the-sun from age 6 years natural skin color and ethnicity silicone skin casts (for cumulative skin damage) and serum for vitamin D status. Ambient ultraviolet radiation (UVR) at the location of residence, with time-in-the-sun, was used to calculate a "UVR dose" for each year of life. In iduals maintained their ranking compared to their peers for time-in-the-sun in summer compared to winter and across ages (Spearman rho 0.24-0.84, all P < 0.001). Time-in-the-sun decreased with age in all birth cohorts, and over calendar time. Summer time-in-the-sun increased with increasing latitude (P < 0.001). Seasonal variation in vitamin D status had greater litude and vitamin D deficiency increased with increasing latitude. Temporal patterns are consistent with effectiveness of sun protection programs. Higher relative time-in-the-sun persists from childhood through adulthood. Lower summer time-in-the-sun in the warmest location may have implications for predictions of UVR-related health risks of climate change.
Midsagittal corpus callosum area and conversion to multiple sclerosis after clinically isolated syndrome: A multicentre Australian cohort study
Publisher: Wiley
Date: 20-12-2016
Abstract: Patients presenting with clinically isolated syndrome (CIS) may proceed to clinically definite multiple sclerosis (CDMS). Midsagittal corpus callosum area (CCA) is a surrogate marker for callosal atrophy, and can be obtained from a standard MRI study. This study explores the relationship between CCA measured at CIS presentation (baseline) and at 5 years post presentation, with conversion from CIS to CDMS. The association between CCA and markers of disability progression is explored. Corpus callosum area was measured on MRI scans at presentation and 5-year review following diagnosis of a first demyelinating event, or evidence of progressive MS, in 143 participants in the Ausimmune/AusLong Study. Relationships between CCA (at baseline and follow-up) and clinical outcomes were assessed. Mean CCA at baseline study was 6.63 cm Baseline CCA obtained from standard MRI protocols may be compared with subsequent MRI examinations as a surrogate for neurodegeneration and cerebral atrophy in patients with MS. This study demonstrates an association between CCA and disability in in iduals presenting with CIS who convert to MS.
Reported changes in dietary behavior following a first clinical diagnosis of central nervous system demyelination
Publisher: Frontiers Media SA
Date: 20-03-2018
Multidisciplinary rehabilitation for adults with multiple sclerosis
Publisher: Wiley
Date: 18-04-2007
Illness perception and health-related quality of life in multiple sclerosis
Publisher: Hindawi Limited
Date: 11-2007
DOI: 10.1111/J.1600-0404.2007.00895.X
Abstract: AIMS - A number of physical and psychological factors have been shown to affect health-related quality of life (HRQoL) in patients with multiple sclerosis (MS). Among these, the role of illness perceptions has not been established as an independent factor. This study, the first of its kind in an Australian population, aimed to use a large s le to determine the relative importance of in idual factors to each domain of HRQoL, in particular the role of illness perception. MATERIALS AND METHODS - 580 patients with confirmed MS were assessed cross sectionally in a designated research clinic to determine the relative impact of physical factors (illness severity, duration, age, fatigue and pain) and psychological factors (mood, cognition and illness representations) on each domain of the SF-36. RESULTS - Categorical regression analysis showed that a combination of physical and psychological factors predicted 38-71% of variance in HRQoL. Illness perception was shown to have an independent effect on HRQoL in MS. The Extended Disability Status Scale was a significant determinant in all domains except for mental health. Depression was less prevalent than anxiety, but had a greater effect on function. CONCLUSION - Illness perception is an independent factor contributing to HRQoL in people with MS. In idual domains of HRQoL are associated with different patterns of physical and psychological factors. In the domains of role and social function, activities most highly valued by patients with MS, depression, anxiety, fatigue and illness perceptions are key determinants, all of which have the potential to be improved through specific interventions.
Effectiveness of rehabilitation intervention in persons with multiple sclerosis: A randomised controlled trial
Publisher: BMJ
Date: 05-06-2008
Molecular mechanisms regulating motor neuron development and degeneration.
Publisher: Springer Science and Business Media LLC
Date: 06-1999
DOI: 10.1007/BF02821714
Longitudinal assessment of antisaccades in patients with multiple sclerosis
Publisher: Public Library of Science (PLoS)
Date: 02-02-2012
A Higher Mediterranean Diet Score, Including Unprocessed Red Meat, Is Associated with Reduced Risk of Central Nervous System Demyelination in a Case-Control Study of Australian Adults
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1093/JN/NXZ089
Abstract: The evidence associating diet and risk of multiple sclerosis (MS) is inconclusive. The aim of this study was to investigate associations between a Mediterranean diet and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. We used data from the 2003-2006 Ausimmune Study, an Australian multicenter, case-control study examining environmental risk factors for FCD, with participants matched on age, sex, and study region (282 cases, 558 controls 18-59 y old 78% female). The alternate Mediterranean diet score (aMED) was calculated based on data from a food-frequency questionnaire. We created a modified version of the aMED (aMED-Red) where ∼1 daily serving (65 g) of unprocessed red meat received 1 point. All other components remained the same as aMED. Conditional logistic regression (254 cases, 451 controls) was used to test associations between aMED and aMED-Red scores and categories and risk of FCD, adjusting for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, education, total energy intake, and dietary underreporting. There was no statistically significant association between aMED and risk of FCD [per 1-SD increase in aMED score: adjusted odds ratio (aOR): 0.89 95% CI: 0.75, 1.06 P = 0.181]. There was evidence of a nonlinear relation between aMED-Red and risk of FCD when a quadratic term was used (P = 0.016). Compared with the lowest category of aMED-Red, higher categories were significantly associated with reduced risk of FCD, corresponding to a 37% (aOR: 0.63 95% CI: 0.41, 0.98 P = 0.039), 52% (aOR: 0.48 95% CI: 0.28, 0.83 P = 0.009), and 42% (aOR: 0.58 95% CI: 0.35, 0.96 P = 0.034) reduced risk of FCD in categories 2, 3, and 4, respectively. A Mediterranean diet, including unprocessed red meat, was associated with reduced risk of FCD in this Australian adult population. The addition of unprocessed red meat to a Mediterranean diet may be beneficial for those at high risk of MS.
The role of neurotransmission and the Chopper domain in p75 neurotrophin receptor death signaling
Publisher: Elsevier
Date: 2004
The Australian Multiple Sclerosis (MS) immunotherapy study: a prospective, multicentre study of drug utilisation using the MSBase platform
Publisher: Public Library of Science (PLoS)
Date: 19-03-2013
Current and past Epstein-Barr virus infection in risk of initial CNS demyelination
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-07-2011
SOCS3 negatively regulates LIF signaling in neural precursor cells.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.MCN.2006.01.005
Abstract: Cytokines that signal through the LIFRbeta/gp130 receptor complex, including LIF and CNTF, promote the self-renewal of embryonic and adult neural precursor cells (NPCs). In non-CNS tissues, the protein suppressor of cytokine signaling-3 (SOCS3) negatively regulates signaling through gp130. Here, we analyze the role of SOCS3 in inhibiting LIF signaling in NPCs in vitro. SOCS3 is rapidly expressed by NPCs in response to LIF stimulation, with this expression largely dependent on recruitment of STAT proteins to the activated gp130 receptor. Proliferating NPC cultures can be generated from SOCS3 knockout (SOCS3KO/KO) embryos and display prolonged STAT3 phosphorylation and induction of the GFAP gene in response to LIF. In comparison with SOCS3 wild-type (SOCS3WT/WT) NPCs, SOCS3KO/KO cultures display enhanced self-renewal capacity. However, the clonal potential of SOCS3WT/WT but not SOCS3KO/KO NPCs is enhanced by exogenous LIF. Thus, SOCS3 acts as a negative regulator of LIF signaling in NPCs.
Variability in vitamin D assays impairs clinical assessment of vitamin D status
Publisher: Wiley
Date: 2012
DOI: 10.1111/J.1445-5994.2011.02471.X
Abstract: Measuring serum 25(OH)D concentration is common in clinical practice despite the questionable reliability of assays. The aim of the present study was to examine agreement in 25(OH)D concentrations measured by different assays and laboratories, and consider related clinical implications. Serum s les from 813 participants in the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study) were assayed for 25(OH)D concentration. Duplicate s les from subsets of subjects were sent to different laboratories, two using DiaSorin Liaison (Laboratory A and B) and one using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS - selected here as the nominal gold standard). Pairwise within-assay (both within-laboratory and between-laboratories) and between-assay agreement was examined using Deming regression and Bland-Altman plots. Common 25(OH)D cut-points for classification of vitamin D deficiency were used to compare the different assays. 25(OH)D concentrations measured using Liaison were substantially lower at Laboratory A than at Laboratory B (mean bias -11.60 nmol/L, 95% limits of agreement -46.39, 23.18). Both Liaison assays returned much lower 25(OH)D concentrations than LC-MS/MS (mean bias up to -26.05 nmol/L, 95% limits of agreement of -13.21, 65.31). For Laboratory A participants, 46% (355/765) were classified as vitamin D deficient (25(OH)D <50 nmol/L) using Liaison compared with 17% (128/765) using LC-MS/MS. For Laboratory B participants, the respective figures were 36% (76/209) and 20% (41/209). Hence, between 1-in-5 and 1-in-3 participants were misclassified as 'deficient'. Bias and variability in 25(OH)D measurements sufficient to affect significantly clinical decision-making were found both between-laboratories and between-assays. The adoption of common standards to allow assay calibration is required urgently.
MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood
Publisher: Public Library of Science (PLoS)
Date: 11-08-2010
Acute median nerve compression by haemorrhage from acute myelomonocytic leukaemia
Publisher: AMPCo
Date: 1985
DOI: 10.5694/J.1326-5377.1985.TB113287.X
Abstract: A 61-year-old male receiving treatment for acute myelomonocytic leukaemia (AMML) developed weakness and sensory loss in the thumb, index and middle finger and half of the ring finger of the left hand as a result of a spontaneous haemorrhage into the carpal tunnel and forearm, an unusual cause of median nerve compression. These findings were confirmed by CT scanning and post-mortem examination. This is the first report of spontaneous haemorrhage occurring in a patient with AMML.
BDNF Exerts Contrasting Effects on Peripheral Myelination of NGF-Dependent and BDNF-Dependent DRG Neurons
Publisher: Society for Neuroscience
Date: 04-2009
DOI: 10.1523/JNEUROSCI.3811-08.2009
Abstract: Although brain-derived neurotrophic factor (BDNF) has been shown to promote peripheral myelination during development and remyelination after injury, the precise mechanisms mediating this effect remain unknown. Here, we determine that BDNF promotes myelination of nerve growth factor-dependent neurons, an effect dependent on neuronal expression of the p75 neurotrophin receptor, whereas BDNF inhibits myelination of BDNF-dependent neurons via the full-length TrkB receptor. Thus, BDNF exerts contrasting effects on Schwann cell myelination, depending on the complement of BDNF receptors that are expressed by different subpopulations of dorsal root ganglion neurons. These results demonstrate that BDNF exerts contrasting modulatory roles in peripheral nervous system myelination, and that its mechanism of action is acutely regulated and specifically targeted to neurons.
MonoMac syndrome with associated neurological deficits and longitudinally extensive cord lesion
Publisher: BMJ
Date: 21-04-2018
Offspring number, pregnancy, and risk of a first clinical demyelinating event the ausimmune study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2012
Adult Neural Precursor Cells from the Subventricular Zone Contribute Significantly to Oligodendrocyte Regeneration and Remyelination
Publisher: Society for Neuroscience
Date: 15-10-2014
DOI: 10.1523/JNEUROSCI.3491-13.2014
Abstract: Parenchymal oligodendrocyte progenitor cells (pOPCs) are considered the principal cell type responsible for oligodendrogenesis and remyelinaton in demyelinating diseases. Recent studies have demonstrated that neural precursor cells (NPCs) from the adult subventricular zone (SVZ) can also generate new oligodendrocytes after demyelination. However, the relative contribution of NPCs versus pOPCs to remyelination is unknown. We used in vivo genetic fate mapping to assess the behavior of each progenitor type within the corpus callosi (CCs) of mice subjected to cuprizone-induced demyelination. Nestin-CreER T2 and Pdgfra-CreER T2 transgenic mice were crossed with fluorescent Cre reporter strains to map the fate of NPCs and pOPCs respectively. In cuprizone-challenged mice, substantial numbers of NPCs migrated into the demyelinated CC and contributed to oligodendrogenesis. This capacity was most prominent in rostral regions adjacent to the SVZ where NPC-derived oligodendrocytes significantly outnumbered those generated from pOPCs. Sixty-two percent of all nodes of Ranvier in this region were flanked by at least one paranode generated from an NPC-derived oligodendrocyte. Remarkably, g-ratios (ratio of the axon diameter to the diameter of the axon plus myelin sheath) of myelinated axons in regions subject to significant NPC-derived remyelination were equivalent to those of unchallenged controls, and immunoelectron microscopy revealed that NPC-derived myelin was significantly thicker than that generated by pOPCs, regardless of axonal caliber. We also demonstrate that a reduced efficiency of remyelination in the caudal CC was associated with long-term impairment in the maturation of oligodendrogenic NPCs but only transient delay in pOPC differentiation. Collectively, our data define a major distinct role for NPCs in remyelination, identifying them as a key target for enhancing myelin repair in demyelinating diseases.
Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis
Publisher: Wiley
Date: 07-2018
DOI: 10.1002/ANA.25263
Therapeutic potential of LIF in multiple sclerosis
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.MOLMED.2010.08.007
Abstract: Therapies for multiple sclerosis (MS) reduce the relapse rate but are unable to stop neurological decline. Here, we evaluate the potential of leukemia inhibitory factor (LIF) as a novel therapeutic in diseases with a neurodegenerative and inflammatory component, such as MS. LIF, which can be a proinflammatory cytokine, can also modulate the immune response in a beneficial way. Recent evidence demonstrates a crucial role of LIF in neuroprotection and axonal regeneration as well as the prevention of demyelination. Finally, LIF is an important survival factor for stem cells and neuronal precursors. Therefore, we propose that LIF is a potential therapeutic candidate for MS.
Control of visually guided saccades in multiple sclerosis: Disruption to higher-order processes
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.NEUROPSYCHOLOGIA.2009.01.040
Abstract: Ocular motor abnormalities are a common feature of multiple sclerosis (MS), with more salient deficits reflecting tissue damage within brainstem and cerebellar circuits. However, MS may also result in disruption to higher level or cognitive control processes governing eye movement, including attentional processes that enhance the neural processing of behaviourally relevant information. The attentional control of eye movement was investigated in 25 in iduals with MS and a comparable number of neurologically healthy in iduals matched for age and IQ. This entailed an evaluation of distractor-related effects on the generation of both unpredictable and predictable visually guided saccades, as well as an evaluation of the effects of presenting endogenous cues prior to target onset. For unpredictable saccades, we revealed an exaggerated distractor effect in MS, with saccade latencies prolonged and endpoints less accurate in the presence of a visual distractor. Predictable saccades tended to be hypometric for MS patients, although we found no significant distractor effects. For endogenously cued saccades, we found no group differences in latency following a valid cue, but an exaggerated increase in latency following invalid cues for MS patients. MS patients also generated a significantly greater proportion of erroneous responses to cue stimuli. These ocular motor characteristics demonstrate considerable sensitivity with respect to evaluating attentional deficits in MS, evident even in the absence of clinical signs of disease.
Comparison of the effectiveness of a tailored cognitive behavioural therapy with a supportive listening intervention for depression in those newly diagnosed with multiple sclerosis (the ACTION-MS trial): protocol of an assessor-blinded, active comparator, randomised controlled trial.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
DOI: 10.1186/S13063-019-4018-8
Abstract: 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 in iduals 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 in iduals 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.
Ndrg1 in development and maintenance of the myelin sheath
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.NBD.2011.01.030
Abstract: CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.
Cell death in the Schwann cell lineage and its regulation by neuregulin
Publisher: Proceedings of the National Academy of Sciences
Date: 20-08-1996
Abstract: The development of Schwann cells, the myelin-forming glial cells of the vertebrate peripheral nervous system, involves a neonatal phase of proliferation in which cells migrate along and segregate newly formed axons. Withdrawal from the cell cycle, around postnatal days 2-4 in rodents, initiates terminal differentiation to the myelinating state. During this time, Schwann cell number is subject to stringent regulation such that within the first postnatal week, axons and myelinating Schwann cells attain the one-to-one relationship characteristic of the mature nerve. The mechanisms that underly this developmental control remain largely undefined. In this report, we examine the role of apoptosis in the determination of postnatal Schwann cell number. We find that Schwann cells isolated from postnatal day 3 rat sciatic nerve undergo apoptosis in vitro upon serum withdrawal and that Schwann cell death can be prevented by beta forms of neuregulin (NRG-beta) but not by fibroblast growth factor 2 or platelet-derived growth factors AA and BB. This NRG-beta-mediated Schwann cell survival is apparently transduced through an ErbB2/ErbB3 receptor heterodimer. We also provide evidence that postnatal Schwann cells undergo developmentally regulated apoptosis in vivo. Together with other recent findings, these results suggest that Schwann cell apoptosis may play an important role in peripheral nerve development and that Schwann cell survival may be regulated by access to axonally derived NRG.
Observational analytic studies in multiple sclerosis: Controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function
Publisher: SAGE Publications
Date: 08-2007
Abstract: Rising multiple sclerosis incidence over the last 50 years and geographic patterns of occurrence suggest an environmental role in the causation of this multifactorial disease. Design options for epidemiological studies of environmental causes of multiple sclerosis are limited by the low incidence of the disease, possible diagnostic delay and budgetary constraints. We describe scientific and methodological issues considered in the development of the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study), which seeks, in particular, to better understand the causes of the well-known MS positive latitudinal gradient. A multicentre, case-control design down the eastern seaboard of Australia allows the recruitment of sufficient cases for adequate study power and provides data on environmental exposures that vary by latitude. Cases are persons with an incident first demyelinating event (rather than prevalent multiple sclerosis), sourced from a population base using a two tier notification system. Controls, matched on sex, age (within two years) and region of residence, are recruited from the general population. Biases common in case-control studies, eg, prevalence-incidence bias, admission-rate bias, non-respondent bias, observer bias and recall bias, as well as confounding have been carefully considered in the study design and conduct of the Ausimmune Study. Multiple Sclerosis 2007 13 : 827—839. msj.sagepub.com
Rat oligodendroglia express c-met and focal adhesion kinase, protein tyrosine kinases implicated in regulating epithelial cell motility
Publisher: Elsevier BV
Date: 2000
DOI: 10.1016/S0304-3940(99)00928-3
Abstract: Oligodendrocytes, the myelinating cells of the central nervous system, arise from a profilerating pool of motile progenitor cells. The proliferation and survival of these cells is dependent on signal transduction via several protein tyrosine kinases (PTKs) including receptors for fibroblast growth factor -2, the platelet-derived growth factor receptors and the neurotrophin receptor, trkC. We hypothesized that additional PTKs could also influence oligodendroglial development. Utilizing RTPCR, we lified from post-natal day 6 rat oligodendroglia 17 distinct kinase domain sequences, 14 of which were not previously known to be expressed by oligodendroglia. Amongst the sequences identified were the c-met and Fak genes, whose protein products regulate the motility of other epithelial cell types. Utilizing immunohistochemistry, we confirmed that both c-met and Fak are expressed by cultured oligodendroglia, suggesting that these proteins could also be implicated in regulating the motility of these cells.
A novel approach for prediction of vitamin D status using support vector regression
Publisher: Public Library of Science (PLoS)
Date: 26-11-2013
Parallel changes in structural and functional measures of optic nerve myelination after optic neuritis
Publisher: Public Library of Science (PLoS)
Date: 28-05-2015
Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement
Publisher: Cold Spring Harbor Laboratory
Date: 06-02-2022
DOI: 10.1101/2022.02.04.22270362
Abstract: Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS 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 MS Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 in iduals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 – 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.
Technologies for Advanced Gait and Balance Assessments in People with Multiple Sclerosis
Publisher: Frontiers Media SA
Date: 02-02-2018
Fyn is an intermediate kinase that BDNF utilizes to promote oligodendrocyte myelination
Publisher: Wiley
Date: 09-10-2015
DOI: 10.1002/GLIA.22927
Abstract: Fyn, a member of the Src family of nonreceptor tyrosine kinases, promotes central nervous system myelination during development however the mechanisms mediating this effect remain unknown. Here we show that Fyn phosphorylation is modulated by BDNF in vivo. Concordant with this, we find that BDNF stimulates Fyn phosphorylation in myelinating cocultures, an effect dependent on oligodendroglial expression of TrkB. Importantly, PP2, a pharmacological inhibitor of Src family kinases, not only abrogated the promyelinating influence of BDNF in vitro, but also attenuated BDNF-induced phosphorylation of Erk1/2 in oligodendrocytes. Over-expression of Fyn in oligodendrocytes significantly promotes phosphorylation of Erk1/2, and promotes myelination to the extent that exogenous BDNF exerts no additive effect in vitro. In contrast, expression of a kinase-dead mutant of Fyn in oligodendrocytes significantly inhibited BDNF-induced activation of Erk1/2 and abrogated the promyelinating effect of BDNF. Analysis of white matter tracts in vivo revealed that phosphorylated Fyn primarily colocalized with mature oligodendrocytes, and was rarely observed in oligodendrocyte progenitor cells, a profile that closely parallels the detection of phosphorylated Erk1/2 in the developing central nervous system. Taken together, these data identify that Fyn kinase exerts a key role in mediating the promyelinating influence of BDNF. Here we identify a pathway in which BDNF activation of oligodendroglial TrkB receptors stimulates the phosphorylation of Fyn, a necessary step required to potentiate the phosphorylation of Erk1/2, which in turn regulates oligodendrocyte myelination.
The engraftment of transplanted primary neuroepithelial cells within the postnatal mouse brain
Publisher: Elsevier BV
Date: 11-1994
DOI: 10.1016/0304-3940(94)90576-2
Abstract: Primary neuroepithelial precursor cells carrying the reporter gene lacZ were transplanted into postnatal murine brain and assessed for their engraftment capacity. Freshly dissected precursors, derived from lacZ transgenic embryonic day 10 mouse brain, predominantly engrafted as discrete clusters, whereas the same precursors cultured in vitro with fibroblast growth factor-2, engrafted as single cells within the parenchyma of the hippoc us. Approximately 0.5% of the transplanted cells survived in the host brain for up to 3 months. Many of these cells displayed neuronal and astrocyte morphologies. These observations suggest that transplanted primary precursors derived from the embryonic brain can engraft and commit in situ to a variety of developmental fates.
Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
A role for insulin-like growth factor-I in the regulation of Schwann cell survival.
Publisher: Society for Neuroscience
Date: 15-03-1999
DOI: 10.1523/JNEUROSCI.19-06-02059.1999
Abstract: During postnatal development in the peripheral nerve, differentiating Schwann cells are susceptible to apoptotic death. Schwann cell apoptosis is regulated by axons and serves as one mechanism through which axon and Schwann cell numbers are correctly matched. This regulation is mediated in part by the provision of limiting axon-derived trophic molecules, although neuregulin-1 (NRG-1) is the only trophic factor shown to date to support Schwann cell survival. In this report, we identify insulin-like growth factor-I (IGF-I) as an additional trophin that can promote Schwann cell survival in vitro . We find that IGF-I, like NRG-1, can prevent the apoptotic death of postnatal rat Schwann cells cultured under conditions of serum withdrawal. Moreover, we show that differentiating Schwann cells in the rat sciatic nerve express both the IGF-I receptor (IGF-I R) and IGF-I throughout postnatal development. These results indicate that IGF-I is likely to control Schwann cell viability in the developing peripheral nerve and, together with other findings, raise the interesting possibility that such survival regulation may switch during postnatal development from an axon-dependent mechanism to an autocrine and/or paracrine one.
The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry
Publisher: BMJ
Date: 28-12-2011
Abstract: The Expanded Disability Status Scale (EDSS) is widely used to rate multiple sclerosis (MS) disability, but lack of disease duration information limits utility in assessing severity. EDSS ranking at specific disease durations was used to devise the MS Severity Score, which is gaining popularity for predicting outcomes. As this requires validation in longitudinal cohorts, we aimed to assess the utility of EDSS ranking as a predictor of 5-year outcome in the MSBase Registry. Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using Spearman's rank correlation. EDSS progression outcomes at 10 years were disaggregated by 5-year EDSS scores. Correlation coefficients for EDSS rank over 5-year intervals increased with MS duration: years 1-6=0.55, years 4-9=0.74, years 7-12=0.80 and years 10-15=0.83. EDSS progression risk at 10 years after onset was highly dependent on EDSS at 5 years one-point progression risk was greater for EDSS score of >2 than ≤2. Two-point progression was uncommon for EDSS score of <2 and more common at EDSS score of 4. EDSS rank stability increases with disease duration, probably due to reduced relapses and less random variation in later disease. After 4 years duration, EDSS rank was highly predictive of EDSS rank 5 years later. Risk of progression by 10 years was highly dependent on EDSS score at 5 years duration. We confirm the utility of EDSS ranking to predict 5-year outcome in in iduals 4 years after disease onset.
Expression of theTyro4/Mek4/Cek4Gene Specifically Marks a Subset of Embryonic Motor Neurons and Their Muscle Targets
Publisher: Elsevier BV
Date: 1996
Abstract: Tyro4 is a member of the eph family of receptor protein-tyrosine kinases. We present sequence analysis that identifies Tyro4 as the rat homolog of mouse Mek4 and chick Cek4. We also present expression studies that demonstrate an evolutionarily conserved pattern of expression for Tyro4, Mek4, and Cek4. Most strikingly, we find this receptor to be specifically expressed, in all three species, in a subset of motor neurons in the medial motor column and in a subset of axial, but not limb, muscles. Mek4 has previously been ascribed a role in guiding retinal axons to their targets in the optic tectum. Our results extend the purported role of Mek4 in axon guidance to include motor neurons of the medial motor column.
Multiple Sclerosis: Basic and Clinical
Publisher: Springer International Publishing
Date: 2017
DOI: 10.1007/978-3-319-57193-5_8
Abstract: Multiple sclerosis (MS) is the most common neurodegenerative disease affecting young adults in our community. It is a complex disease influenced by gender, genetic and environmental factors. MS is a chronic inflammatory disease of the central nervous system caused by aberrant immune activation resulting in damage to myelin sheaths within the brain and spinal cord and axonal loss. The demyelinating insult initially impairs the speed and efficiency of nerve cell function. In the majority of cases, this is followed by an innate endogenous repair response that can restore the myelin sheath and nerve cell function to relatively normal levels. However over time and with subsequent demyelinating events, this capacity is lost ultimately leading to neural degeneration. The influences that oligodendrocytes and myelin exert upon nerve cells to sustain their health and viability have begun to be identified. While immune-directed therapies can reduce the frequency of relapses and development of new lesions, they have little effect upon remyelination and nerve cell repair. This presents the next big challenge in MS therapeutics complementing immune targeted therapies with strategies that directly target the primary cause of disability, that of remyelination.
Fibre-specific white matter changes in multiple sclerosis patients with optic neuritis
Publisher: Elsevier BV
Date: 2018
Analytical Bias in the Measurement of Serum 25-Hydroxyvitamin D Concentrations Impairs Assessment of Vitamin D Status in Clinical and Research Settings
Publisher: Public Library of Science (PLoS)
Date: 12-08-2015
Myelin Gene Regulatory Factor Is Required for Maintenance of Myelin and Mature Oligodendrocyte Identity in the Adult CNS
Publisher: Society for Neuroscience
Date: 05-09-2012
DOI: 10.1523/JNEUROSCI.1069-12.2012
Abstract: Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an inducible conditional knock-out strategy to investigate whether continued oligodendrocyte expression of the recently identified transcription factor myelin gene regulatory factor (MRF) is required to maintain the integrity of myelin in the adult CNS. Genetic ablation of MRF in mature oligodendrocytes within the adult CNS resulted in a delayed but severe CNS demyelination, with clinical symptoms beginning at 5 weeks and peaking at 8 weeks after ablation of MRF. This demyelination was accompanied by microglial/macrophage infiltration and axonal damage. Transcripts for myelin genes, such as proteolipid protein, MAG, MBP, and myelin oligodendrocyte glycoprotein, were rapidly downregulated after ablation of MRF, indicating an ongoing requirement for MRF in the expression of these genes. Subsequently, a proportion of the recombined oligodendrocytes undergo apoptosis over a period of weeks. Surviving oligodendrocytes gradually lose the expression of mature markers such as CC1 antigen and their association with myelin, without reexpressing oligodendrocyte progenitor markers or reentering the cell cycle. These results demonstrate that ongoing expression of MRF within the adult CNS is critical to maintain mature oligodendrocyte identity and the integrity of CNS myelin.
Short-term effects of methylprednisolone on cerebral volume in multiple sclerosis relapses
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.JOCN.2005.08.012
Abstract: We prospectively investigated the short-term effects of intravenous methyl-prednisolone (IVMP) on cerebral volume in patients suffering a multiple sclerosis (MS) relapse. Ten patients underwent MRI brain studies immediately before and after IVMP treatment, and 4 and 8 weeks later. Whole brain volumes decreased significantly over the 8-week period. The greatest change occurred during IVMP administration. This has implications for MS treatment trials using cerebral atrophy as an endpoint.
Nanodiamonds with silicon vacancy defects for nontoxic photostable fluorescent labeling of neural precursor cells
Publisher: The Optical Society
Date: 11-10-2013
DOI: 10.1364/OL.38.004170
Immunosuppressive therapy is valuable in aggressive multiple sclerosis
Publisher: Elsevier BV
Date: 11-2000
Erratum: Comparison of the effectiveness of a tailored cognitive behavioural therapy with a supportive listening intervention for depression in those newly diagnosed with multiple sclerosis (the ACTION-MS trial): Protocol of an assessor-blinded, active comparator, randomised controlled trial (Trials (2020) 21: 100 DOI: 10.1186/s13063-019-4018-8)
Publisher: Springer Science and Business Media LLC
Date: 20-03-2020
DOI: 10.1186/S13063-020-04261-X
Abstract: After publication of our article [1] the authors have notified us that three of the names have been incorrectly spelled.
A pilot randomized controlled trial of a tailored cognitive behavioural therapy based intervention for depressive symptoms in those newly diagnosed with multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 12-2016
No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis
Publisher: Oxford University Press (OUP)
Date: 13-11-2013
DOI: 10.1093/HMG/DDT574
Abstract: Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within in iduals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control in iduals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.
Leukaemia inhibitory factor abrogates Paclitaxel-induced axonal atrophy in the Wistar rat.
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/S0006-8993(01)02627-0
Abstract: A prominent side effect of Paclitaxel chemotherapy is sensorimotor peripheral neuropathy. Leukaemia inhibitory factor (LIF) supports the survival and regrowth of axotomised sensory and motor neurons and we therefore investigated if systemically administered LIF abrogated Paclitaxel-induced neuropathy. We found that whereas animals administered Paclitaxel alone exhibited a significant decrease in the percentage of large myelinated axons, this reduction was prevented by the co-administration of LIF.
A Transcription Factor Map as Revealed by a Genome- Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 12-2010
Sun Exposure across the Life Course Significantly Modulates Early Multiple Sclerosis Clinical Course
Publisher: Frontiers Media SA
Date: 02-2018
Cloning and growth of multipotential neural precursors: Requirements for proliferation and differentiation
Publisher: Elsevier BV
Date: 02-1993
DOI: 10.1016/0896-6273(93)90316-J
Abstract: The importance of intrinsic commitments and epigenetic influence to the development of mature neural cell phenotypes was assessed using embryonic day 10 murine neuroepithelial cells, isolated from telencephalon and mesencephalon. Two types of clones were generated with fibroblast growth factor: type-A clones consisted of large, amorphous cells, and type-B clones contained epithelial-like cells. In many type-B clones, very large numbers of precursor cells were produced. Twenty-four percent of type-B clones contained small numbers of neurons, and 59% of clones containing neurons also contained astrocytes, indicating that this clonal type was derived from a bipotential precursor cell. Neuronal differentiation was enhanced by culturing precursor cells with conditioned medium derived from an immortalized astroglial-like cell line. These results indicate that neuroepithelial precursors have discrete epigenetic requirements for their proliferation and differentiation.
Predictors and dynamics of postpartum relapses in women with multiple sclerosis
Publisher: SAGE Publications
Date: 09-10-2013
Abstract: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies. To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. An observational case–control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses. The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model. Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.
Anxiety, depression and fatigue at 5‐year review following
CNS
demyelination
Publisher: Hindawi Limited
Date: 12-01-2016
DOI: 10.1111/ANE.12554
Abstract: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.
A new era in the treatment of multiple sclerosis
Publisher: AMPCo
Date: 08-2015
DOI: 10.5694/MJA14.01218
Abstract: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.
Gas6 Increases Myelination by Oligodendrocytes and Its Deficiency Delays Recovery following Cuprizone-Induced Demyelination
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Associations between silicone skin cast score, cumulative sun exposure, and other factors in the ausimmune study: A multicenter Australian study
Publisher: American Association for Cancer Research (AACR)
Date: 11-2009
DOI: 10.1158/1055-9965.EPI-09-0191
Abstract: Past sun exposure is linked to a wide range of disease outcomes but is difficult to measure accurately. Silicone skin casts measure skin damage, but some studies show that age rather than sun exposure is the most important determinant of cast score. We examined skin damage scores from silicone casts of the back of the hand in a large adult s le (n = 534) with a broad range of past cumulative UV radiation (UVR) doses. Participants were ages 18 to 61 years and resided in one of four locations down the eastern Australian seaboard, spanning 27-43°S. Data were collected by questionnaire and during a nurse-led interview and examination. Silicone casts were graded from 1 to 6, where higher score represents greater damage. Higher skin damage score was associated with lighter skin pigmentation [adjusted odds ratio (AOR), 4.51 95% confidence interval (95% CI), 2.33-8.75], fairer natural hair color, particularly red hair (AOR, 11.31 95% CI, 4.08-31.36), and blue/gray eyes (AOR, 1.72 95% CI, 1.14-2.59). Higher cumulative UVR dose, particularly before age 18 years, was associated with higher skin damage score (AOR, 2.06 95% CI, 1.15-2.67 per 1,000 KJ/m2), as was number of sunburns, even after adjustment for cumulative UVR dose (AOR, 2.86 95% CI, 1.50-5.43 for & sunburns ever compared with no sunburns ever). Silicone casts of the dorsum of the hand provide a measure of cumulative UVR dose and number of sunburns over the lifetime, which persists after adjustment for chronological age. They can be used as an objective measure of cumulative past sun exposure in epidemiologic studies, but other determinants of skin damage, such as skin pigmentation, should be concurrently evaluated. (Cancer Epidemiol Biomarkers Prev 2009 (11):2887–94)
Prospects for stem cell transplantation in multiple sclerosis
Publisher: Elsevier BV
Date: 07-2002
Induction of postnatal schwann cell death by the low-affinity neurotrophin receptor in vitro and after axotomy.
Publisher: Society for Neuroscience
Date: 08-2000
DOI: 10.1523/JNEUROSCI.20-15-05741.2000
Abstract: Schwann cells express the low-affinity neurotrophin receptor (p75), but no role for either the neurotrophins or their cognate receptors in Schwann cell development has been established. We have found that Schwann cells isolated from postnatal day 1 (P1) or P2 mice that were p75-deficient exhibited potentiated survival compared to wild-type cells after growth factor and serum withdrawal. There was, however, no disparity in the survival of p75-deficient and wild-type Schwann cells isolated at embryonic day 15, suggesting that the death-inducing effects of p75 are developmentally regulated. A comparable degree of cell death was also observed in the sciatic nerves of both wild-type and p75-deficient mice at P1. However, 24 hr after axotomy, there was a 13-fold increase in the percentage of apoptotic nuclei in the distal nerve stumps of the transected sciatic nerves of neonatal wild-type but not p75-deficient mice. The expression of both the p75 and nerve growth factor (NGF) genes was upregulated after axotomy in neonatal wild-type nerves. Collectively, these results suggest that NGF-mediated activation of p75 is likely to be an important mediator of Schwann cell apoptosis in the context of peripheral nerve injury.
Adherence to MRI protocol consensus guidelines in multiple sclerosis: An Australian multi-centre study
Publisher: Wiley
Date: 12-2012
Abstract: Multiple sclerosis (MS) is a debilitating disease that causes significant morbidity within a young demographic. Diagnostic guidelines for MS have evolved, and imaging has played an increasingly important role in diagnosis over the last two decades. For imaging to contribute to diagnosis in a meaningful way, it must be reproducible. Consensus guidelines for MRI in MS exist to define correct sequence type and imaging technique, but it is not clear to what extent they are followed. This study reviewed MRI studies performed on Australian in iduals presenting with a first clinical diagnosis of central nervous system demyelination (FCD) for adherence to published guidelines and discussed practical implementation of MS guidelines in light of recent updates. The Ausimmune study was a prospective case control study of Australian participants presenting with FCD from 2003 to 2006. Baseline cranial and spinal cord MRI studies of 226 case participants from four separate Australian regions were reviewed. MRI sequences were classified according to anatomical location, slice plane, tissue weighting and use of gadolinium-containing contrast media. Results were compared with the 2003 Consortium of Multiple Sclerosis Centres MRI protocol for the diagnosis of MS. The composition of core cranial MRI sequences performed varied across the 226 scans. Of the studies, 91% included sagittal fluid attenuated inversion recovery (FLAIR) sequences. Cranial axial T2-weighted, axial FLAIR and axial proton density-weighted sequences were performed in 88%, 60% and 16% (respectively) of scans. Only 25% of the studies included a T1-weighted contrast-enhanced sequence. Concordance with the guidelines in all sequences was very low (2). Only a small number of MRI investigations performed included all of the sequences stipulated by consensus guidelines. This is likely due to poor awareness in the imaging community of the guidelines and the rationale behind certain sequences. Radiologists with a sub-speciality interest in neuroradiology should take ownership of this issue and ensure that recommended imaging guidelines are followed.
The TAM receptor Tyro3 regulates myelination in the central nervous system
Publisher: Wiley
Date: 02-2017
DOI: 10.1002/GLIA.23113
Abstract: Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro. Gas6 can bind to and activate all three TAM receptors, but the high level of expression of Tyro3 on oligodendrocytes makes this receptor the principal candidate for transducing the pro-myelinating effect of Gas6. In this study, we establish that in the absence of Tyro3, the pro-myelinating effect of Gas6 is lost, that developmental myelination is delayed and that the myelin produced is thinner than normal. We show that this effect is specific to the myelination process and not due to changes in the proliferation or differentiation of oligodendrocyte precursor cells. We have further demonstrated that the reduction in myelination is due to the loss of Tyro3 on oligodendrocytes, and this effect may be mediated by activation of Erk1. Collectively, our findings indicate the critical importance of Tyro3 in potentiating central nervous system myelination. GLIA 2017 GLIA 2017 :581-591.
Tyro3 Contributes to Retinal Ganglion Cell Function, Survival and Dendritic Density in the Mouse Retina
Publisher: Frontiers Media SA
Date: 14-08-2020
TAM Receptor Signalling and Demyelination
Publisher: S. Karger AG
Date: 2009
DOI: 10.1159/000231894
Abstract: The TAM family (Tyro3, Axl and Mer) of receptor protein tyrosine kinases play pivotal roles in a number of major cellular processes: cell survival and proliferation, immunomodulation and phagocytosis. These processes are central to both the initial development and pathological course of human multiple sclerosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS), including in oligodendrocytes, the myelin-producing cell of the CNS. Recent studies have shown that Gas6-dependent TAM receptor signalling is an important modulator of oligodendrocyte survival and microglial phenotype both in vitro and in vivo. Multiple lines of evidence allow us to hypothesise that, during a demyelinating challenge, dysfunctional TAM receptor signalling could lead to a 'vicious cycle' of cell death, reduced phagocytosis and deleterious immune hyper-activation. A current challenge in this field is to expand our understanding of TAM receptor signalling from rodent models of central demyelination to human disease.
REGULATION OF NEURAL PRECURSOR DIFFERENTIATION IN THE EMBRYONIC AND ADULT FOREBRAIN
Publisher: Wiley
Date: 08-1995
DOI: 10.1111/J.1440-1681.1995.TB02066.X
Abstract: 1. Precursors form the neuroepithelium of the developing cortex and also from the adult sub-ventricular zone, can be cloned in vitro after stimulation with fibroblast growth factor (FGF)-2 and have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyteprecursor line, Ast-1, or FGF-1. 2. Neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol-lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the PCL gamma pathway. 3. The sequential expression of FGF-2 and FGF-1 within the developing forebrain neuroepithelium fits with the different functions the two FGF play in precursor regulation. 4. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan (HSPG) expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2 however, the differentiation into GFAP positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor beta receptor.
The Role of Neurotrophins in the Regulation of Myelin Development
Publisher: S. Karger AG
Date: 2009
DOI: 10.1159/000231893
Abstract: Neurotrophins comprise a family of growth factors that are expressed in a variety of cell types, and which exert influences on a large range of cellular activities that are important for development and the maintenance of the nervous system, as well as in neurodegenerative and psychiatric disorders. More recently, neurotrophins have been implicated in influencing the dynamic and complex signals that occur between neurons and glial cells, including Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system that regulate myelination. Here we review the recent studies that identify neurotrophins as important regulators of both peripheral and central myelination, highlight some of the many questions that remain to be answered, and identify possibilities for further research.
LIF potentiates the NT-3-mediated survival of spiral ganglia neurones in vitro.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1997
DOI: 10.1097/00001756-199705060-00017
Abstract: The survival of auditory neurones depends on the continued supply of trophic factors. Early postnatal spiral ganglion cells (SGC) in a dissociated cell culture were used as a model of auditory innervation to test the trophic factors leukaemia inhibitory factor (LIF) and neurotrophin-3 (NT-3) for their ability, in idually or in combination, to promote neuronal survival. The findings suggest that LIF supports neuronal survival in a concentration-dependent manner. Moreover LIF potentiated NT-3-mediated spiral ganglion neuronal survival in a synergistic fashion.
Increasing age at disability milestones among MS patients in the MSBase Registry
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.JNS.2012.03.017
Abstract: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period. We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subs les of patients diagnosed according to Poser or McDonald criteria. The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (p<0.001), and for EDSS 6/6.5 - by 4.9 years, from 48 to 53 year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets. The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed.
Leukaemia inhibitory factor or related factors promote the differentiation of neuronal and astrocytic precursors within the developing murine spinal cord
Publisher: Wiley
Date: 02-1996
DOI: 10.1111/J.1460-9568.1996.TB01213.X
Abstract: Previously we have shown that leukaemia inhibitory factor (LIF) potentiates the development of murine spinal cord neurons in vitro, suggesting that it, or related factors, may play an important regulatory role in neuronal development. We have further investigated this role and show here that the generation of neurons in cultures of embryonic day 10 spinal cord cells is inhibited by antibodies to the beta subunit of the LIF receptor. Since there are more undifferentiated precursors in antibody-treated cultures than in control and LIF-treated cultures, it is concluded that the primary action of LIF, or related molecules, is to promote neuronal differentiation, not precursor survival. In addition, the failure of LIF to support neuronal survival in the period immediately following differentiation suggests that the increased numbers of neurons generated with LIF are not attributable to its neurotrophic action. By selecting neuronal precursors on the basis of their inability to express class 1 major histocompatibility complex molecules, it was shown that LIF acted directly upon these cells and not via an intermediary cell. LIF also appears to be involved in regulating the differentiation of astrocytes, since it increases the number of glial fibrillary protein (GFAP)-positive cells present in the cultures and since the spontaneous production of GFAP-positive cells is blocked by antibodies to the LIF beta receptor. These findings suggest that LIF or related factors promote the differentiation of neural precursors in the spinal cord, but that they are not involved in preferentially promoting precursors down a specific differentiation pathway.
Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis
Publisher: Oxford University Press (OUP)
Date: 28-11-2012
DOI: 10.1093/HMG/DDS491
Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes
Publisher: Oxford University Press (OUP)
Date: 12-02-2013
DOI: 10.1093/HMG/DDT062
Abstract: Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in in iduals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 s les and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools this result has important implications for the design of future fine-mapping studies.
Leukemia inhibitory factor promotes the neuronal development of spinal cord precursors from the neural tube
Publisher: Wiley
Date: 11-1992
Abstract: Recent evidence from our laboratory has shown that leukemia inhibitory factor (LIF) can act early in peripheral nervous system development. We have investigated a potential role of LIF in the developing spinal cord. In explants and dissociated cultures of spinal cord primordium, LIF stimulated a profuse neurite outgrowth. To determine if these effects were related to neuronal differentiation, cells were plated at low cell density and stained for neurofilament. LIF stimulated an increase in the number of newly differentiated neurons, without inducing proliferation of the precursors. Given that LIF has previously reported effects as a cholinergic switching factor for sympathetic neurons, we investigated whether LIF had similar effects in these spinal cord cultures. LIF increased the number of cholinergic neurons in proportion to its overall effect on the stimulation of all neurofilament positive neurons in the culture. These data show that LIF stimulates the generation of spinal cord neurons from their precursors and further implicates a role for LIF in nervous system development.
Exposure to infant siblings during early life and risk of multiple sclerosis
Publisher: American Medical Association (AMA)
Date: 26-01-2005
Abstract: The "hygiene hypothesis" has implicated sibship as a marker of infection load during early life and suggests that exposure or reexposure to infections can influence the developing immune system. Viral infection has also been implicated in the pathogenesis of multiple sclerosis (MS). To evaluate whether exposure to infant siblings in early life is associated with the risk of MS, and to explore the possible mechanism for any apparent protective effect, including altered Epstein-Barr virus (EBV) infection patterns. Population-based case-control study in Tasmania, Australia, from 1999 to 2001 based on 136 cases of magnetic resonance imaging-confirmed MS and 272 community controls, matched on sex and year of birth. Risk of MS by duration of contact with younger siblings aged less than 2 years in the first 6 years of life. Increasing duration of contact with a younger sibling aged less than 2 years in the first 6 years of life was associated with reduced MS risk (adjusted odds ratios [AORs]: <1 infant-year, 1.00 [reference] 1 to <3 infant-years, 0.57 [95% confidence interval {CI}, 0.33-0.98] 3 to or =5 infant-years, 0.12 [95% CI, 0.02-0.88] test for trend, P = .002). A history of exposure to infant siblings was associated with a reduced IgG response to EBV among controls. Controls with at least 1 infant-year contact had a reduced risk of infectious mononucleosis and a reduced risk of very high composite EBV IgG titers (AOR, 0.33 95% CI, 0.11-0.98) compared with other controls. The inverse association between higher infant contact and MS was independent of EBV IgG titer. Higher infant sibling exposure in the first 6 years of life was associated with a reduced risk of MS, possibly by altering childhood infection patterns and related immune responses.
Brain-Derived Neurotrophic Factor Promotes Central Nervous System Myelination via a Direct Effect upon Oligodendrocytes
Publisher: S. Karger AG
Date: 2010
DOI: 10.1159/000323170
Abstract: The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain-derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes.
Familial recurrence risks for multiple sclerosis in Australia
Publisher: BMJ
Date: 07-05-2011
Abstract: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites. The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 29-09-2013
DOI: 10.1038/NG.2770
Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially
Publisher: Oxford University Press (OUP)
Date: 18-04-2013
DOI: 10.1111/CEI.12077
Abstract: The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case–control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18–59 years controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma sibling profile (number dates of birth) and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68 95% CI: 0·49, 0·95) but not asthma (OR = 1·47 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative ‘sibling effect’.
The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system
Publisher: Wiley
Date: 12-09-2018
DOI: 10.1002/GLIA.23481
Abstract: Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Major deficits arise in MS patients due to an inability to repair damaged myelin sheaths following CNS insult, resulting in prolonged axonal exposure and neurodegeneration. The TAM receptors (Tyro3, Axl, and Mertk) have been implicated in MS susceptibility, demyelination and remyelination. Previously, we have shown that Tyro3 regulates developmental myelination and myelin thickness within the optic nerve and rostral region of the corpus callosum (CC) of adult mice. In this study we have verified and extended our previous findings via a comprehensive analysis of axonal ensheathment and myelin thickness in the CC of unchallenged mice, following demyelination and during myelin repair. We show that the loss of the Tyro3 receptor correlates with significantly thinner myelin sheaths in both unchallenged mice and during remyelination, particularly in larger caliber axons. The hypomyelinated phenotype observed in the absence of Tyro3 occurs independently of any influence upon oligodendrocyte precursor cell (OPC) maturation, or density of oligodendrocytes (OLs) or microglia. Rather, the primary effect of Tyro3 is upon the radial expansion of myelin. The loss of Tyro3 leads to a reduction in the number of myelin lamellae on axons, and is therefore most likely a key component of the regulatory mechanism by which oligodendrocytes match myelin production to axonal diameter.
De novo generation of neuronal cells from the adult mouse brain
Publisher: Proceedings of the National Academy of Sciences
Date: 15-09-1992
Abstract: Cells of neuronal morphology, expressing the 150- and 200-kDa neurofilament proteins, were generated in vitro from populations of neural cells dissociated from adult (greater than 60-day-old) mouse brain. Most of these neurons arose from iding precursors, as demonstrated by the incorporation of [3H]thymidine during the culture period and autoradiography. Neuronal production was optimal under the conditions in which precursors were initially stimulated with basic fibroblast growth factor and then exposed to medium conditioned by an astrocytic cell line, Ast-1, in serum-free medium. Few, if any, neurons arose in control cultures or in cultures kept in serum and fibroblast growth factor. These results suggest that neuronal precursors exist in the adult mammalian brain, but they require discrete epigenetic signals for their proliferation and differentiation.
The neurotrophins act synergistically with LIF and members of the TGF-β superfamily to promote the survival of spiral ganglia neurons in vitro
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S0378-5955(99)00152-5
Abstract: A number of growth factor families have been implicated in normal inner ear development, auditory neuron survival and protection. Several growth factors, including transforming growth factor-beta5 (TGF-beta5) and TGF-beta3, neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were tested for their ability, in idually or in combination, to promote auditory neuron survival in dissociated cell cultures of early rat post-natal spiral ganglion cells (SGCs). The results indicate that at discrete concentrations all growth factors act in an additive fashion and some in synergy when promoting neuronal survival. These findings support the hypothesis that growth factors from different families may be interdependent when sustaining neuronal integrity.
The MSReactor computerized cognitive battery correlates with the processing speed test in relapsing-remitting multiple sclerosis
Publisher: Elsevier BV
Date: 08-2020
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Florey Institute Of Neuroscience And Mental Health
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