Florey Department of Neuroscience and Mental Health - Research Publications
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ItemNo Preview AvailableEvidence for decreased copper associated with demyelination in the corpus callosum of cuprizone-treated mice(OXFORD UNIV PRESS, 2024-01-05)Demyelination within the central nervous system (CNS) is a significant feature of debilitating neurological diseases such as multiple sclerosis and administering the copper-selective chelatorcuprizone to mice is widely used to model demyelination in vivo. Conspicuous demyelination within the corpus callosum is generally attributed to cuprizone's ability to restrict copper availability in this vulnerable brain region. However, the small number of studies that have assessed copper in brain tissue from cuprizone-treated mice have produced seemingly conflicting outcomes, leaving the role of CNS copper availability in demyelination unresolved. Herein we describe our assessment of copper concentrations in brain samples from mice treated with cuprizone for 40 d. Importantly, we applied an inductively coupled plasma mass spectrometry methodology that enabled assessment of copper partitioned into soluble and insoluble fractions within distinct brain regions, including the corpus callosum. Our results show that cuprizone-induced demyelination in the corpus callosum was associated with decreased soluble copper in this brain region. Insoluble copper in the corpus callosum was unaffected, as were pools of soluble and insoluble copper in other brain regions. Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum. This effect was associated with significant mitigation of cuprizone-induced demyelination. These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed.
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ItemNo Preview AvailableLocus for severity implicates CNS resilience in progression of multiple sclerosis(NATURE PORTFOLIO, 2023-07-13)Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.
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ItemNo Preview AvailableThe Tolerogenic Influence of Dexamethasone on Dendritic Cells Is Accompanied by the Induction of Efferocytosis, Promoted by MERTK.(MDPI AG, 2023-11-02)Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone's tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone's effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses.
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ItemNo Preview AvailableMertk-expressing microglia influence oligodendrogenesis and myelin modelling in the CNS.(Springer Science and Business Media LLC, 2023-11-06)BACKGROUND: Microglia, an immune cell found exclusively within the CNS, initially develop from haematopoietic stem cell precursors in the yolk sac and colonise all regions of the CNS early in development. Microglia have been demonstrated to play an important role in the development of oligodendrocytes, the myelin producing cells in the CNS, as well as in myelination. Mertk is a receptor expressed on microglia that mediates immunoregulatory functions, including myelin efferocytosis. FINDINGS: Here we demonstrate an unexpected role for Mertk-expressing microglia in both oligodendrogenesis and myelination. The selective depletion of Mertk from microglia resulted in reduced oligodendrocyte production in early development and the generation of pathological myelin. During demyelination, mice deficient in microglial Mertk had thinner myelin and showed signs of impaired OPC differentiation. We established that Mertk signalling inhibition impairs oligodendrocyte repopulation in Xenopus tadpoles following demyelination. CONCLUSION: These data highlight the importance of microglia in myelination and are the first to identify Mertk as a regulator of oligodendrogenesis and myelin ultrastructure.
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ItemNo Preview AvailableThe Patient-Determined Disease Steps scale is not interchangeable with the Expanded Disease Status Scale in mild to moderate multiple sclerosis(WILEY, 2024-01)BACKGROUND AND PURPOSE: The validity, reliability, and longitudinal performance of the Patient-Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. METHODS: We included relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test-retest reliability was examined. Longitudinal data were analysed with mixed-effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). RESULTS: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient-reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test-retest reliability was good to excellent (concordance correlation coefficient = 0.73-0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. CONCLUSION: The PDDS has greater correlation with other PROs but less correlation with other MS-related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.
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ItemNo Preview AvailableMouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system(NATURE PORTFOLIO, 2023-05-22)Microglia regulate multiple processes in the central nervous system, exhibiting a considerable level of cellular plasticity which is facilitated by an equally dynamic transcriptional environment. While many gene networks that regulate microglial functions have been characterised, the influence of epigenetic regulators such as small non-coding microRNAs (miRNAs) is less well defined. We have sequenced the miRNAome and mRNAome of mouse microglia during brain development and adult homeostasis, identifying unique profiles of known and novel miRNAs. Microglia express both a consistently enriched miRNA signature as well as temporally distinctive subsets of miRNAs. We generated robust miRNA-mRNA networks related to fundamental developmental processes, in addition to networks associated with immune function and dysregulated disease states. There was no apparent influence of sex on miRNA expression. This study reveals a unique developmental trajectory of miRNA expression in microglia during critical stages of CNS development, establishing miRNAs as important modulators of microglial phenotype.
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ItemNo Preview AvailableHigh-efficiency pharmacogenetic ablation of oligodendrocyte progenitor cells in the adult mouse CNS(CELL PRESS, 2023-02-27)Approaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent CNS have limitations in the extent and duration of OPC depletion. We have developed a pharmacogenetic approach for conditional OPC ablation, eliminating >98% of OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found that new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+NG2+ cells with the capacity to proliferate and migrate extensively throughout the dorsal anterior forebrain. Further application of this approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.
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ItemGait and balance deterioration over a 12-month period in multiple sclerosis patients with EDSS scores ≤ 3.0(IOS PRESS, 2017)BACKGROUND AND PURPOSE: It is not currently known whether gait and balance measures are responsive to deterioration of motor function in multiple sclerosis (MS) patients with low EDSS scores (≤3.0). The aim of this study was to quantify MS-related gait and balance deterioration over a 12-month period. METHODS: Thirty-eight participants with MS (33 female, mean age: 41.1 ± 8.3 years), mean time since diagnosis 2.2 ± 4.1 years, EDSS score ≤3.0 and without clinical evidence of gait deterioration, were recruited. Participants performed walking trials and Functional and Lateral Reach Tests. Kinematics of the ankle and knee, and electromyography of the tibialis anterior and medial gastrocnemius muscles were also measured. RESULTS: Three participants reported relapses with worsening EDSS scores and 4 non-relapsing participants had worse EDSS scores at 12 months. There were significant decreases in mean gait speed, stride length and balance scores, and a significant increase in double support. Marked changes in ankle kinematics, with decreased medial gastrocnemius activity were observed. CONCLUSION: Gait and balance performance of non-disabled RRMS participants may progressively decline, even in the absence of both acute clinical relapse and change in clinical status measured by the EDSS.
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ItemGait stability reflects motor tracts damage at early stages of multiple sclerosis(SAGE PUBLICATIONS LTD, 2022-10)BACKGROUND: Gait in people with multiple sclerosis (PwMS) is affected even when no changes can be observed on clinical examination. A sensitive measure of gait deterioration is stability; however, its correlation with motor tract damage has not yet been established. OBJECTIVE: To compare stability between PwMS and healthy controls (HCs) and determine associations between stability and diffusion magnetic resonance image (MRI) measures of axonal damage in selected sensorimotor tracts. METHODS: Twenty-five PwMS (Expanded Disability Status Scale (EDSS) < 2.5) and 15 HCs walked on a treadmill. Stability from sacrum (LDESAC), shoulder (LDESHO) and cervical (LDECER) was calculated using the local divergence exponent (LDE). Participants underwent a 7T-MRI brain scan to obtain fibre-specific measures of axonal loss within the corticospinal tract (CST), interhemispheric sensorimotor tract (IHST) and cerebellothalamic tract (CTT). Correlation analyses between LDE and fibre density (FD) within tracts, fibre cross-section (FC) and FD modulated by FC (FDC) were conducted. Between-groups LDE differences were analysed using analysis of variance (ANOVA). RESULTS: Correlations between all stability measures with CSTFD, between CSTFDC with LDESAC and LDECER, and LDECER with IHSTFD and IHSTFDC were significant yet moderate (R < -0.4). Stability was significantly different between groups. CONCLUSIONS: Poorer gait stability is associated with corticospinal tract (CST) axonal loss in PwMS with no-to-low disability and is a sensitive indicator of neurodegeneration.
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ItemImplementing education: Personal communication with a healthcare professional is a critical step to address vaccine hesitancy for people with multiple sclerosis(ELSEVIER SCI LTD, 2022-07)BACKGROUND: People with Multiple Sclerosis (PwMS) were first able to access COVID-19 vaccines in Australia from March 2021, when vaccine hesitancy in the general population was high (14-43%). High uptake of vaccination is important globally and critical to protect this vulnerable population. We conducted an on-line survey to examine factors influencing COVID-19 vaccination willingness among PwMS in Australia. METHODS: 149 PwMS living in Australia completed the on-line survey (April-September 2021) examining demographic, environmental and clinical factors with respect to vaccine willingness, including attitudes towards COVID-19 illness and vaccines. Additional items explored the influence of different information sources on vaccination decisions. Continuous and ordinal data were compared using the Mann-Whitney U test. All tests were two-tailed, with alpha set at 0.5. RESULTS: A majority of the respondents were female (87.2%) with relapsing-remitting MS (77.5%) treated by a neurologist (94.0%). A majority were on high efficacy disease-modifying therapies (DMTs) (64.9%), while 19.9% were on no DMTs. About one third of respondents (32.9%) had had two doses, 20.8% had received their first dose, and 22.1% were unvaccinated, while 24.2% of responses were missing. When asked about vaccine intentions, 60.6% of the unvaccinated indicated they were likely to extremely likely to get vaccinated, while 15.2% were very unlikely or extremely unlikely to do so and 24.2% were undecided. Unvaccinated people were significantly more concerned about vaccine side effects (mean 5.3 versus 3.1/10; p < .001). Only 53.3% of people on DMTs were vaccinated, compared to 75% of those who were not. People on ocrelizumab therapy (n = 35) had a lower vaccination rate (39%) than those on other medications (n = 86, 59%). Vaccine willingness in the unvaccinated was most highly correlated with knowledge regarding the vaccine (rs2=.709), agreement with the statement that COVID-19 vaccination is "too new for me to be confident about getting vaccinated" (rs2= -.709), anticipation of regret due to side effects of vaccination (rs2= -.642), and lack of knowledge regarding interactions between COVID-19 vaccines and DMTs (rs2= -.570). Almost two thirds had read MS-specific information about COVID-19 vaccinations and found it easy to understand (67.6%) and applicable to their situation (53.6%). However, less than half (47.8%) reported the information helped them make a personal vaccination decision. Over two-thirds (64.9%) had discussed vaccinations with their healthcare professional and 31.1% had not. Those who had not, were significantly more uninformed about the interactions of the vaccine with MS medications (mean 3.9 versus 2.9/10; p = .044) and significantly lower intention of vaccine uptake than those who had (mean 5.8 versus 7.9/10; p = .009). CONCLUSION: Our study highlights that vaccination efforts should be delivered by healthcare professionals, focus on educating those who are managed with DMTs, and include individual recommendations related to specific DMTs, how the vaccines work, expectations regarding potential side-effects, potential exacerbation of MS symptoms, likelihood of recovery from any exacerbation, and the relative risks of side effects versus COVID-19 infection. Specific recommendations are provided.