Sessions

Deb has worked in the public health and prevention space at all levels of government – Federal, State and Local – and not for profit sectors to contribute to the health and well-being of communities. She has worked to capture the voices of all parts of the community impacted by services, programs, and research including access and inclusion, Aboriginal and Torres Strait Islander people, culturally and linguistically diverse communities, children and young people, those with mental health challenges, and those connected with health and community services.

She has always worked connecting institutions, organisations, government, and community with a well-being focus, and was a representative on WA Sustainable Health Review with this in mind. She has been appointed to the NHMRC’s Consumer Statement Advisory Committee to review and develop new national principles and guidelines for involvement of people with lived experience in research, together with the Medical Research Future Fund Consumer-led Grant Assessment Committee.

Deb’s role leading the Consumer and Community Involvement Program (CCIProgram) as a platform of the Western Australia Health Translation Network is to connect researchers in WA Universities, Medical Research Institutes, Government, and Health Service Providers and Funders with people with lived experience to support and encourage best practice research. She has been involved in the development of the WA Future Health Research and Innovation (FHRI) Fund Strategy’s Research Principles and Grant Scheme governance and part of the consultation for the development of the WA Health and Medical Research Strategy 2023 – 2033. Of note, has been her involvement in the Executive Group developing and guiding WA’s first Mental Health Research Strategy that has the lived experience of people with mental health challenges as it’s foundation. Newly appointed as the Chair, Australian Health Research Alliance (AHRA) Consumer and Community Involvement Advisory Committee ensures that conversations at a national level are relevant and inclusive of the best practice work of involving people in research being conducted in institutions and health care providers both nationally and in WA.

Deb is passionate about ensuring research can impact policy, practice and wellbeing of communities and enjoys bringing people together to make a difference.

Dr Anna Ritchie achieved fellowship of the Royal Australian College of General Practitioners in 2011 and worked as a GP until her MS diagnosis in 2020. She attained further qualifications in women’s health and has many years’ experience in this field working at Family Planning Tasmania. Anna joined the University of Tasmania's Menzies Institute for Medical Research MS Research Flagship’s Consumer and Community Reference Committee in 2021 after attending the Flagship’s Research with Connections event that year. She very much enjoys the opportunity to contribute her skills and experiences to help shape the future of MS care through research.

Dr Nicholas Blackburn is a Research Fellow in Computational Genomics at the Menzies Institute for Medical Research, University of Tasmania. He leads the MS Family Study where together with his team he uses genomic approaches to understand the genetics of families where multiple relatives are affected by MS. By hunting for MS genes in families his work aims to understand the biological causes of MS, how the disease initiates, and how we can target biology for therapy development. Nicholas is a strong advocate for consumer involvement in research and is currently an MS Australia Research Fellow.

Collaborating with the multiple sclerosis community to co-design an online nutrition education program for people with multiple sclerosis.

Background: Nutrition education programs can provide people with the knowledge, skills, and support to achieve high-quality diets in line with recommendations. Co-designed programs are rated as more acceptable and result in positive behaviour change; however, no co-designed nutrition programs exist for people with multiple sclerosis (MS).  

Objective: We aimed to use the best practice principles for nutrition education by collaborating with people with MS and MS stakeholders to co-design a nutrition education program. The proposed program would be grounded in theory and targeted to the needs and experiences of people with MS. 

Methods: We used a multiphase mixed-methods design. The development was guided by our Stakeholder Reference Group (people with MS and MS health professionals; n=10). MS community involvement included focus groups (n=34) and a survey (n=114) to explore preferences for nutrition content and delivery mode, two workshops (n=6) to provide feedback on the draft program, and cognitive interviews (n=8) to explore acceptability and ease of comprehension of one online prototype module. 

Results: The co-design process revealed preferred content: MS-specific dietary guidance (including foods, diets, and supplements), overcoming barriers (including MS symptoms) to dietary changes, where to seek dietary advice, judging the credibility of information, and suitability of the national dietary guidelines. The preferred mode was online and one-hour per module. The prototype module was described as acceptable, and the positive tone, actionable messages, and person-centred language were empowering and motivating.

Conclusions: People with MS are interested in online resources and in managing their MS through lifestyle modifications, including diet. By collaborating with the MS community, we co-designed an acceptable and easy to understand nutrition education program with content that aligned with their online learning needs. 

Funding sources: This research was supported by MSWA and an MS Australia Incubator Grant (#21-1-072).  

RDR was supported by an Australian Government RTP Scholarship, an MSWA PhD Top-Up Scholarship, and a Graduate Women (WA) Inc. Open Scholarship. 

LJB is supported by MSWA and an MS Australia Postdoctoral Fellowship.  

Keywords: Nutrition education, co-design, community engagement, diet, lifestyle factors 

Authors: Rebecca RUSSELL (1), Lucinda BLACK (2), Justine PURDUE (1), Alison DALY (1), and Andrea BEGLEY (1) 

Author affiliations: 
1. Curtin School of Population Health, Curtin University 
2. Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University 

Associate Professor Anne Brüstle is an immunologist at The John Curtin School of Medical Research

Her work centres around the autoimmune component of Multiple Sclerosis. Her group investigates key immune populations driving the pathogenesis of this complex condition, such as the Il-17 producing Th17 cells and neutrophil granulocytes, using laboratory model systems to understand the underlying biological principals. In collaboration with diverse industrial partners her group further evaluates potential new targets for conceptually novel MS treatments and deciphers their biological mechanisms in neuroinflammation. In 2018 she was awarded the Young Tall Poppy Award for her work for and with the MS community. She further is the chair and MS research lead of “Our Health in Our Hands” an interdisciplinary program to develop personalised monitoring and managing approaches for chronic autoimmune conditions such as MS and diabetes in collaboration and co-designed by people with lived experience.

Anne completed her PhD in Human Biology 2008 at the Institute of Medical Microbiology, Philipps-University in Marburg, Germany. She was recruited to ANU in mid 2014, after being a post-doctoral fellow at the University of Toronto, Canada.

Deb has worked in the public health and prevention space at all levels of government – Federal, State and Local – and not for profit sectors to contribute to the health and well-being of communities. She has worked to capture the voices of all parts of the community impacted by services, programs, and research including access and inclusion, Aboriginal and Torres Strait Islander people, culturally and linguistically diverse communities, children and young people, those with mental health challenges, and those connected with health and community services.

She has always worked connecting institutions, organisations, government, and community with a well-being focus, and was a representative on WA Sustainable Health Review with this in mind. She has been appointed to the NHMRC’s Consumer Statement Advisory Committee to review and develop new national principles and guidelines for involvement of people with lived experience in research, together with the Medical Research Future Fund Consumer-led Grant Assessment Committee.

Deb’s role leading the Consumer and Community Involvement Program (CCIProgram) as a platform of the Western Australia Health Translation Network is to connect researchers in WA Universities, Medical Research Institutes, Government, and Health Service Providers and Funders with people with lived experience to support and encourage best practice research. She has been involved in the development of the WA Future Health Research and Innovation (FHRI) Fund Strategy’s Research Principles and Grant Scheme governance and part of the consultation for the development of the WA Health and Medical Research Strategy 2023 – 2033. Of note, has been her involvement in the Executive Group developing and guiding WA’s first Mental Health Research Strategy that has the lived experience of people with mental health challenges as it’s foundation. Newly appointed as the Chair, Australian Health Research Alliance (AHRA) Consumer and Community Involvement Advisory Committee ensures that conversations at a national level are relevant and inclusive of the best practice work of involving people in research being conducted in institutions and health care providers both nationally and in WA.

Deb is passionate about ensuring research can impact policy, practice and wellbeing of communities and enjoys bringing people together to make a difference.

Professor Jeremy Chataway MA, PhD, FRCP Professor of Neurology, University College London and the National Hospital for Neurology and Neurosurgery (NHNN), Queen Square, University College Foundation NHS Trust.

After qualifying in medicine at Cambridge and Oxford Universities and general medical training in London, he specialised in Neurology with posts in Edinburgh, Cambridge and London. He was awarded a PhD from Cambridge University in genetic epidemiology of multiple sclerosis and took up his post as a consultant Neurologist in 2001.

He has a particular interest in advanced (such as multi-arm multi-stage) clinical trial design and is the Chief Investigator of the MS-STAT, MS-SMART and OCTOPUS trial programmes in Progressive MS. He is a Programme Lead for Neurodegeneration at the MRC Clinical Trial Unit.

Current International Positions

Member: International Advisory Committee on Clinical Trials (IACCT) in MS: 2021-current. This is a major international committee co-sponsored by the European Committee for treatment and Research in Multiple Sclerosis (ECTRIMS) and the National (US) Multiple Sclerosis Society).

Member: International Progressive MS Alliance Experimental Medicine Committee: 2018-current.

Yasmine Probst is an Associate Professor with the School of Medical, Indigenous and Health Sciences at the University of Wollongong and Research Fellow at the Illawarra Health and Medical Research Institute. She holds dual Masters degrees in Dietetics and Health Informatics and is recognised as an Advanced Accredited Practising Dietitian with Dietitians Australia and a Fellow of the Australasian Institute for Digital Health. Yasmine holds a current Senior Research fellowship with MS Australia. As a person living with MS, her research and teaching focuses on nutrition for people living with MS.

Viv commenced work at the University of Tasmania's  Menzies Institute for Medical Researching in January 2018 as the inaugural project manager for the MS Research Flagship program.  She was responsible for establishing and implementing governance structures and stakeholder management. The embedding of consumer and community involvement within the program was a priority of her role.

In March 2020, she was appointed as the and Consumer and Community Involvement Manager for the MS Research Flagship at Menzies and is a member of the Flagship's leadership group. She has strong links with the MS Community in Tasmania and interstate and has a lived experience of MS of over 27 years since her diagnosis in 1996.

Chris is the current Chair of the MS research Flagship’s consumer and community reference committee at the Menzies Institute for Medical Research.  She served as deputy chair of that committee for 2 years from 2021-2023 and was an inaugural member, joining the committee at its inception in September 2019.

Chris is a retired health-professional training as a registered nurse and midwife and eventually working her way up to the position of Theatre Manager for a private hospital.

Following her diagnosis of MS, Chris moved to an administrative role where she worked as the risk manager for the hospital. In this role she managed the health, safety, and quality functions.  This included oversight of the hospital’s accreditation process, complaints, and incidents management.

Throughout her career in the health sector, Chris served on numerous committees, chairing some in relation to the national standards on safety and quality in healthcare services (NSQHS standards).   ‘Partnering with Consumers’ was one of the NSQHS standards which required the organisation that Chris worked for to pass all areas, to become an accredited healthcare organisation.  This was achieved with Chris taking a leadership role in this area.

Since retiring, Chris has volunteered with the local MS Plus office in Hobart in an administrative capacity.  She is also a facilitator of an MS peer support group and provides some one-on-one peer mentoring support.    Chris also features in the ‘lived experience’ video series in the highly successful Understanding MS MOOC and has provided many hours of consumer involvement across various MS research projects conducted at Menzies.

Now 65 years young, Chris lives with secondary progressive MS. She has 3 adult daughters and seven grandchildren which provide her with much joy. She enjoys reading and sewing when she is not too busy spending precious time with family and friends or volunteering in and for the MS Community!

Of her involvement in research through the Menzies MS Research Flagship’s consumer committee Chris says, “Getting involved in research has given me a deeper understanding and appreciation of the ‘research world’ and the importance of consumer involvement throughout the research cycle”.

Melanie Kiely, currently the CEO of MSWA, is a seasoned leader and non executive director with over 30 years of global and Australian experience across the listed, private, and non-profit sectors. She is also currently a director of Aia health insurance Nds Australia.

In addition to her current roles, Melanie has had roles as CEO of Good Sammy, a partner at Accenture and executive roles in South Africa, the uk and Australia. 

Melanie has a clear passion for and expertise in client-centered transformational change and has navigated organisations through complex regulatory environments, including APRA, ASIC, and the NDIA. She has a proven track record in sectors like disability employment, aged and community care, mental health, financial services and insurance (health, life, and general).

Professor Bruce Taylor is a clinician-scientist with more than 20 years of experience in MS research. He is a clinical neurologist at the Royal Hobart Hospital and a Professor of Neurological Research at the Menzies Institute for Medical Research, University of Tasmania. His research interests include the genetics of MS, MS epidemiology and treatment efficacy.

Professor Tomas Kalincik is Dame Kate Campbell Professorial Fellow, the head of the Clinical Outcomes Research (CORe) Unit at the University of Melbourne and of the Neuroimmunology Centre at the Royal Melbourne Hospital.

Together with his research group, CORe, Tomas specialises in analytics of observational data in neurology. He has led a number of international collaborative research initiatives - including studies of comparative effectiveness of MS therapies, management of treatment failure and individual treatment response. His main research interests span treatment outcomes in MS and other neuroimmunological diseases, individualised therapy, prognostics (including emerging biomarkers), causal inference, epidemiology and utility of volumetric MRI. He worked with the MS International Federation and WHO on scoping the first WHO Essential Medicines List for MS. He is the vice-chair of the Scientific Leadership Group of the global MSBase registry, and collaborates with multiple national MS registries. Tomas convenes the international CORe Advanced Statistics Course, endorsed by the European Committee for Treatment and Research in MS, co-chairs the scientific committee of the MS Australia Progress in MS Research conference, and convenes preceptorships for neurologists and nurses at the RMH Neuroimmunology Centre.

Dr. Wee Yong is a Professor at the University of Calgary. His research interests in neuroimmunology are guided by multiple sclerosis, glioblastoma and intracerebral hemorrhage. His bench results have been translated into eight clinical trials. Dr. Yong has published 390 manuscripts which have been cited >39,500 times (h-index of 110). He has mentored over 30 trainees who are professors at universities worldwide. Dr. Yong has been the President of the International Society of Neuroimmunology, and he continues to co-direct its Americas and Global Schools. Dr. Yong is an elected fellow of the Canadian Academy of Health Sciences and the Royal Society of Canada. He is a recipient of the Allyn Taylor International Prize in Medicine. Dr. Yong was profiled in the August 2021 issue of Lancet Neurology.

Perivascular astrocytes are early contributors to neurodegeneration by promoting platelet trafficking across the blood brain barrier.

Background: Our laboratory has generated proof-of-concept that platelets are a substrate of neurodegeneration in multiple sclerosis (MS). Using the experimental autoimmune encephalomyelitis (EAE) model, we demonstrated early neuron-platelet associations and the efficacy of platelet-targeting in modifying disease course and in promoting remyelination and functional restoration.  

Objective: These observations imply the existence of mechanisms underlying the specific targeting of neurons by platelets and platelet trafficking across the blood brain barrier (BBB). This study aimed to identify signals driving platelet infiltration and the route of entry of platelets across the BBB .  

Methods: We used two EAE variants, namely the MOG35-55-induced C57BL/6 and the PLP178-191-induced SJL/J variants, which differ by the absence of requirement for pertussis toxin (PTx) in the SJL/J mice for disease induction. Controls were sham-injected mice. The focus was on the pre-symptomatic stage (4 to 9 days post-immunization [dpi]). Approaches included quantitative confocal microscopy with IMARIS analysis of astrocytes and correlative light and electron microscopy (CLEM) for platelet identification.  

Results: We demonstrate early (4dpi) reactive platelet accumulation on endothelial cells and specific platelet-perivascular astrocyte end-feet association in both EAE variants and in grey and white matter. Platelets traverse rather than circumvent end-feet (9 dpi) and remain associated with astrocyte processes and cell bodies. These interactions were not observed with other glial cells, or in controls. We also demonstrate fibrinogen leakage into the parenchyma and neuronal expression of the fibrinogen receptor.   

Conclusions: We propose a mechanism whereby platelet targeting of neurons  is triggered by BBB leakage and fibrinogen/fibrinogen receptor interaction. This drives platelet infiltration via a process in which astrocytes play a pivotal role. These data are relevant to the generation of platelet-targeting therapeutical strategies. 

Acknowledgements: The authors received funding from private donations, La Trobe University Research Focus Area and Multiple Sclerosis Research Australia award number 20-032. DL Maxwell and H Alsaraji are recipients of La Trobe University Graduate Research Scholarships. 

Keywords: Astrocytes, Blood Brain Barrier, EAE-model, Neurodegeneration, Platelets 

Targeting the neuropeptide receptor PAC1 to reduce neuroinflammation in the cuprizone demyelination model of multiple sclerosis.

Background: Multiple sclerosis is an immune-mediated disorder of the central nervous system (CNS) characterized by white matter lesions and axonal degeneration. Pituitary-adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two endogenous neuropeptides that signal through three G-protein coupled receptors; PAC1, VPAC1 and VPAC2.  

Objective: These neuropeptides exert neuroprotective activities. However, the anti-inflammatory potential of PAC1 receptors is less clear. Here, we tested the effects of treatment with PACAP, VIP and the PAC1 agonist maxadilan in the cuprizone demyelination model and in primary astrocytes exposed to an immune challenge. 

Methods: Mice (n=12/group) fed a regular or a 0.2% cuprizone-supplemented diet to induce MS-like symptoms received saline or 5nM PACAP, VIP or maxadilan. Locomotor deficits were assessed using the horizontal ladder/open field tests. Myelin health and neuroinflammation were investigated by immunohistochemistry and real-time PCR. In vitro, primary astrocytes/microglia were challenged with the endotoxin lipopolysaccharide (LPS) for 12-24h, and inflammatory/endoplasmic reticulum (ER) stress markers were interrogated by co-immunofluorescence and real-time PCR.  

Results: Whereas all neuropeptides improved clinical wellbeing and locomotor function in cuprizone-fed mice, only mice treated with the PAC1-preferring peptide PACAP or maxadilan had preserved myelin integrity and reduced glial cell activation in the brain. In vitro, astrocytes and microglial cells challenged with LPS showed increased inflammation and signs of endoplasmic reticulum (ER) stress, which were rapidly and completely reversed in the presence of PACAP and maxadilan.  

Conclusions: Collectively, in vivo and in vitro data demonstrates the anti-inflammatory properties of PACAP and maxadilan in the demyelinated CNS white matter. In addition, our results suggest that inflammation-induced ER stress may be complicit in the chronicity of the neuroinflammatory response. 

Keywords: Multiple sclerosis; neuroinflammation; pituitary adenylate cyclase-activating polypeptide; vasoactive intestinal peptide; Maxadilan 

Authors: Margo I. Jansen (1), Yasir Mahmood (1), Jordan Lee (1), Sarah Thomas Broome (1), James A. Waschek (2), Alessandro Castorina (1) 

1. Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney 2007, Australia. 

2. Intellectual Development and Disabilities Research Centre, Semel Institute for Neuroscience and Human Behaviour/Neuropsychiatric Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095 

Molecular control of pathogenic Th17 cell migration to the inflamed CNS.

Background: Pathogenic Th17 cells that co-produce multiple pro-inflammatory cytokines are critical for the development of neuroinflammation in mouse models and implicated in MS. The molecular cues used by these cells for recruitment to the CNS are not completely understood and may represent tractable targets for treatment of MS.

Objective: We sought to understand the molecules involved in recruitment of pathogenic Th17 cells to the inflamed CNS in experimental autoimmune encephalomyelitis.

Methods: We utilised a novel gating strategy to specifically isolate pathogenic Th17 cells from EAE mice to perform RNAseq. Subsequently gene-knock out mice and blocking antibodies evaluated the role of specific chemokine receptors in recruitment of pathogenic Th17 cells to the CNS.

Results: Comparing pathogenic to non-pathogenic Th17 cell transcriptomes in EAE we found differential expression of 14 chemokine receptors with pathogenic Th17 cells particularly enriched in expression of CXCR6, CCR2 and CCR8. We validated this at the protein level by flow cytometry. Mice deficient in Cxcr6 or with a T cell specific deletion in Ccr2 have reduced accumulation of pathogenic Th17 cell in the CNS.

Conclusion: Pathogenic Th17 cells appear to utilise both CXCR6 and CCR2 for recruitment to the CNS. Future studies aimed at blocking both of these receptors simultaneously, or in combination with other migratory receptors selectively used by pathogenic Th17 cells, may be a viable option for treatment of MS.

This work is funded by MS Australia.

Keywords: T cells, EAE, chemokines, Th17, cell migration

Authors: Iain Comerford (1), Caleb Wong Han (1), Aaron Han Heng (1), Stephen Pederson (2), Shaun McColl (1)

Affiliations:
1. The Chemokine Biology Laboratory, Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, South Australia 5005.

2 . The Telethon Kids Institute, North Terrace, Adelaide, South Australia 5000.

Transcriptional regulation governing Th17 cells in experimental CNS autoimmunity.

Background: Th17 cells mediate pathology in mouse models of neuroinflammation and MS. Th17 cells are heterogeneous, consisting of non-pathogenic and pathogenic subsets with distinct roles in driving autoimmunity. Transcriptional mechanisms governing these distinct Th17 subsets are unclear, and may present targets for the treatment of MS.

Objective: We aimed to gain insight into transcriptional regulation governing pathogenic and non-pathogenic Th17 cell states in experimental autoimmune encephalomyelitis.

Methods: A novel strategy to specifically isolate pathogenic and non-pathogenic Th17 cells from EAE mice for RNA-seq was utilized. We generated a novel mouse line with a targeted knock out of a transcription factor in T cells, in order to assess the impact on the regulation of both pathogenic and non-pathogenic Th17 cells.

Results: Comparing pathogenic and non-pathogenic Th17 cell transcriptomes, we observed the gene encoding the transcription factor RUNX2 to be specifically increased in pathogenic Th17s. Flow cytometry analysis validated this at the protein level. Mice with a targeted T cell-specific deficiency of Runx2 displayed heightened severity of EAE, accompanied by an increased pathogenic Th17 cells infiltrating the CNS. Th17 priming in the spleen was also skewed towards pathogenic than non-pathogenic phenotypes in the absence of RUNX2.

Conclusion: Th17 cells express RUNX2 and this increases polarisation of these cells to a non-pathogenic phenotype in EAE. Future studies to understand the mechanisms that underpin this and to modulate this system for therapeutic benefit in neuroinflammation are required.

Funded by MS Australia.

Keywords: EAE, Th17, transcriptional regulation

Authors: Caleb Wong Han, Aaron Han Heng, Stephen Pederson, Shaun McColl, Iain Comerford

Affiliations:
1.The Chemokine Biology Laboratory, Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, South Australia 5005.
2. The Telethon Kids Institute, North Terrace, Adelaide, South Australia 5000.

Preclinical trial of a small molecule to promote neuroprotection and repair in an animal model of neuroinflammatory demyelination.

Background: Myelin producing human oligodendrocyte cells express the main thyroid hormone plasma membrane transporter known as monocarboxylate transporter 8 (MCT8). Our group has demonstrated that MCT8 is dysfunctional in conditions of developmental or acquired myelin diseases such as progressive MS. 

Objective: To trial novel small molecules that may improve re-myelination and provide neuroprotection in the central nervous system (CNS) following immune-mediated damage in rodent disease models that mimic MS-like disease. 

Methods: 

• Proteomic studies on Human tissue and Animal disease models: Western blots, immunoprecipitation, metabolomic analysis. 
• Mouse model of neuroinflammation: Experimental Autoimmune Encephalomyelitis (EAE) 
• Transmission Electron Microscopy: analysis of myelin thickness (G-ratio), size, distribution and integrity in EAE mice treated with experimental drugs. 
• Transgenic mouse model of de/re-myelination: Cuprizone neurotoxicant model of demyelination in PDGFRα Cre-Lox mice. 

Results:

• Dysregulated thyroid hormone-dependent signaling during acute inflammatory spinal cord demyelination and axonal damage during the peak-stage of EAE. 
• Human post-mortem tissue proteomics demonstrated dysregulated thyroid hormone-dependent signaling in chronic degenerative demyelinating lesions together with deficits in mitochondrial function in metabolomic analyses. 
• Downregulated MCT8 expression in mature oligodendrocytes during the peak stage of EAE leads to profound cell death and demyelination around inflammatory lesions. 
• DITPA acted independent of MCT8 through integrin-dependent non-genomic signaling. 
• Enhanced re-myelination in the optic nerves of DITPA treated mice during EAE. 

Conclusion: Our consolidated data stresses the reliance of MCT8 in oligodendrocyte survival, maturation, and differentiation in the CNS. We conclude that DITPA is a capable alternative to MCT8 for transporting thyroid hormone into the CNS and may result in a novel therapeutic target in treating MS. 

Keywords: Diiodothyropropionic acid (DITPA), re-myelination, experimental autoimmune encephalomyelitis, monocarboxylate transporter 8, oligodendrocytes. 

Trajectories of multiple sclerosis disease progression are associated with differential risk of disability accumulation, relapse phenomenology, and MRI metric.

Background: The identification of disability trajectories after the diagnosis of multiple sclerosis (MS) and throughout the disease course could significantly enhance disease management strategies. Disability trajectories encapsulate longitudinal variations in MS outcomes. Studies on disability trajectories and their associations with MS outcomes are limited. 

Objective: To identify trajectories of disability progression post-diagnosis, and to examine whether they were associated with differential risk of disability accumulation, relapse symptoms, relapse complications, and MRI T2 lesion load. 

Methods: Outcomes data were obtained from the MSBase (10,716 cases, 59,725 person-years), and the TasMSPG and AusLong studies (566 cases, 4370 person-years). Utilising the MSBase cohort, disability trajectories were identified using latent class modelling of longitudinal disability scores. Multivariable Poisson models were used to estimate associations of disability trajectories with relapse symptoms, relapse complications, and T2 lesion load. Markov transition models were used to estimate the rates of changing disability levels. 

Results: Among 10,716 MSBase cases (360 primary progressive, 1038 secondary progressive, 9318 relapse-remitting; mean[SD] age, 40.2[10.5]years; 7611(71%) females), 4 disability trajectories were identified and validated in the TasMSPG-AusLong database: rapidly deteriorating (N=860[8.03%]); moderately deteriorating (N=676[6.31%]); slowly deteriorating (N=2511[23.43%]); and stable (N=6669 [62.23%]). Compared to the stable group, the other trajectories were associated with a higher burden of relapse symptoms and complications, higher T2 lesion load, and more rapid disability decline. 

Conclusion: These findings show a clinically meaningful gradient of increasing risk across the 4 disability trajectories. Future interventions should target individuals with higher predicted risk of progression as early as possible after diagnosis, to mitigate disability progression. 

Keywords: Multiple sclerosis, progression, disability, trajectories 

Funding: This work was supported by the National Health and Medical Research Council of Australia [APP1127819, 1947180, 544922], Kate-Scott Memorial Scholarship (to Valery Fuh-Ngwa); Multiple Sclerosis Research Australia (MSRA); National Health and Medical Research Council investigator Grant L1 [GNT1173155] (to Yuan Zhou); and the Macquarie Foundation MSRA Clinical Research Fellowship (to Bruce V. Taylor). 

Authors: Valery Fuh-Ngwa (1), Ingrid van der Mei (1), Yuan Zhou (1), Andrew J. Palmer (1), AusLong Investigators (2), MSBase investigators (3), and Bruce V. Taylor (1). 

Author affiliations:
1. Menzies Institute for Medical Research, University of Tasmania. 

2. The MSBase foundation

3. Multiple sclerosis research Australia

Cuprizone causes region-specific copper depletion in mouse brain.

BACKGROUND: Cuprizone is a common pre-clinical model of demyelination, however its mode(s) of action are not known. One chemical property of cuprizone is to chelate copper, so many postulate demyelination is caused by brain Cu deficiency. Proof of cuprizone-induced brain Cu deficiency, however, has remained elusive. 

OBJECTIVE: The aim of our study was to directly map Cu distribution at micron spatial resolution with nM detection limit in mouse brain tissue sections, to determine if Cu deficiency does or does not exist in the cuprizone model. 

METHODS: Brain tissue was obtained from 14-week-old male C57BL/6 mice fed 0.2 % W/W cuprizone for 6 weeks, and age-matched controls (n = 7). To prevent sample preparation-induced distortion of Cu content or distribution, tissue was rapidly frozen in liquid nitrogen-cooled isopentane without perfusion or fixation. Cryosections (10-µm-thick tissue sections) were cut and air-dried onto X-Ray transparent substrate for elemental mapping with X-Ray fluorescence microscopy (XFM) at ANSTO-Australian Synchrotron. 

RESULTS: XFM revealed brain Cu content (and Cl, K, Ca, Fe, Mn, Zn) at 4 µm spatial resolution with 0.1 ngcm-2 detection limit. Luxol fast blue assessment of myelin showed pronounced demyelination of lateral corpus callosum and striatal white matter, with minimal demyelination at medial locations (coronal sections, bregma 1 mm). Two-Way ANOVA revealed significant localised reduction in Cu in lateral, but not medial corpus callosum and striatum white matter. 

CONCLUSION: This is the first study to definitively visualise cuprizone-induced brain Cu deficiency. This observation provides key evidence that Cu deficiency is a driver of demyelination in the cuprizone model, making it relevant to recently observed alterations in Cu homeostasis during clinical multiple sclerosis. 

KEY WORDS: X-Ray Fluorescence, Synchrotron, Demyelination, Glia, Metals 

Health economic investigation of the cost of informal care for people living with multiple sclerosis - A comprehensive systematic review.

Background: MS is a high-cost and high-burden disease that has substantial health and economic impacts. Economic studies in MS often exclude the costs of Informal Care (IC) which will likely underestimate the cost-effectiveness of interventions aimed to slow, prevent, or halt MS-related disability progression.  

Objectives: No studies have provided a comprehensive synthesis of global health economics evidence regarding IC, particularly in regard to regional differences and MS-related disability severity impacts. We aimed to summarise and synthesise health economics evidence regarding informal care costs for people living with MS. 

Methods: A registered study protocol adopting validated guidelines was followed (PROSPERO:CRD42023396457). Searches were conducted in eight biomedical/economic databases. Two authors independently screened and extracted healthcare utilisation and cost data for summary and synthesis. A quality appraisal of included studies was conducted. Proportions of IC costs were estimated using direct, indirect, and total costs. Costs were inflated using relevant central bank Consumer Price Indices and converted to 2022 United States dollars (USD). 

Results: N=6,305 articles were identified; 60 studies from 25 countries were included.  Most adopted a societal perspective (direct+indirect costs) gathered from the person with MS. Average monthly caregiving time was 60.1 hours. IC costs were 15% of total societal costs. Regionally (similar healthcare sectors), costs for Western Europe were USD9,313 and Eastern Europe USD1,488. Despite study heterogeneity, IC costs escalated with increased disability severity (mild disability severity USD1,109; severe USD16,023). 

Conclusions: Costs of IC contribute considerably to MS-related costs. MS cost-effectiveness studies that do not include IC costs are likely to be inaccurate. Importantly, when considering costs of IC, data should be extracted directly from the carer – our proposed MS carers cohort study will achieve this. 

Funding: This work is supported by Dr Julie Campbells MS Australia Research Fellowship number 19-0702 

Key words: multiple sclerosis, informal care costs, cost-effectiveness, country income  

Authors: Tadele Girum Adal (1), Ingrid van der Mei (1), Bruce V Taylor (1), Andrew J Palmer (1), Barbara de Graaff (1), Glen Henson (1), Julie A Campbell (1). 

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Medical Sciences Precinct, 17 Liverpool Street, Hobart, Tasmania, Australia 7000 

Reduced Likelihood of High-efficacy Disease Modifying Therapy Prescription during the COVID-19 Pandemic.

Background: The COVID-19 pandemic significantly impacted the treatment of people with multiple sclerosis (pwMS). Clinicians made treatment choices with concerns that immunotherapy could worsen COVID-19 infections.  Subsequent studies demonstrated an association between certain high-efficacy disease modifying therapies (DMT) and greater COVID-19 severity.  

Objective: This study aimed to examine the impact of the COVID-19 pandemic on DMT prescribing patterns in pwMS. Primary outcome was high-efficacy DMT use pre- and during-pandemic (onset defined as 11 March 2020). Secondary outcomes were the prescribing patterns of specific DMTs pre- and during-pandemic.  

Methods: A multi-centre longitudinal study was conducted using data from the MSBase COVID-19 sub-study. Trends in DMT prescribing rates between 2018-2022 were analysed using multivariable mixed-effects logistic regression. DMT initiation referred to the first prescription of any DMT in that timeframe, DMT switches denoted a change in DMT regimen within 6 months of last DMT use.  

Results: During the pandemic, there was a significant decrease in odds of initiating high-efficacy DMTs (OR 0.42,p<0.001). Odds of initiating or switching to anti-CD20 monoclonal antibodies (Ocrelizumab, Rituximab) were significantly lower (OR 0.32,p<0.001;OR 0.66,p=0.03). Odds of DMT initiation with injectable immunomodulators (glatiramer acetate, interferons) and immunosuppressive agents were lower during-pandemic (OR 0.42,p=0.001;OR 0.13,p<0.001). Odds for DMT switches to natalizumab, immunosuppressive agents and injectable immunomodulators were higher during-pandemic (OR 1.92,p=0.05;OR 2.30,p=0.02;OR 5.52,p=0.006). 

Conclusion: During the COVID-19 pandemic, there was a reduction in overall initiation of high-efficacy DMTs. Clinicians were less likely to initiate or switch patients to anti-CD20 monoclonal antibody therapies, potentially impacting disease activity in pwMS. Swift, evidence-based guidance is crucial during such global health events. 

Keywords: COVID-19, Disease-modifying therapy, prescribing patterns, anti-CD20 monoclonal antibodies, natalizumab 

DNA methylation discriminates between responder and non-responder status in a long-term study of cladribine tablet use in Multiple Sclerosis.

Background: DNA methylation at CpG sites is an epigenetic mechanism that can influence gene expression. Epigenome-wide association studies (EWASs) of immune cells have implicated differential methylation in Multiple Sclerosis (MS) and are associated with treatment use. However, whether EWASs can predict response to treatment is unknown. 

Objective: The objective of this study was to assess if there are changes in global DNA methylation between three- and 30-months post first dose of cladribine tablets that can predict response to cladribine tablets in people with MS (pwMS). 

Methods: Whole blood DNA was collected from the prospectively followed cohort of the CLOBAS study, which is a phase IV, multicentre, open label, six-year study of cladribine tablets for pwMS. Non-responders were participants who had a clinical relapse or new MRI activity. Global DNA methylation was analysed using the ChAMP R package. GLMNet was used to select meaningful features of baseline DNA methylation that could discriminate between responders and non-responders. 

Results: Fifteen of 102 participants were non-responders after 30 months of cladribine tablet use. The most significant feature was cg15041948, which maps to the transcription start site of the GPBP1 gene (Vasculin protein).  This CpG has a good ability to discriminate between responders and non-responders (Area Under the Curve (AUC) = 0.78). Using the top 28 features identified by GLMNet, the ability to discriminate between responders and non-responders was perfect (AUC=1.0) 

Conclusion: We are able to use global DNA methylation profiles to discriminate between responders and non-responders to cladribine treatment. Low numbers mean results should be interpreted with caution, however, the CLOBAS study is a six-year prospective cohort, therefore, longer term follow studies will follow. 

Funding Source: This study was funded by a Investigator Initiated grant from Merck Healthcare Pty. Ltd. 

Key words: Epigenetics, Cladribine, DNA methylation  

Authors: Vicki E. Maltby (1,2,3), Alexandre Xavier (3,5), Mastura Monif (5,6,7), Myintzu Min (1), Marzena J. Fabis-Pedrini (8), Katherine Buzzard (6,9), Tomas Kalincik (6,10), Allan G. Kermode (8,11), Bruce Taylor (12), Suzanne Hodgkinson (13,14,15), Pamela McCombe (16), Meaghan Osborne (17), Helmut Butzkueven (5,9,18), Michael Barnett (19,20), Rodney A. Lea (2,3,21), Jeannette Lechner-Scott (1,2,3). 

Author Affiliations: 
1. Department of Neurology, John Hunter Hospital, New Lambton Heights, NSW 

2. School of Medicine and Public Health, University of Newcastle, Newcastle NSW 

3. Immune Health Program, Hunter Medical Research Institute, Newcastle NSW 

4. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle Australia 

5. Department of Neuroscience, Monash University, Melbourne ,VIC 

6. MS Centre, Department of Neurology, Melbourne Health, Melbourne, VIC 

7. Department of Neurology, Alfred Health, Melbourne, VIC 

8. Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, University of Western Australia, Perth, WA. 

9. Department of Neuroscience, Eastern Health Clinical School, Eastern Health, Melbourne, VIC 

10. CORe, Department of Medicine, University of Melbourne, VIC 

11. Institute for Immunology and Infectious Disease, Murdoch University, Western Australia, Perth, WA. 

12. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 

13. University of New South Wales, Sydney, NSW 

14. Department of Neurology, Liverpool Hospital, Sydney, NSW 

15. Immune Tolerance Laboratory (ITG), Ingham Institute, Sydney, NSW 

16. Centre for Clinical Research, University of Queensland, Brisbane, QLD. 

17. Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia 

18. Managing Director, MSBase Foundation 

19. Brain and Mind Centre, University of Sydney, Sydney, NSW 

20. Sydney Neuroimaging Analysis Centre, Sydney, NSW 

21. Institute of Health and Biomedical Innovations, Genomics Research Centre, Queensland University of Technology, Kelvin Grove, QLD 

Step exergame training to reduce falls in people with multiple sclerosis: The i-FIMS multi-centre randomised controlled trial.

Background: Cognitive-motor step training is safe and can improve stepping, balance and mobility in people with multiple sclerosis (MS), but efficacy of the cognitive-motor step training in preventing falls has not been demonstrated.  

Objective: This multi-site randomised controlled trial aimed to determine whether a six-month home-based step exercise training program could reduce falls and improve associated fall risk factors compared with usual care in people with MS. 

Methods: 461 people with MS aged 22-81 years (n=366 women, Expanded Disability Status Scale score 1.5-6.0) were randomly allocated to usual care (control) or a six-month home-based step exergames training program (120 minutes/week). The primary outcome was rate of falls over six months. Secondary outcomes included physical, cognitive, and psychosocial function at six months and number of falls over twelve months. 

Results: Mean (SD) exergames play duration was 70 (51) min/week over six months. Fall rates did not differ between groups (incidence rate ratio 0.96, 95% confidence interval 0.69 - 1.34, p = 0.816). Participants in the intervention group performed faster in tests of choice-stepping reaction time at six months, compared with control participants. No serious training-related adverse events occurred.  

Conclusion: The step exergame training program did not reduce falls among people with MS. However, it significantly improved voluntary stepping in cognitively challenging tests. 

Keywords: Accidental falls, fall prevention, cognitive training, balance training, stepping, Multiple Sclerosis. 

Funding sources: MSRA (Postdoctoral Fellowship 13-003_PH); MS Plus (Grant-in-aid) 

Authors: Phu D. Hoang1,2, Daina L. Sturnieks1,3, Carly Chaplin1, Cameron Hicks1, Sophie Robinson, Natassia Smith1, Stephen R. Lord1, Jasmine C Menant1,3. 

Author affiliations: 
1. Neuroscience Research Australia, Randwick NSW 

2. MS Plus 

3. University of New South Wales 

The association of comorbidities with sleep quality among Australians with multiple sclerosis: Insights from the Australian Multiple Sclerosis Longitudinal Study.

Introduction: Comorbidities and poor sleep are both common among people living with multiple sclerosis (MS). While longitudinal studies have shown that presence of comorbidities predict poorer health outcomes in MS, little is known about their impact on sleep quality.  

Objective: This study examined if the presence and number of individual comorbidities are associated with sleep quality and the relative contributions of groups of comorbidities to sleep quality in MS 

Methods: This cross-sectional study included 1,597 participants with MS, assessed by questionnaire regarding the presence of 30 medical comorbidities. Sleep quality was assessed using Pittsburgh Sleep Quality Index (PSQI). We used linear regression to examine relationships between the number of comorbidities and the presence of individual comorbidities and sleep quality. General dominance analysis was applied to determine the relative contributions of 13 different groups of comorbidities to sleep quality.  

Results: In total, 16 of 28 comorbidities were associated with significantly worse sleep quality (p<0.05), with the strongest associations seen for “other autoimmune diseases” (β=1.98), depression (β=1.76), anxiety (β=1.72), and rheumatoid arthritis (β=1.62). Having more comorbidities was associated with poorer sleep quality (p for trend <0.001). 13 groups of comorbidities together explained 12.9% of the variance in PSQI; mental health disorders contributed half of this variance.  

Conclusions: Many individual comorbidities are associated with poorer sleep quality, with mental health disorders making the largest relative contribution. Optimal treatment and management of comorbidities that make the greatest contributions could improve sleep in people living with MS.  

Keywords: Comorbidities; PSQI; Dominance analysis; Multiple sclerosis; Sleep.    

Authors: Baye Dagnew (1,2), Laura L Laslett (1), Cynthia A Honan (3), Leigh Blizzard (1), Tania Winzenberg (1), Bruce Taylor (1), Ingrid van der Mei (1)

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 

2. College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia  

3. School of Psychological Sciences, University of Tasmania, Launceston, Australia. 

Higher protein intake is associated with lower likelihood of a first clinical diagnosis of central nervous system demyelination.

Background: A Mediterranean diet, an anti-inflammatory diet, higher consumption of fish and unprocessed red meat are associated with lower likelihood of a first clinical diagnosis of CNS demyelination (FCD). Whether specific nutrients, common to these dietary factors, are associated with likelihood of FCD, is unknown. 

Objective: To test associations between dietary components contributing to energy intake and the likelihood of FCD. 

Methods: We used data from the 2003–2006 Ausimmune Study, a multicentre, case control study (272 cases, 519 controls) of Australian adults (aged 18-59 years) with an FCD.  Covariate-adjusted logistic regression was used to test associations between FCD and dietary components contributing to energy intake (g/day) (protein, saturated fat, polyunsaturated and monounsaturated fats, carbohydrate, fibre, sugar, and alcohol). Final models were bootstrapped. 

Results: Higher protein intake was statistically significantly associated with lower likelihood of FCD (adjusted OR, per 100 g/day=0.31; 95% CI 0.10-0.97; p=0.045).  There were no statistically significant associations with the other dietary components and likelihood of FCD. 

Conclusion: The lower likelihood of FCD associated with higher protein intake lends support to our previously published findings, which focused on diets and foods. Whether protein intake is associated with disease progression in people with MS is unknown.  

Key words: Ausimmune Study; Australia; nutrition; protein; multiple sclerosis; diet 

Authors: Alison Daly (1), Michael Phillips (2), Eleanor Dunlop (1), Ausimmune Investigator Group, and Lucinda J Black (1,3) 

Author affiliations: 
1. Curtin School of Population Health, Curtin University, Perth, Australia  

2. Royal Perth Hospital, Medical Research Foundation, Perth, Australia 

3. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Melbourne, Australia 

Progress in MS Research Conference Organising Committee Chair; Deputy Chair, MS Australia

George is a Director at Flinders Financial Services, specialising in taxation advice and planning, business consulting and business structuring. He has significant expertise and a particular interest in providing tailored advice for family businesses, sportspeople and aged care facilities.

George was a former President of MSWA.

George’s interest in MS is due to seeing his Mum, uncle and close friends live with the disease.

Dr. Piccio obtained an M.D. and a Ph.D. degree from the School of Medicine at the University of Milan in Italy.  She completed a neurology residency program at the University of Milan. In 2005, she was awarded a post-doctoral fellowship from the National Multiple Sclerosis Society (NMSS) during which she worked under the mentorship of Dr. Anne H Cross at Washington University in St Louis. In 2008 Dr. Piccio started to be on faculty in the Department of Neurology at Washington University. In February 2019, she joined the University of Sydney as an Associate Professor in the School of Medical Sciences and she works at the Brain and Mind Centre. She currently has a joint appointment between Washington University and the University of Sydney.

During her career Dr. Piccio was the recipient of several awards including the Harry Weaver Neuroscience Award from the National MS Society, the Dana Neuroscience Scholar award from the Dana Foundation and the Whitaker prize from the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Piccio has published over 90 peer-reviewed articles in international Journals. Her research integrates clinical and research aspects related to multiple sclerosis and currently focuses on two major areas: the role of innate immune cells and the complex interactions between diet, the immune system and metabolism in multiple sclerosis and its animal models.

Horst is a business strategy and process improvement specialist, with extensive knowledge in traditional financial management.

Horst has extensive experience managing finance and corporate service departments in leadership roles as part of a senior executive team.

Horst’s established career has spanned numerous management disciplines, including risk and compliance, treasury, taxation, business strategy and organisational development. This work included the management of major projects, including organisational restructures, system implementations and large tenders.

Horst says the development and mentoring of many staff over the years has been his most rewarding career achievement as a leader.

Melanie Kiely, currently the CEO of MSWA, is a seasoned leader and non executive director with over 30 years of global and Australian experience across the listed, private, and non-profit sectors. She is also currently a director of Aia health insurance Nds Australia.

In addition to her current roles, Melanie has had roles as CEO of Good Sammy, a partner at Accenture and executive roles in South Africa, the uk and Australia. 

Melanie has a clear passion for and expertise in client-centered transformational change and has navigated organisations through complex regulatory environments, including APRA, ASIC, and the NDIA. She has a proven track record in sectors like disability employment, aged and community care, mental health, financial services and insurance (health, life, and general).

Professor Broadley has been researching the causes and treatment of multiple sclerosis (MS) and related disorders, including neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody associated demyelination (MOGAD), for 20 years. He has undertaken work that has contributed to the establishment of a familial link between MS and other autoimmune diseases, discovered over 200 genes that cause MS, investigated the link between vitamin D and MS, and explored the impact of a number of environmental factors on the disease. He has been a principal investigator on several clinical trials of highly effective therapies for MS.

Professor Broadley has over 150 peer reviewed publications and has an H-factor of 45. He has been associated with competitive research grant funding totaling $10 million. He is involved in several international research collaborations including, MSBase, Guthy-Jackson International Clinical Consortium, International MS Genetics Consortium and PAMRINO. He is the Chair of the NMO Australia and New Zealand Collaboration and is the Chair of MS Neurology (ANZAN). He is Co-Chief Editor of Multiple Sclerosis Journal - Experimental Translational and Clinical.

Professor Broadley's current projects include the Queensland NMOSD/MOGAD prevalence study, the RAMBLE clinical trial of rituximab to reduce the risk of autoimmune adverse events after alemtzumab in the treatment of MS and the AusLong longitudinal study of MS across Australia. He is a Chief Investigator on the PrevANZ (vitamin D) and RELIEF (treatment of fatigue) investigator clinical trials in MS.

Professor Broadley undertook his undergraduate training at the University of Manchester before completing training in neurology in London, Bristol and Adelaide. He completed his PhD on the Genetics of MS at the University of Cambridge. He is currently appointed as Professor of Neurology at Griffith University and as Senior Staff Specialist in Neurology at Gold Coast Univesity Hospital.

Development of venom peptide inhibitors of acid-sensing ion channel 1 as novel therapeutics for multiple sclerosis.

Background: Acidosis is a hallmark of CNS lesions in multiple sclerosis. Overactivation of acid-sensing ion channel 1a (ASIC1a) is associated with nerve injury in mouse models of MS and in MS patient tissues. Inhibition ASICs shows strong therapeutic potential in the EAE mouse model of MS.

Objective: Our group develops potent venom-derived ASIC inhibitors to validate ASIC1a as a potential neuroprotective drug target in MS. Our aim is to test if our peptides can decrease disease symptoms in animal models of MS and understand how well they get into the nervous system.

Methods: We test the ability of the peptides to decrease disease development using the experimental autoimmune encephalomyelitis mouse model of progressive MS using several different doses and monitoring its effect on muscle paralysis and spinal cord damage. We also label the peptides with a fluorescent tag to be able to track where the peptide goes in the mouse and if it gets into the damaged spinal cord.

Results: We show that the peptide Hi1a decreases the development of muscle paralysis and spinal cord damage in a dose-dependent manner but loses effectiveness at higher doses. We also show that following peripheral injection, fluorescently labelled Hi1a can get into the spinal cord of EAE mice but not in those of control mice. This suggests that our peptide can have a direct protective effect in the central nervous system.

Conclusion: These advances in our understanding of the protective effect, biodistribution and target engagement of Hi1a in preclinical mouse models of disease should help guide studies on this promising peptide through further preclinical development. 

Keywords: Multiple sclerosis; neuroprotection; acid-sensing ion channels, drug discovery 

Authors:  
Lachlan Rash (1), Maleeha Waqar (1), Neville Butcher (1), Nemat Khan (1). 

Author affiliations: 
1. School of Biomedical Sciences, The University of Queensland. 

Using human iPSC-derived 'MiniBrains' to model de- and re-myelination.

Background: Mechanistic understanding of Multiple Sclerosis (MS) is critical for identifying new treatments. However, this remains challenging due to current model systems being limited in their capacity to recapitulate the complex human myelination processes resulting in a lack of available treatments targeting remyelination for MS patients.  

Objective: We therefore aimed to pioneer an organoid model of human demyelination.  

Methods: Using human induced pluripotent stem cells (iPSC), we generated 3D organoids containing microglia, myelinating oligodendrocytes, neurons and astrocytes, which we successfully demyelinated using lysolecithin (LPC). Briefly, after patterning we commence myelin induction (time 0). After 3 weeks we seeded in TdTomato-tagged microglia-like precursor cells. At 11 weeks, we treat organoids with LPC (or vehicle) and then collect organoids for characterisation of: demyelination at 5h, 24h and 1 week, and signs of remyelination at 4 and 8 weeks following LPC.  

Results: Myelin fragmentation was quantified using the 3D analysis software, IMARIS, to measure myelin sheath length; fragmentation was significantly higher at 5 h, 24 h, 7 d and 14 d in LPC treated organoids, compared to vehicle (p<0.05 for all). Microglia had elevated HLA-DR expression, which correlated to increased microglial phagocytosis of myelin, in LPC treated organoids compared to vehicle control (p=0.0396 and p=0.0017, respectively). The extent of oligodendrogenesis and remyelination following LPC was assessed by quantifying the proportion of cells double positive for EdU and CNPase. There was a twofold increase in EdU+CNP+ cells in LPC treated organoids compared to vehicle at 4 weeks (p=0.027). 

Conclusion: We have successfully generated a humanised model of demyelination and remyelination using iPSC-derived organoids. This system will allow mechanistic insight into pathogenesis and a platform for screening drugs that may promote remyelination providing hope for MS patients. 

Keywords: Demyelination, Remyelination, Oligodendrocytes, Microglia, Organoids 

Authors: Shwathy Ramesan (1), Joel Mason (1), Sam Mills (3), Matthew Rutar (2-3), Molly E Swanson (4), David Gonsalvez (5) & Samantha K Barton (1) 

Author affiliations: 
1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3052, Australia 
2. Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, ACT 2617, Australia 
3. Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC 3052, Australia 
4. Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand 
5. Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC 3168, Australia  

Dr. Yvonne Learmonth is an accredited physiotherapist who specialises in physical activity research in multiple sclerosis. She has a PhD in rehabilitation from the University of Glasgow. She leads an exercise and cognition research group based at Murdoch University, WA and has advocated for consumer-based research for almost 10 years. Yvonne is currently an MS Australia Research Fellow..

Targeting Platelets as an Alternative Therapeutic Strategy for Neuroprotection in Multiple Sclerosis.

Platelets, Novel therapeutic approach, Remyelination, Neuroprotection, Immunomodulation    

The underlying hypothesis is that early platelet targeting exerts neuroprotective effects. This is based on preliminary investigations demonstrating  early platelet inflitration in the  experimental autoimmune encephalomyelitis (EAE) model and platelet-neuron and platelet-myelin interactions. Additionally, prevention of demyelination and inflammation with prophylactic platelet depletion was achieved.  

This project has two main objectives (1) to validate the therapeutic efficacy of platelet targeting using a novel drug denoted TargetedCD39 (TargCD39) with anti-aggregatory and anti-inflammatory properties. (2) To demonstrate qualitative and quantitative evidence of functional restoration and hallmarks of remyelination after platelet targeting treatment.  

Using an attenuated murine EAE model, a therapeutic drug trial was carried out comparing TargCD39 to Fingolimod which targets T cells. Functional recovery was then measured using a grip strength test. To study the effect of platelet targeting on myelin levels, glial cell responses and neuronal survival, immunochemistry and the IMARIS software were utilised to analyse spinal cord tissue samples. Subsequent quantification was conducted using the software QuPath and ImageJ.   

The drug trial result shows significantly (p<0.0001) higher efficacy in modification of disease course with TargCD39 relative to Fingolimod. At experimental end-point, the grip strength test showed significant (p<0.05) regaining of upper limb strength with TargCD39 treatment. Platelet targeting significantly (p<0.05) reduced CD3+ cell infiltration and neuronal loss. More importantly, TargCD39 induced remyelination (p<0.01) as evidenced by upregulation of myelin marker expression alongside significant (p<0.0001) expansion of the oligodendrocyte population.  

The data show that platelet targeting is more effective than T cell targeting in blocking neuroinflammation. Morevoer, TargCD39 induces changes the central nervous system environment from destructive to reparative, with a neuroprotective outcome. Platelet targeting holds promise as a clinically relevant therapeutic approach for MS. 

Authors: Vernise Lim (1), Nishat I. Tabassum (2), Chris van der Poel (2), Karlheinz Peter (3), Jacqueline M. Orian (1). 

Author affiliations: 

(1) Biochemistry and Chemistry, La Trobe Institute for Molecular Science, Bundoora, Melbourne VIC 3083  

(2) Microbiology, Anatomy, Physiology & Pharmacology, La Trobe University, Bundoora, Melbourne VIC 3083  

(3) Atherosclerosis and Vascular Biology, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne VIC 3004 

Associate Professor Anne Brüstle is an immunologist at The John Curtin School of Medical Research

Her work centres around the autoimmune component of Multiple Sclerosis. Her group investigates key immune populations driving the pathogenesis of this complex condition, such as the Il-17 producing Th17 cells and neutrophil granulocytes, using laboratory model systems to understand the underlying biological principals. In collaboration with diverse industrial partners her group further evaluates potential new targets for conceptually novel MS treatments and deciphers their biological mechanisms in neuroinflammation. In 2018 she was awarded the Young Tall Poppy Award for her work for and with the MS community. She further is the chair and MS research lead of “Our Health in Our Hands” an interdisciplinary program to develop personalised monitoring and managing approaches for chronic autoimmune conditions such as MS and diabetes in collaboration and co-designed by people with lived experience.

Anne completed her PhD in Human Biology 2008 at the Institute of Medical Microbiology, Philipps-University in Marburg, Germany. She was recruited to ANU in mid 2014, after being a post-doctoral fellow at the University of Toronto, Canada.

Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in Multiple Sclerosis.

Background: Regulatory B cells play a pivotal role in suppressing immune responses. While several regulatory B cell subsets have been described in humans, a lack of cell surface markers hinders their precise identification for functional assessment.  

Objective: Here we investigated the role of human memory B cells expressing TIM-1 and TIGIT to determine their potential regulatory function in healthy donors and those with relapsing-remitting multiple sclerosis (MS). 

Methods: Fluorescence-activated cell sorted TIM-1+/-TIGIT+/- memory B cells were co-cultured with allogenic CD4 T cells. T cell proliferation and induction of inflammatory markers to determine Th1/Th17 cell differentiation and their capacity to induce FoxP3 regulatory T cells were measured by flow cytometry and cytokine quantification. Transcriptional differences were assessed by SMARTSeq2 RNA sequencing analysis. 

Results: T cells cultured with the TIM-1+TIGIT+ memory B cells exhibited low levels of proliferation and cytokine expression. In MS, TIM-1+TIGIT+ memory B cells were less inhibitory compared to healthy controls and were increased in frequency in individuals who responded to anti-CD20 therapy. Transcriptomic analyses showed MS TIM-1+TIGIT+ memory B cells exhibited increased expression of genes associated with T cell activation and survival and decreased expression of anti-inflammatory genes. 

Conclusion: These findings demonstrate the existence of a regulatory memory B cell subset defined by the co-expression of TIM-1 and TIGIT  that is functionally impaired in MS. A deeper understanding of B cell subsets in MS may lead to more targeted therapies in the future.  

Dr Claudia Marck is a MS Australia Fellow and a Momentum Fellow at the Disability and Health Unit at the University of Melbourne. She has degrees in psychology and neuroscience from Utrecht University in the Netherlands. She has worked in MS research for almost a decade, with a focus on understanding the role of health behaviours such as smoking, physical activity and diet on health outcomes in people with MS. Her current work also investigates the use and quality of evidence-based guidelines in MS care, and the impact of disasters on the MS community

Exploring the role of the innate immune system during relapse in multiple sclerosis

Background: Diagnosis of relapse in multiple sclerosis (MS) is impeded by both ‘pseudo-relapses’ and the low sensitivity and specificity of current diagnostic measures. This poses a risk for sub-optimal treatment of patients. Currently there is limited knowledge on changes in the innate immune response during relapse.  

Objective: This study proposes to determine changes in peripheral blood cell ratios, cytokines, chemokines and proteins from MS patients in relapse versus remission in an attempt to differentiate the two disease states based on immunological changes.  

Methods: Full blood examination data was collected both prospectively (N=20) and retrospectively (N=100) from relapsing-remitting MS (RRMS) patients during relapse and remission. From this we derived multiple cell ratios and percentages. Additional parameters analysed in the prospective cohort include changes across relapse and remission in 14 cytokines/chemokines as well as soluble P2X7R in plasma (Luminex multiplex ELISA), neurofilament light in serum (SIMOA) and gene expression levels of monocyte RNA (qPCR).  

Results: In patients with contrast enhancing lesions on MRI (n=52), total monocytes (p=0.0211) and lymphocytes counts (p=0.0191) were significantly lower and neutrophils higher (p=0.0125) at the time of relapse versus remission. Monocytes were also lower in treatment naïve group (n=56) at the relapse timepoint (p=0.0193). Microarray analysis revealed differential expression of various monocyte genes in relapse versus remission. Of 14 plasma cytokines studied there was no difference in the two states. 

Conclusion: This study helps build our understanding of cellular and molecular mechanisms of MS relapse which may lead to the development of better biomarkers to accurately diagnose the disease state.  

Funding sources: MS Australian Project Grant. 

Keywords: immunology, relapse, diagnosis, innate, biomarkers 

Authors: Meltem Karadeniz (1), Robb Wesselingh (1,2), Padmakrishnan Jayakrishnan (1), Marie John (1), Louise Rath (2), Katherine Fazzolari (3), Richard Sequeira (1), Nabil Seery (1,2), Lisa Taylor (3), Foong Yi Chao (1,2), Tracie Tan (1,2), Wei Yeh (1,2), Michael Zhong (1,2), Francesca Bridge (1,2), Cassie Nesbitt (1,2), Olga Skibina (1,2), Tomas Kalincik (3,4), Anneke Van Der Walt (1,2), Helmut Butzkueven (1,2), Mastura Monif (1,2,3) 

Author affiliations: 
1 Department of Neuroscience, Monash, University  

2 Department of Neurology, Alfred Hospital  

3 Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital  

4 Clinical Outcomes Research Unit, Department of Medicine, The University of Melbourne  

Yasmine Probst is an Associate Professor with the School of Medical, Indigenous and Health Sciences at the University of Wollongong and Research Fellow at the Illawarra Health and Medical Research Institute. She holds dual Masters degrees in Dietetics and Health Informatics and is recognised as an Advanced Accredited Practising Dietitian with Dietitians Australia and a Fellow of the Australasian Institute for Digital Health. Yasmine holds a current Senior Research fellowship with MS Australia. As a person living with MS, her research and teaching focuses on nutrition for people living with MS.

Characterisation of clonally-expanded B cells in multiple sclerosis.

Background: Multiple sclerosis (MS) is associated with B cell dysfunction and aberrant antibody responses against Epstein-Barr virus (EBV). Identifying the specific B cell subsets that are activated and/or dysfunctional at the onset of MS disease could form the basis of new treatments. 

Objective: A single cell multi-omics approach was used to characterise circulating B cells of MS patients and compare these with controls. We aimed to investigate B cell clonal expansion, activation and phenotypes in blood taken from treatment-naive individuals with a recent MS diagnosis. 

Methods: B cells were enriched from peripheral blood mononuclear cells, and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) with B cell receptor (BCR)-sequencing was performed to investigate B cell clonal repertoires, transcriptomes and surface proteomes. Phylogenetic relationships between cells were reconstructed to identify expanded B cell clones. CITE-seq data were analysed for expression features to identify the phenotypes of B cells involved in expanded clones. 

Results: Approximately 2% of B cells analysed belonged to expanded clones of three or more cells in people with MS and controls. The largest B cell clones in people with MS were enriched for plasmablasts, as well as antigen-experienced memory B cells and marginal zone-like B cells. The presence of pre-plasmablasts within these clones in people with MS only, suggested that some expanded B cell clones may have been recently activated.  

Conclusion: New-onset MS was associated with expansion of B cell clones containing pre-plasmablasts, indicating recent immune responses, plasmablasts, memory and marginal zone-like B cells. Analysis of clonally-expanded B cells, including their BCR sequence, may identify EBV antigens and autoantigens involved in the onset of MS. 

Funding sources: MS Australia Project Grant 

Authors: Stephanie Trend (1,2), Alice White (2), Jesse Armitage (3,4), Emma de Jong (5), James Read (5,6), Marzena Fabis-Pedrini (1,7), Jonatan Leffler (2), Carlos Aya-Bonilla (3,8), Sébastien Malinge (3,8), Prue Hart (2), Martyn French (9,10), Allan Kermode (1,7,11) 

Author affiliations: 
1. Demyelinating Diseases Group, Perron Institute for Neurological and Translational Science  
2. Inflammation Team, Telethon Kids Institute, University of Western Australia, Perth, Australia 
3. Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, Australia 
4. Cancer Immunotherapy Unit, School of Biomedical Sciences, University of Western Australia, Perth, Australia 
5. Systems Immunology Team, Telethon Kids Institute, University of Western Australia, Perth, Australia 
6. Asthma and Airway Disease Research Center, The University of Arizona, United States of America 
7. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University 
8. UWA Medical School, University of Western Australia, Perth, Australia 
9. School of Biomedical Sciences, University of Western Australia, Perth, Australia 
10. Immunology Division, PathWest Laboratory Medicine, Perth, Australia 
11. Institute for Immunology and Infectious Disease, Murdoch University, Perth, Australia  

Characterisation of immunometabolic profile after Autologous Haematopoietic Stem Cell Transplantation in people with Multiple Sclerosis.
 

Background: Multiple Sclerosis (MS) is an autoinflammatory disease of central nervous system characterised by demyelination, axonal degeneration, and dysregulated immunological self-tolerance. Studies indicate that autologous haematopoietic stem cell transplantation (AHSCT) improves clinical outcomes in MS, but evidence of how AHSCT induces clinical remission is limited. 

Objective: A central factor regulating fate and function of immune cells is their metabolic state. However, minimal immunometabolic studies exist in MS, with none in peri-transplant setting. In this study, we identify metabolic changes occurring in immune subsets of people with MS (PwMS) undergoing AHSCT. 

Methods: PBMCs from PwMS (n=14) were run using an 18-colour immunometabolic flow cytometry panel to detect metabolic proteins: Glucose transporter-1 (Glut-1;glucose transport), Hexokinase-1 (HK1;glycolysis), isocitrate dehydrogenase-2 (IDH-2;Krebs cycle), ATP5A (electron transport chain), and carnitine palmitoyltransferase-1A (CPT1A;fatty acid oxidation). Their median fluorescent intensity on lymphocyte subsets pre- and post-AHSCT were statistically analysed using linear mixed-effects model and Holm-Sidak test (p<0.05), with logarithmic transformations if required after residual analysis, using GraphPad Prism 8. 

Results: Significant increases were observed for Glut1 and ATP5A expression on T-regulatory (Tregs), T-conventional (Tconv) and CD56hi natural killer (NK) cells at Day+14 post-AHSCT, with HK1 elevated in Tregs, CD56hi, CD56dim NK subsets at Day+14 post-AHSCT. Significant elevations for CPT1A and IDH2 expression on Tregs, T-conv, CD56hi and CD56dim NK cells were observed at Day+14 post-AHSCT, notably, with elevation sustained until long-term post-AHSCT, 24months and 12months respectively, only within Tconv cells. 

Conclusion: This is the first study identifying immunometabolic changes in PwMS post-AHSCT. Our findings indicate an early upsurge in metabolic activity, possibly triggered by the lymphophenic milieu. Sustained higher CPT1A and IDH2 expression in Tconv post-AHSCT suggests preference towards energy-efficient fatty acid metabolism via mitochondrial respiration. 

Funding sources: The funding for this study was provided by Postdoctoral fellowship scholarship from Multiple Sclerosis Australia and grant from Bourne Foundation. The research program is also supported by funding from Medich Family Foundation, NHMRC, St Vincent’s Clinic Research Foundation, Maple-Brown Family Charitable Foundation, Reset Australia, and John Kirkpatrick Medical Foundation. 

Keywords: Multiple sclerosis, AHSCT, Immunometabolism, Met-flow, Immune reconstitution, Autoimmune diseases. 

Authors: Malini Visweswaran (1,2), Jennifer C Massey (1,2,3,4), Melissa L Khoo (1,2), Barbara Withers (1,2,4), David D F Ma (1,2,4), John J Moore (1,2,4) 

Author affiliations: 
1. Blood Stem cells and Cancer Laboratory, St. Vincent’s Centre for Applied Medical Research, Darlinghurst, Sydney, New South Wales, Australia 

2. School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney, Australia. 

3. Department of Neurology, St.Vincent’s Hospital, Darlinghurst, Sydney, New South Wales, Australia 

4. Department of Haematology, St. Vincent’s Hospital, Darlinghurst, Sydney, New South Wales, Australia 

Prof Jeannette Lechner-Scott is a senior staff specialist in the department of Neurology, Newcastle, and a conjoint Professor of the University of Newcastle. She is the head of the Neuroimmunology clinic in the John Hunter Hospital in Newcastle as well as of Neuroimmunology at the Immune Health program in the Hunter Medical Research Program, Board member of MS Plus, and member of MSIF and chief editor of MSARD. She is the recipient of the 2023 Ian McDonald award for outstanding research in MS. Her research stretches over multiple fields (genetics/epigenetics, new MRI technologies, pregnancy, cognition in MS etc), but always has the person with MS in its center.

Environmental and genetic mixture effect on MS risk mediated by differential DNA methylation in the Ausimmune case-control study.

Background: A number of environmental factors have been implicated in MS risk, including sun/vitamin D and Epstein-Barr virus (EBV), as well as HLA-DRB1*1501 risk genotype. How and whether these factors may act in combination to affect first clinical demyelination (FCD) risk is unclear.  

Objective: To apply weighted quantile sum (WQS) regression to assess the association between a mixture of environmental and genetic factors and FCD risk; to evaluate the population attributable fraction; and to assess if and to what extent this association is mediated by differential DNA methylation 

Methods: 206 FCD cases subsequently converting to MS by 10-year follow-up with whole-blood DNA-methylation data compared with 348 controls. Six CpG clusters derived from 2,432 EWAS-defined FCD-associated CpGs using weight-gene correlation network analysis. WQS assessed mixture effect on FCD of glandular fever history, anti-EBV-EBNA-Ig, deseasonalised-25(OH)D, pre-FCD summer/winter sun exposures, smoking, and HLA-DRB1*1501 (each scored 0/1). PAF estimated using PAF_calc_continuous R package. Mediation by the CpG clusters assessed using medflex R package. 

Results: The environmental-genetic mixture significantly predicted FCD risk (10-90% OR=11.02,95%CI=2.48-48.91, p<0.001), PAF=87.2%, persisting if the genetic component, HLA-DRB1*1501 was excluded from the mixture (OR=6.75,95%CI=1.73-26.31, p<0.001), PAF=77.2%. Blue and Turquoise CpG clusters each independently mediated 19% and 12% of associations with FCD risk (22% and 12% if HLA-DRB1*1501 excluded), and jointly mediated 28% of association with FCD risk (34% if HLA-DRB1*1501 were excluded). No other CpG clusters showed comparable mediation.  

Conclusion: We have shown that key environmental and genetic risk factors act in combination to predict FCD risk, and that a substantial amount of this association acts via differential DNA methylation at MS onset, indicating multiple potentially modifiable epigenetic mechanisms to reduce MS risk.  

Funding sources: Funding sources for this work include the National Health and Medical Research Council of Australia, MS Research Australia, and the National Multiple Sclerosis Society of the United States of America.  

Keywords: multiple sclerosis, environment, HLA-DRB1*1501, epigenetic, mediation 

Authors: Steve Simpson-Yap (1,2,3,4) & Ellen Morwitch (1), Sarah Thomson (1), Sam Tanner (1), Rod A Lea (5,6,7), Trevor Kilpatrick (1), Jeannette Lechner-Scott (6,7,8), Rodney Scott (7,9), Alexandre Xavier (7,9), Vicki E Maltby (6,7,8), Bruce Taylor (4), Brett Lidbury (10), Simon Broadley (11), Ingrid van der Mei (3), Maja Jagodic (12,13), Lars Alfredsson (12,13), Ausimmune Investigators Group, Anne-Louise Ponsonby (4,10,14) 
 

Author affiliations: 
1. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia; 
2. Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, Australia; 
3. CORe, Department of Medicine, The University of Melbourne, Parkville, Australia; 
4. MS Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; 
5. Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology, Kelvin Grove, Australia; 
6. School of Medicine and Public Health, Newcastle University, Callaghan, Australia; 
7. Hunter Medical Research Institute, Newcastle University, Callaghan, Australia; 
8. Department of Neurology, John Hunter Hospital, New Lambton Heights, Australia; 
9. School of Biomedical Sciences and Pharmacy, Newcastle University, Callaghan, Australia; 
10. National Centre for Epidemiology and Population Health, ANU College of Health and Medicine, Australia National University, Acton, Australia; 
11. School of Medicine and Dentistry, Gold Coast Campus, Griffith University, Southport, Australia; 
12. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 
13. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;                                                                                                                     
14. Murdoch Children’s Research Institute, The University of Melbourne, Parkville, Australia. 

Using human iPSC-derived 'MiniBrains' to model de- and re-myelination.

Background: Mechanistic understanding of Multiple Sclerosis (MS) is critical for identifying new treatments. However, this remains challenging due to current model systems being limited in their capacity to recapitulate the complex human myelination processes resulting in a lack of available treatments targeting remyelination for MS patients.  

Objective: We therefore aimed to pioneer an organoid model of human demyelination.  

Methods: Using human induced pluripotent stem cells (iPSC), we generated 3D organoids containing microglia, myelinating oligodendrocytes, neurons and astrocytes, which we successfully demyelinated using lysolecithin (LPC). Briefly, after patterning we commence myelin induction (time 0). After 3 weeks we seeded in TdTomato-tagged microglia-like precursor cells. At 11 weeks, we treat organoids with LPC (or vehicle) and then collect organoids for characterisation of: demyelination at 5h, 24h and 1 week, and signs of remyelination at 4 and 8 weeks following LPC.  

Results: Myelin fragmentation was quantified using the 3D analysis software, IMARIS, to measure myelin sheath length; fragmentation was significantly higher at 5 h, 24 h, 7 d and 14 d in LPC treated organoids, compared to vehicle (p<0.05 for all). Microglia had elevated HLA-DR expression, which correlated to increased microglial phagocytosis of myelin, in LPC treated organoids compared to vehicle control (p=0.0396 and p=0.0017, respectively). The extent of oligodendrogenesis and remyelination following LPC was assessed by quantifying the proportion of cells double positive for EdU and CNPase. There was a twofold increase in EdU+CNP+ cells in LPC treated organoids compared to vehicle at 4 weeks (p=0.027). 

Conclusion: We have successfully generated a humanised model of demyelination and remyelination using iPSC-derived organoids. This system will allow mechanistic insight into pathogenesis and a platform for screening drugs that may promote remyelination providing hope for MS patients. 

Keywords: Demyelination, Remyelination, Oligodendrocytes, Microglia, Organoids 

Authors: Shwathy Ramesan (1), Joel Mason (1), Sam Mills (3), Matthew Rutar (2-3), Molly E Swanson (4), David Gonsalvez (5) & Samantha K Barton (1) 

Author affiliations: 
1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3052, Australia 
2. Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, ACT 2617, Australia 
3. Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC 3052, Australia 
4. Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand 
5. Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC 3168, Australia  

Step exergame training to reduce falls in people with multiple sclerosis: The i-FIMS multi-centre randomised controlled trial.

Background: Cognitive-motor step training is safe and can improve stepping, balance and mobility in people with multiple sclerosis (MS), but efficacy of the cognitive-motor step training in preventing falls has not been demonstrated.  

Objective: This multi-site randomised controlled trial aimed to determine whether a six-month home-based step exercise training program could reduce falls and improve associated fall risk factors compared with usual care in people with MS. 

Methods: 461 people with MS aged 22-81 years (n=366 women, Expanded Disability Status Scale score 1.5-6.0) were randomly allocated to usual care (control) or a six-month home-based step exergames training program (120 minutes/week). The primary outcome was rate of falls over six months. Secondary outcomes included physical, cognitive, and psychosocial function at six months and number of falls over twelve months. 
 

Results: Mean (SD) exergames play duration was 70 (51) min/week over six months. Fall rates did not differ between groups (incidence rate ratio 0.96, 95% confidence interval 0.69 - 1.34, p = 0.816). Participants in the intervention group performed faster in tests of choice-stepping reaction time at six months, compared with control participants. No serious training-related adverse events occurred.  

Conclusion: The step exergame training program did not reduce falls among people with MS. However, it significantly improved voluntary stepping in cognitively challenging tests. 

Keywords: Accidental falls, fall prevention, cognitive training, balance training, stepping, Multiple Sclerosis. 

Funding sources: MSRA (Postdoctoral Fellowship 13-003_PH); MS Plus (Grant-in-aid) 

Authors: Phu D. Hoang (1,2), Daina L. Sturnieks (1,3), Carly Chaplin (1), Cameron Hicks (1), Sophie Robinson, Natassia Smith (1), Stephen R. Lord (1), Jasmine C Menant (1,3). 

Author affiliations: 

1 Neuroscience Research Australia, Randwick NSW 

2 MS Plus 

3 University of New South Wales

Identifying copy number variants and genes associated with multiple sclerosis.

Background: The impact of copy number variants (CNVs) on multiple sclerosis (MS) remains understudied. Understanding how these structural variants influence MS susceptibility can provide important insights into the genetic triggers of MS.  

Objective: To systematically examine the role of CNVs in MS susceptibility. 

Methods: We assessed CNV burdens in ANZgene (n= 3,307 cases and 2,738 controls), UK Biobank (n= 1,072 cases and 296,583 controls) and WTCCC2 (n= 9,772 cases and 527 controls) cohorts, followed by a CNV genome-wide association study (GWAS) identifying regions of MS-associated CNVs. To prioritise gene candidates within CNV regions, we integrated transcriptomics data at tissue-level (nblood=31,684; nbrain=2,865) and cell-level (nimmune=982; nbrain=192) into MS GWAS (n=14,802 cases and 26,703 controls).  

Results: Our meta-analysis of CNV length burdens found higher CNV loads were associated with increased MS risk (odds ratio= 1.18, 95% confidence interval= 1.09-1.28, P= 6.3x10-5). Further, our GWAS analysis identified several independent novel genomic regions where CNVs were associated with MS risk (P< 5x10-8). Within the identified CNV regions, we further discovered MS-associated genes at tissue-level and cell-level. We are currently working to additionally incorporate whole-exome sequencing data.  

Conclusion: This is so far the largest CNV project for MS and findings from our study highlight an important role of CNVs in MS development. 

Funding: This work was supported by funding from the Medical Research Future Fund (B.V.T., EPCD000008), and the Australian National Health and Medical Research Council (B.V.T., 2009389 & Y.Z., 1173155). 

Keywords: copy number variation; GWAS; post-GWAS gene mapping; transcriptomics; multiple sclerosis. 

Authors: Xin Lin (1*), Vikrant Singh (1*), Yuanhao Yang (2,3*), ANZgene consortium, Nicholas B. Blackburn (1), Allan Motyer (4), Bennet J. McComish (1), Stephen Leslie (5), Simon Broadley (6), Vilija Jokubaitis (7), Allan Kermode (8,9), Jeanette Lechner-Scott (10), Grant P. Parnell (11), Marzena J. Fabis-Pedrini (8,12), Rodney J. Scott (13), Trevor J. Kilpatrick (14,15), Justin P. Rubio (14,15), Jacob Gratten (2), Bruce V. Taylor (1†), and Yuan Zhou (1†). 

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia 
2. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia 
3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia 
4.Schools of BioSciences, and Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia. 
5. Melbourne Integrative Genomics, The University of Melbourne, Parkville, Melbourne, VIC, Australia 
6. Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia. 
7. Department of Neuroscience, Monash University, Melbourne, VIC, Australia; Department of Neurology, The Alfred Hospital, Melbourne, VIC, Australia. 
8. Perron Institute for Neurological and Translational Science, The University of Western Australia, Perth, WA, Australia. 
9. Queen Elizabeth II Medical Centre, Perth, Australia. 
10. Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, NSW, Australia 
11. Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia. 
12. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia. 
13. Division of Molecular Medicine, NSW Health Pathology-North, John Hunter Hospital, Newcastle, NSW, Australia. 
14. The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. 
15. Florey Department, University of Melbourne, VIC, Australia. 

*These authors contribute equally to this work 

†These authors jointly supervise this work. 

Disability, Health-Related Quality of Life, and Self-Concept Change in People with Multiple Sclerosis: A Moderated Mediation.

Background: Disability informs self-concept (opinions of self) change following MS diagnosis. Health-related quality of life (HRQoL) and relationship satisfaction are also known to influence self-concept in people with MS. Whether these psychosocial factors account for the relationship between disability and self-concept change however is not known.  

Objectives: To investigate the potential mediation effect of HRQoL on the relationship between disability and self-concept change in people with MS, and whether relationship satisfaction is a moderator of the mediated relationship. 

Methods: 995 people with MS (79.5% female; Age M = 59.72 years, SD = 11.15) completed the Self-Reported Disease Steps Scales (assessing disability), the AQoL-8D (assessing HRQoL), and the MS Self-Concept Change Scale. Of these, 726 participants who indicated they were currently in a relationship also completed the Relationship Assessment Scale (assessing relationship satisfaction). Moderated mediation (conditional process) and parallel mediation analyses were used to analyse the data in SPSS. 

Results: The relationship between disability and self-concept change was partially mediated by HRQoL. Across the eight subdomains of HRQoL, only the ‘relationships’ and ‘coping’ subdomains mediated the relationship between disability and self-concept change. However, for those participants in a relationship, relationship satisfaction did not moderate any mediation effects.  

Conclusion: The findings highlight the role that perceptions of HRQoL in some domains may have in explaining the relationship between disability and self-concept change. Further research is needed to explicate the causal direction of these relationships in longitudinal studies. 

Funding statement: MS Australia funds the Australian MS Longitudinal Study. Professor van der Mei receives funding through a Senior Research Fellowship from MS Australia and an Accelerated Research Grant from the Australian Medical Research Future Fund funds the Menzies MS Flagship Program. Miss Emery was supported by an Australian Government Research Training Program Scholarship awarded by the College of Health and Medicine, University of Tasmania.  

Keywords: multiple sclerosis, self-concept change, health-related quality of life, relationship satisfaction 

Authors: Holly Emery (1), Ingrid van der Mei (2), Christine Padgett (3), Cynthia Honan (1). 

Author affiliations: 

1 School of Psychological Sciences, University Tasmania, Launceston, Australia 

2 Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 

3 School of Psychological Sciences, University of Tasmania, Hobart, Australia 

The Shared Genetic Landscape of Blood Cell Traits and Risk of Multiple Sclerosis.

Background: Phenotypic associations have been reported between blood cell traits (BCTs) and MS. The development of blood-based biomarkers for MS has garnered significant attention. However, it remains unclear whether BCT-MS associations have a genetic basis, and to what extent genetic correlations reflect causality versus pleiotropy.  

Objective: To systematically investigate the shared genetic landscape underlying BCTs and MS. 

Methods: We estimate genome-wide and local genetic correlations (rg) between MS and 29 BCTs, using genome-wide association study (GWAS) summary statistics. We evaluate putative causal relationships between BCT-MS trait pairs using Mendelian randomisation and we identify putatively functional genes and regulatory elements shared by specific pairs of BCTs and MS using Summary-data-based Mendelian Randomisation. 

Results: We identified significant rg between MS and lymphocytes and white blood cells. We identified numerous significant local rg, including for BCTs with no detectable genome-wide rg with MS. We observed a suggestive causal effect of higher lymphocyte count on MS, suggesting potential lymphocyte-based biomarkers for MS diagnosis. We identified multiple functional genes and regulatory elements shared by specific MS-BCT pairs, some of which may represent drug re-purposing opportunities for MS. 

Conclusion: These results enrich our understanding of the shared genetic landscape underlying BCTs and MS and provide a foundation for future work to improve prognosis, prevention, and treatment of multiple sclerosis. 

Keywords: blood cell traits, genetic correlation, Mendelian randomisation, blood-based biomarkers 

Authors: Yuanhao Yang (1,2), Yuan Zhou (3), Dale R. Nyholt (4), Chloe X. Yap (1,2), Rudolph K. Tannenberg (1), Ying Wang (5,6,7), Yang Wu (2), Zhihong Zhu (8,2), Bruce V. Taylor (3), Jacob Gratten (1) 

Author affiliations: 
1. Mater Research Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia  

2. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia  

3. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia 

4. School of Biomedical Sciences, Faculty of Health, and Centre for Genomics and Personalised Health, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia 

5. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA 

6. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 

7. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 

8. National Centre for Register-based Research, Aarhus University, Aarhus 8210, Denmark 

Deb has worked in the public health and prevention space at all levels of government – Federal, State and Local – and not for profit sectors to contribute to the health and well-being of communities. She has worked to capture the voices of all parts of the community impacted by services, programs, and research including access and inclusion, Aboriginal and Torres Strait Islander people, culturally and linguistically diverse communities, children and young people, those with mental health challenges, and those connected with health and community services.

She has always worked connecting institutions, organisations, government, and community with a well-being focus, and was a representative on WA Sustainable Health Review with this in mind. She has been appointed to the NHMRC’s Consumer Statement Advisory Committee to review and develop new national principles and guidelines for involvement of people with lived experience in research, together with the Medical Research Future Fund Consumer-led Grant Assessment Committee.

Deb’s role leading the Consumer and Community Involvement Program (CCIProgram) as a platform of the Western Australia Health Translation Network is to connect researchers in WA Universities, Medical Research Institutes, Government, and Health Service Providers and Funders with people with lived experience to support and encourage best practice research. She has been involved in the development of the WA Future Health Research and Innovation (FHRI) Fund Strategy’s Research Principles and Grant Scheme governance and part of the consultation for the development of the WA Health and Medical Research Strategy 2023 – 2033. Of note, has been her involvement in the Executive Group developing and guiding WA’s first Mental Health Research Strategy that has the lived experience of people with mental health challenges as it’s foundation. Newly appointed as the Chair, Australian Health Research Alliance (AHRA) Consumer and Community Involvement Advisory Committee ensures that conversations at a national level are relevant and inclusive of the best practice work of involving people in research being conducted in institutions and health care providers both nationally and in WA.

Deb is passionate about ensuring research can impact policy, practice and wellbeing of communities and enjoys bringing people together to make a difference.

Yasmine Probst is an Associate Professor with the School of Medical, Indigenous and Health Sciences at the University of Wollongong and Research Fellow at the Illawarra Health and Medical Research Institute. She holds dual Masters degrees in Dietetics and Health Informatics and is recognised as an Advanced Accredited Practising Dietitian with Dietitians Australia and a Fellow of the Australasian Institute for Digital Health. Yasmine holds a current Senior Research fellowship with MS Australia. As a person living with MS, her research and teaching focuses on nutrition for people living with MS.

I’m 53. From London, I moved to Australia in 2005 and was diagnosed with MS in 2010. I have two boys. I receive services from MSWA, including Physio and Care Support.  I also attend the new facility at Butler.

I exercise as much as possible and I also receive NDIS support.

I enjoy posting my outfits to Instagram and also have a YouTube channel showing my journey with MS.

Viv commenced work at the University of Tasmania's  Menzies Institute for Medical Researching in January 2018 as the inaugural project manager for the MS Research Flagship program.  She was responsible for establishing and implementing governance structures and stakeholder management. The embedding of consumer and community involvement within the program was a priority of her role.

In March 2020, she was appointed as the and Consumer and Community Involvement Manager for the MS Research Flagship at Menzies and is a member of the Flagship's leadership group. She has strong links with the MS Community in Tasmania and interstate and has a lived experience of MS of over 27 years since her diagnosis in 1996.

My name is Hayley Long, I am 29 years old and diagnosed with MS at 26 years old. I started suffering symptoms at the age of 16, when I woke up one morning in able to physically hold myself up or walk more than a few steps. I work part time in admin, run puppy training classes, I love spending my free time with my pets and partner, I’m very artistic and often express how I feel in drawings and/or makeup creations. 

High-efficacy therapy delays disability in paediatric-onset multiple sclerosis.
 

Background: High-efficacy disease-modifying therapies have been proven effective in reducing disability accumulation in patients with multiple sclerosis (MS). Whether they modify the patterns of transition among disability states in paediatric-onset MS is unknown.  

Objectives: We aimed to evaluate the effect of high-efficacy therapies on disability transitions across five states ranging from negligible disability to significant impairment of gait and secondary progressive MS in patients with paediatric-onset MS. 

Methods: Longitudinal clinical data were obtained from the MSBase registry and the Italian MS Register. The primary outcome was defined as the time to change in disability state: negligible disability (EDSS 0-1.5), minimal disability (EDSS 2.0-2. 5), moderate disability (EDSS 3.0-3.5), gait impairment (EDSS ≥4.0), and clinician diagnosed secondary progressive MS. A multi-state model was constructed to simulate the natural course of MS by modelling both disability worsening and improvement simultaneously.  

Results: A total of 5224 patients (71% female) who were diagnosed with MS before reaching the age of 18 years were included in the analyses. High-efficacy therapies reduced the risk of disability worsening with the largest reduction (HR 0.41 [95% CI: 0.31, 0.53]) observed in patients who were treated while in the negligible disability state, compared to those remain untreated. The impact of high-efficacy therapies decreased gradually as disability increased. Frequent relapses increased the likelihood of disability worsening, including a high risk of a 3-step transition from negligible disability to gait impairment (5.11 [3.91, 6.68]). 

Conclusion: Treatment with high-efficacy therapy, even when the disability is negligible, substantially reduces the risk of further disability worsening in patients with paediatric-onset MS. The persistence of disability worsening due to frequent relapses, despite improved relapse recovery observed in this population, emphasizes the need for early aggressive treatment to better preserve the neurological capacity of paediatric patients in the long run. 

Funding: This study was funded by the NHMRC [grant 1129189 and fellowship 1140766]. The MSBase Foundation is a not-for-profit organization that receives support from Merck, Biogen, Novartis, Roche, Bayer Schering, Sanofi Genzyme, and Teva Pharmaceutical Industries. The study was conducted separately and apart from the guidance of the sponsors. 

Keywords: paediatric-onset multiple sclerosis; disability transitions; disease-modifying therapy 

Authors: Sifat Sharmin; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 

Izanne Roos; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 

Charles Malpas; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 

Jeannette Lechner-Scott; Hunter Medical Research Institute, University Newcastle, Newcastle, Australia; Hunter New England Health, John Hunter Hospital, NSW Australia 

Katherine Buzzard; Department of Neurosciences, Box Hill Hospital, Melbourne, Australia; Monash University, Eastern Health Clinical School, Box Hill, Australia 

Olga Skibina; Department of Neurology, Box Hill Hospital, Melbourne, Australia; Department of Neurosciences, Eastern Health Clinical School, Monash University, Melbourne, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Australia 

Nevin John; Monash Health, Melbourne, Australia; Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia 

Anneke van der Walt; Department of Neurology, The Alfred Hospital, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia 

Helmut Butzkueven; Department of Neurology, The Alfred Hospital, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia 

Michael Barnett; Brain and Mind Centre, Sydney, Australia 

Tomas Kalincik; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia on behalf of the MSBase investigators.

Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis.

Background: Cladribine, a purinergic antimetabolite that triggers lymphocyte apoptosis, reduces the frequency of relapses by 57% and disability worsening by 33% compared to placebo in relapsing-remitting multiple sclerosis (RRMS). No head-to-head comparisons of cladribine to other potent immunotherapies are available. 

Objective: Compare the effectiveness of cladribine with fingolimod, natalizumab, ocrelizumab and alemtuzumab in patients with RRMS. 

Methods: Patients with RRMS who were treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab from January 2018 were identified in the global MSBase cohort study and 2 UK centres.  Included patients were followed for at least 6 months and had a minimum of 3 in-person assessments of disability. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARR), and disability endpoints. All subsequent events were analysed, regardless of changes in treatment status. 

Results: The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab), or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (ARR 0.07 vs 0.12, p=0.006), and a higher ARR than natalizumab (0.10 vs 0.06, p=0.03), ocrelizumab (0.09 vs 0.05, p=0.008), and alemtuzumab (0.17 vs 0.04, p<0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (HR1.08, 95%CI 0.47-2.47) or alemtuzumab (0.73, 0.26-2.07), but was lower for patients treated with natalizumab (0.35, 0.13-0.94) and ocrelizumab (0.45, 0.26-0.78).  

Conclusion: Cladribine is an effective MS therapy, associated with low absolute ARR. While cladribine effectiveness on relapses is superior to fingolimod, alemtuzumab is superior to cladribine in reducing relapses. Natalizumab and ocrelizumab are superior to cladribine in reducing both relapses and disability accrual. Cladribine can thus be viewed as a step-up in effectiveness from fingolimod, but less effective than the most potent intravenous MS therapies in RRMS. 

Keywords: cladribine; comparative effectiveness; observational; multiple sclerosis 

Authors: Izanne Roos, Sifat Sharmin, Charles B Malpas, Jeannette Lechner-Scott, Suzanne Hodgkinson, Anneke van der Walt, Helmut Butzkueven, Katherine Buzzard, Olga Skibina, Tomas Kalincik 

On behalf of the MSBase study group 

Author Affiliations:
Izanne Roos; Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia 

Sifat Sharmin; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia 

Charles B Malpas; Neuroimmunology Centre; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia 

Jeannette Lechner-Scott; Hunter Medical Research Institute, University Newcastle, Newcastle, Australia; Hunter New England Health, John Hunter Hospital, NSW Australia 

Suzanne Hodgkinson; Immune tolerance laboratory Ingham Institute and Dept of Medicine, UNSW, Sydney, Australia 

Anneke van der Walt; Department of Neurology, The Alfred Hospital, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia 

Helmut Butzkueven; Department of Neurology, The Alfred Hospital, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia 

Katherine Buzzard; Department of Neurology, Box Hill Hospital, Melbourne, Australia; Department of Neurosciences, Eastern Health Clinical School, Monash University, Melbourne, Australia; Neuroimmunology Centre, Royal Melbourne Hospital, Melbourne, Australia 

Olga Skibina; Department of Neurology, Box Hill Hospital, Melbourne, Australia; Department of Neurosciences, Eastern Health Clinical School, Monash University, Melbourne, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Australia 

Tomas Kalincik; Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia 

Patient-determined disease steps is not interchangeable with the Expanded Disease Status Scale in mild to moderate multiple sclerosis

Background: Patient Determined Disease Steps (PDDS) is a patient-reported disability measure in multiple sclerosis. Its popularity has risen due to its simplicity and low cost. However, its validity, reliability, and longitudinal performance is unknown in people with multiple sclerosis (pwMS) with mild to moderate disability.  

Objective: Examine the psychometric properties and longitudinal performance of the PDDS in pwMS with mild to moderate disability. 

Methods: We prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients across six MS centres in Australia. Participants completed an iPad-based MS performance test (MSPT) which includes an electronic version of the PDDS and other patient-reported outcomes. Correlation coefficients were calculated between PDDS and other outcome measures. Lin’s correlation coefficient was calculated for test-retest reliability. Longitudinal data was examined with linear mixed effect modelling and Cohen’s kappa for confirmed disability progression (CDP). 

Results:  We enrolled 904 pwMS. The baseline correlation between PDDS and EDSS was weak. PDDS correlated better with PROs whilst EDSS had stronger correlations with age, disease duration, functional systems(FS) and Processing Speed Test(PST). Test-retest reliability was good to excellent.  

Longitudinally, PDDS was associated with EDSS, age and depression. The magnitude of associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. 

Conclusion: The PDDS correlates better with PROs but less with other MS-related outcome measures compared to the EDSS. In longitudinal analysis, it was only weakly correlated with the EDSS, with no concordance in CDP. Our findings suggest that the PDDS should not replace the EDSS. 

Keywords: disability, multiple sclerosis, patient-reported outcomes, digital biomarkers 

Prof Jeannette Lechner-Scott is a senior staff specialist in the department of Neurology, Newcastle, and a conjoint Professor of the University of Newcastle. She is the head of the Neuroimmunology clinic in the John Hunter Hospital in Newcastle as well as of Neuroimmunology at the Immune Health program in the Hunter Medical Research Program, Board member of MS Plus, and member of MSIF and chief editor of MSARD. She is the recipient of the 2023 Ian McDonald award for outstanding research in MS. Her research stretches over multiple fields (genetics/epigenetics, new MRI technologies, pregnancy, cognition in MS etc), but always has the person with MS in its center.

Kelly Engelhardt was diagnosed with MS in 2001 just 6 weeks short of her 21st birthday. The diagnosis came as a complete shock and created much anxiety as to her future. Kelly was in the third year of her teaching degree and went on to graduate and start her teaching career.

Since that time she has married the love of her life and has two sons (15 and 10).

Due to the progression of her illness she has had to give up teaching for a part time administrative job from home.

Kelly loves raising awareness of MS and advocating for the many challenges people with MS are faced with.

Katie is the National Policy Manager at MS Australia and has over 25 years’ experience working across the federal and local government and not-for-profit sectors with a focus on aged care, disability and health. She has experience in policy and programs areas and frontline service delivery in both Canberra and Alice Springs.  Before joining MS Australia, Katie held senior policy roles in two National organisations, Palliative Care Australia and NACCHO with a focus on policy and advocacy in aged care, disability and people with diverse needs, including Aboriginal and Torres Strait Islander people.

Jeremy was appointed Head of Advocacy at MS Australia in 2022.

He is a highly regarded communications and media specialist with a 30+ years’ experience working across the government, private and not-for-profit sectors, and a successful track record delivering effective and impactful national advocacy and awareness-raising campaigns.

For the last ten years Jeremy has worked in public health. Before joining MS Australia, Jeremy held Director of Communications roles for two National advocacy organisations, Palliative Care Australia and the Foundation for Alcohol Research and Education.

Vascular comorbidities are associated with grey matter atrophy in secondary progressive multiple sclerosis.

Background: Vascular risk factors can be associated with brain atrophy in multiple sclerosis (MS). This has been examined in mixed MS cohorts in prospective or observational studies, however the association between vascular comorbidities (VCM) in secondary progressive MS (SPMS) and brain atrophy has been less well studied.  

Aim: In a post-hoc analysis of 445 patients from MS-SMART–a multi-arm multicentre phase-2b randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS (NCT01910259), we aimed to investigate the cross-sectional and longitudinal association between VCM and brain atrophy in SPMS.  

Methods: The presence of VCM (hypertension, hyperlipidaemia) were recorded. Brain segmentation was completed using Geodesic Information Flows; normalised brain volume (NBV) and percentage brain volume change were calculated using SIENAX and SIENA methods respectively. Multiple linear regression was used to investigate cross-sectional and longitudinal relationships between VCM and whole brain, GM and white matter atrophy. Models were adjusted for age, sex, ethnicity, disease duration, treatment allocation, lesion-load and body-mass index (BMI).  

Results: The cohort was predominantly female(67%), mean-age 55(SD 7) with median EDSS of 6.0(range 4.0-6.5). 13% and 9% had hypertension and hyperlipidaemia respectively. In cross-sectional regression models, VCM were associated with decreased cortical GM volume [(hypertension β=-0.30,95%CI-0.54 to-0.06,p=0.01);(hyperlipidaemia β=-0.37,95%CI-0.64 to -0.09,p=0.008)]; but not with NBV. High BMI(>30) was associated with decreased NBV (β=-0.73,95%CI-1.14 to-0.31,p<0.001) and decreased cortical GM volume (β=-0.93,95%CI-1.32 to-0.53,p<0.001). There was no association between VCM, BMI and brain atrophy over 96-weeks.  

Conclusion: VCM and high BMI are associated with cortical GM atrophy with high BMI additionally associated with whole brain atrophy in SPMS. However, VCM do not appear to increase the rate of brain atrophy once in the secondary progressive phase of MS.  

Disclosures: NAJ is primary investigator on MS studies sponsored by Novartis, Roche and Sanofi-Genzyme. FDA, FC, AD, AC, TW, TP, CWGK do not have any relevant financial disclosures. FB serves on the steering committee or iDMC member for Biogen, Merck, Roche, EISAI, and Prothena. He acts as a consultant for Roche, Biogen, Merck, IXICO, Jansen, and Combinostics. He has research agreements with Merck, Biogen, GE Healthcare, and Roche. He is co-founder and shareholder of Queen Square Analytics LTD. JC In the last 3 years, JC has received support from the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR UCLH Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS Society; a local principal investigator for commercial trials funded by Ionis, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. 

Authors: Nevin A John (1,2), Floriana De Angelis (3), Ferran Prados Carrasco (3,4,5), Anisha Doshi (3), Alberto Calvi (3), Thomas Williams (3), Thanh Phan (1,2), Frederik Barkhof (4, 6, 7), Claudia A. M. Gandini Wheeler-Kingshott (3,8,9), Jeremy Chataway (3,6) for the MS-SMART Investigators. 

Affiliations: 

1. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia 

2. Department of Neurology, Monash Health, Clayton, Australia 

3. Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK 

4. Centre for Medical Image Computing (CMIC), University College London, UK. 

5. e-Health Center, Universitat Oberta de Catalunya, Barcelona, Spain 

6. National Institute for Health Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre (BRC), London, UK 

7. Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, The Netherlands 

8. Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy 

9. Brain Connectivity Center, C. Mondino National Neurological Institute, Pavia, Italy 

Estimation of transition probabilities from a large cohort of Australians living with MS for changing disability severity classifications

Background: The probability of transitions from one health state (level of disability) to another are important input metrics for health economics models that provide advice about resource allocation including MS disease modifying therapies (DMT). Transition probabilities are also used clinically in the assessment of disease progression. 

Objectives: We aimed to estimate annual transition probabilities from a large cohort of Australians to describe MS-related disability progression from no disability, mild, moderate, and severe disability. We also aimed to estimate transition probabilities for relapsing remitting and progressive MS phenotypes. 

Methods: Data were obtained from Australian MSBase participants. We used a four-state continuous-time Markov model to describe how people with MS transition between disability milestones defined by the Expanded Disability Status Scale (EDSS; scale 0-10); no disability (EDSS:0), mild (EDSS:1–3.5), moderate (EDSS:4–6), and severe (EDSS:6.5–9.5), all recorded by the treating neurologist. Model covariates included sex, DMT usage, MS-phenotype (relapsing-remitting or progressive) and disease duration. Subgroup analyses were performed. 

Results: N=6,369 participants (mean age 42.5, 75.0% female) yielded 38,837 person-years of follow-up and 54,570 clinical reviews for the study. Annual transition probabilities included: remaining in the no, mild, moderate, and severe states (54.2%, 82.0%, 69.9%, 77.8% respectively); and transitioning from no to mild (42.3%); mild to moderate (11.4%); moderate to severe (9.4%). Secondary progressive MS was associated with a 150.9% increase in the hazard of disability progression versus relapsing-remitting MS. 

Conclusions: Our transition probabilities are being applied in a publicly available health economics simulation model for Australia and similar populations. This model is intended to support reimbursement decisions pertaining to a plethora of interventions, including DMTs. These probabilities can also be applied in the clinical setting. 

Funding: This work was supported by Dr Julie Campbell’s Postdoctoral Research Fellowship number 19-0702 

Key words: health economics, transition probabilities, disability progression, cost-effectiveness analysis 

Authors:  Julie A Campbell* and Glen J Henson*, Valery Fuh Ngwa, Bruce V Taylor, Ingrid van der Mei, MS Base Australian Researchers (2) and Andrew J Palmer (1)

*denotes joint first authorship and equal contribution  

Author affiliations: 

1. Menzies Institute for Medical Research, University of Tasmania, Medical Sciences Precinct, 17 Liverpool Street, Hobart, Tasmania, Australia 7000 

2. MS Base, Central Clinical School at The Alfred Centre, 99 Commercial Road, Melbourne, Victoria, Australia 3004  

The quality-of-life impact of the COVID-19 pandemic on people living with multiple sclerosis and the general population: a comparative study.
 

Background: Studies have shown that people living with MS were substantially impacted by the COVID-19 pandemic. However, no study has compared the quality-of-life impact of the COVID-19 pandemic on people living with MS and the general population. Differences would have implications for future, pandemic-related policies. 

Objectives: This study aimed to compare the prevalence and health-related quality-of-life impact of COVID-19-related adversity in the general population and people living with multiple sclerosis. It also investigated the discriminatory power of the novel EQ-5D-5L-Psychosocial multi-attribute utility instrument. 

Methods: Cross-sectional data were obtained from the How Is Your Life Australian general population study (comprised of subsamples with and without chronic disease) and the AMSLS from August-October 2020. Quality-of-life was measured using health state utilities (HSUs; represented on a zero [death] to one [full-health] scale) generated by the EQ-5D-5L-Psychosocial. COVID-19-related adversity was measured via specialised survey items. Descriptive and multivariable regression analyses were conducted. 

Results: 1020 general population and 1635 MS participants entered the study (mean age 52.4 and 58.4; female 80.2% and 52.4%, respectively). COVID-19-related adversity prevalence was higher among people living with MS (PR: 1.90 [CI: 1.56, 2.32]). However, the HSU impact of COVID-19-related adversity was not dependent on disease status (p>0.20, test for interaction). Additionally, the EQ-5D-5L-Psychosocial could discriminate between non-disease and disease cohorts (Δ0.14 [p<0.01] multiple sclerosis versus no chronic diseases). 

Conclusion: This study found that people living with MS were more likely to experience COVID-19-related adversity compared to the general population, though the individual-level quality-of-life impact was similar. This demonstrates that people living with MS require additional support when the countries are experiencing pandemic conditions. 

Keywords: COVID-19, Health Economics, Multi-Attribute Utility Instrument, Quality-of-Life 
 

Authors: Glen J Henson (1), Bruce V Taylor (1), Ingrid van der Mei (1), Andrew J Palmer (1), Gang Chen (*2) and Julie A Campbell (*1) 

Author affiliations: 
1. Menzies Institute for Medical Research, University of Tasmania 

2. Centre for Health Economics, Monash University 

*Joint Senior Authors 

Longitudinal enlargement of choroid plexus is associated with inflammation and neurodegeneration in RRMS patients.

Background: The Choroid Plexus (CP) plays a potential role in the initiation and propagation of neuroinflammatory processes in MS. However, the progressive change of the CP and its associations with biomarkers of acute and chronic inflammation, along with MS-related brain structure atrophy, have not been investigated. 

Objective: This study aims to explore the longitudinal dynamics of the CP in RRMS patients and assess its relationship with inflammation and with atrophy in various brain compartments. 

Methods: 57 RRMS patients were examined annually for a minimum of 60 months using following MRI protocols: pre- and post-contrast (gadolinium) Sagittal 3D T1, FLAIR CUBE, diffusion weighted MRI. CP was manually segmented at baseline and last follow-up and normalised by head size. Annually lesion segmentation was performed by iQ-MSTM software suite and brain was segmented using AssemblyNet. 

Results: Over the study period, the volume of CP increased by an average of 1.4% annually. The magnitude of CP enlargement significantly correlated with central brain atrophy, and to a lesser extent, total brain atrophy, white matter, and deep grey matter atrophy. Furthermore, progressive CP enlargement was significantly associated with the volume and severity of chronic lesion expansion (r=0.66, p<0.001), but not with the number or volume of new lesions. 

Conclusion: Our findings indicate that ongoing inflammatory activity in the CP is linked to low-grade demyelination at the rim of chronic lesions and associated neurodegeneration of periventricular white and grey matter. 

Authors: Samuel Klistorner (1), Michael H Barnett (2,3), Chenyu Wang (2,3), John Parratt (4), Con Yiannikas (4), Alexander Klistorner (1) 

Author affiliations: 
1. Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia,  
2. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia,  
3. Sydney Neuroimaging Analysis Centre, Camperdown, New South Wales, Australia,   
4. Royal North Shore Hospital, Sydney, New South Wales, Australia,  

Functional and microstructural brain changes associated with speech in people with multiple sclerosis.

Background: Over 40% of people with multiple sclerosis (pwMS) develop dysarthria, a motor speech disorder. Dysarthria in MS is associated with higher disease severity and lower quality of life. Despite this, little is still known about the underlying mechanisms of dysarthria in pwMS. 

Objective: To evaluate the pathophysiology of speech impairments in MS using functional and diffusion magnetic resonance imaging (MRI).

Methods: Sixty-two pwMS (mean EDSS=4.3, 74% female) and 14 healthy controls (HC, 64% female) underwent 3T MRI with functional and diffusion components while completing a word repetition task. All participants completed an array of clinical and speech measures. We used a general linear model through FSL Feat to complete functional MRI analysis, and fixel-based analysis through MRTrix for diffusion data. Mann-Whitney U tests and Spearman correlations were used for statistical analyses. 

Results: Functional MRI show that pwMS have significantly lower widespread activation during speech preparation and higher activation during speech production, than HC (p<.05). This increase during speech production is seen in the left Brodmann area 45 (BA45-L). Further, we see significant reduction in fibre density and cross section in pwMS compared to HC (p<.05). Both function and diffusion MRI changes in pwMS correlate with measures of dysarthria and cerebellar function. 

Conclusion: Higher functional activation during speech production may represent compensation for underlying MS-related axonal injury.  This study provides new insights into the underlying mechanisms of dysarthria in pwMS that have implications for the development of monitoring strategies for cerebellar function in MS. 

This research was funded by NHMRC Grant #1085461. 

 Keywords: Neuroimaging, speech

Authors: Katherine Kenyon (a,b), Gustavo Noffs (a,b,c,d), Myrte Strik (j,k), Angela Morgan (h,i), Adam P. Vogel (b,d,e,f), Scott Kolbe (a), Frederique Boonstra (a), Anneke van der Walt (a,c,f). 

Author affiliations: 
a. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC;
b. Centre for Neuroscience of Speech, University of Melbourne, Melbourne, VIC;
c. Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia;
d. Redenlab Inc, Melbourne, VIC, Australia;
e. Division of Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany & Center for Neurology, University Hospital Tübingen, Germany;
f. The Bionics Institute, Melbourne, VIC, Australia; g Department of Medicine and Radiology, University of Melbourne, Parkville, Australia;
h. Murdoch Childrens Research Institute, Parkville, Australia; iDepartment of Speech Pathology and Audiology, University of Melbourne, Parkville, Australia;
j. Melbourne Brain Centre Imaging Unit, Department of Radiology, University of Melbourne, Melbourne, VIC, Australia;
k. MS Center Amsterdam, Anatomy and Neurosciences, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, the Netherlands 

3D Amide proton transfer weighted imaging for evaluating Multiple Sclerosis lesions and normal-appearing white matter.

Background: Autoimmune attacks in MS disease cause inflammatory demyelination, leading to axonal loss and destruction of myelin. Amide proton transfer weighted (APTw) imaging is a novel type of magnetic resonance imaging (MRI) that can detect the interaction between mobile protons, found in the intra/extra-cellular myelin debris proteins and surrounding tissue water. 

Objective: To evaluate APTw signal differences between MS lesions and contralateral normal-appearing white matter (cNAWM). Cellular changes during the demyelination process were assessed by comparing APTw signal intensity in T1-weighted isointense (ISO) and hypointense (black hole-BH) lesions in relation to cNAWM. 

Methods: 24 people with relapsing-remitting MS were recruited (19 females and 5 males with mean age:48.11 years; mean disease duration:11.25 years; median EDSS:2). MRI/APTw acquisitions were undertaken on 3T. For assessment of MS lesions, 3D T1-MPRAGE and T2-FLAIR were used. Pre/post-processing APTw analysis, co-registration and identifying regions of interest were performed with Olea Sphere. Generalized linear model univariate ANOVA was undertaken to test the hypotheses that differences in mean APTw signal intensity. Receiver operating characteristic curve analyses were performed.  

Results:  Mean APTw signal intensity of MS lesions were higher than cNAWM (lesion=0.44,cNAWM=0.13,F=44.12,p<0.001). The mean APTw of ISO were higher than cNAWM (ISO=0.42,cNAWM=0.21,F=12.12,p<0.001). The mean APTw signal of BH were higher than cNAWM (BH=0.47,cNAWM=0.033,F=40.3,p<0.001). The effect size (difference between lesion and cNAWM) for BH was found to be higher than for ISO (14 vs.2). Diagnostic performance showed that APTw was able to discriminate between all lesions and cNAWM with accuracy of greater than 75% (AUC=0.79,SE=0.014). Discrimination between ISO and cNAWM was accomplished with accuracy greater than 69% (AUC=0.74,SE=0.018), while discrimination between BH and cNAWM was achieved at accuracy of greater than 80% (AUC=0.87,SE=0.021). 

Conclusion: Our results highlight the potential of APTw imaging to provide essential molecular information so that the stages of inflammation and degeneration in MS lesions can be better characterized. 

Funding: This study was supported by MS Research Australia (MSRA) [grant No.18-0533].  

Keywords: Multiple Sclerosis (MS), Amide proton transfer 

Authors: Ibrahim Khormi (1,2,3), Oun Al-iedani (2,4), Stefano Casagranda (5), Christos Papageorgakis (5), Abdulaziz Alshehri (1,2,6), Rodney Lea (2), Patrick Liebig (7), Saadallah Ramadan (1,2), Jeannette Lechner-Scott (2,8,9) 

Author affiliations: 
1. School of Health Sciences, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia.
2. Hunter Medical Research Institute, New Lambton Heights, Australia.
3. College of Applied Medical Sciences, University of Jeddah, Jeddah, Saudi Arabia. 4. School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia.
5. Department of R&D Advanced Applications, Olea Medical, La Ciotat, France.
6. Department of Radiology, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
7. Siemens Healthcare GmbH, Erlangen, Germany.
8. Department of Neurology, John Hunter Hospital, New Lambton Heights, Australia. 9. School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia. 

Professor Tomas Kalincik is Dame Kate Campbell Professorial Fellow, the head of the Clinical Outcomes Research (CORe) Unit at the University of Melbourne and of the Neuroimmunology Centre at the Royal Melbourne Hospital.

Together with his research group, CORe, Tomas specialises in analytics of observational data in neurology. He has led a number of international collaborative research initiatives - including studies of comparative effectiveness of MS therapies, management of treatment failure and individual treatment response. His main research interests span treatment outcomes in MS and other neuroimmunological diseases, individualised therapy, prognostics (including emerging biomarkers), causal inference, epidemiology and utility of volumetric MRI. He worked with the MS International Federation and WHO on scoping the first WHO Essential Medicines List for MS. He is the vice-chair of the Scientific Leadership Group of the global MSBase registry, and collaborates with multiple national MS registries. Tomas convenes the international CORe Advanced Statistics Course, endorsed by the European Committee for Treatment and Research in MS, co-chairs the scientific committee of the MS Australia Progress in MS Research conference, and convenes preceptorships for neurologists and nurses at the RMH Neuroimmunology Centre.

Yasmine Probst is an Associate Professor with the School of Medical, Indigenous and Health Sciences at the University of Wollongong and Research Fellow at the Illawarra Health and Medical Research Institute. She holds dual Masters degrees in Dietetics and Health Informatics and is recognised as an Advanced Accredited Practising Dietitian with Dietitians Australia and a Fellow of the Australasian Institute for Digital Health. Yasmine holds a current Senior Research fellowship with MS Australia. As a person living with MS, her research and teaching focuses on nutrition for people living with MS.