Anatomy and Neuroscience - Research Publications

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    Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B-cell-targeted therapies
    Ai-Lan, N ; Gresle, M ; Marshall, T ; Butzkueven, H ; Field, J (WILEY, 2017-07-01)
    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, and one of the most common causes of disability in young adults. Over the last decade, new disease-modifying therapies have emerged, including monoclonal antibodies (mAbs) that provide highly targeted therapies with greater efficacy than platform therapies. In particular, monoclonal antibodies directed against CD20-positive B cells have shown remarkable results in recent clinical trials and renewed interest in the mechanism of B cell-depleting therapies to ameliorate relapse activity and progression in MS. Here, we review the mechanisms of action and clinical evidence of approved and emerging mAbs, with a focus on B cell-targeted therapies.
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    Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
    Patsopoulos, NA ; Barcellos, LF ; Hintzen, RQ ; Schaefer, C ; Van Duijn, CM ; Noble, JA ; Raj, T ; Gourraud, P-A ; Stranger, BE ; Oksenberg, J ; Olsson, T ; Taylor, BV ; Sawcer, S ; Hafler, DA ; Carrington, M ; De Jager, PL ; De Bakker, PIW ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2013-11-01)
    The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.
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    Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis
    Lin, R ; Charlesworth, J ; Stankovich, J ; Perreau, VM ; Brown, MA ; Taylor, BV ; Toland, AE (PUBLIC LIBRARY SCIENCE, 2013-03-05)
    Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10(-6)). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.
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    MicroRNAs miR-17 and miR-20a Inhibit T Cell Activation Genes and Are Under-Expressed in MS Whole Blood
    Cox, MB ; Cairns, MJ ; Gandhi, KS ; Carroll, AP ; Moscovis, S ; Stewart, GJ ; Broadley, S ; Scott, RJ ; Booth, DR ; Lechner-Scott, J ; Jacobson, S (PUBLIC LIBRARY SCIENCE, 2010-08-11)
    It is well established that Multiple Sclerosis (MS) is an immune mediated disease. Little is known about what drives the differential control of the immune system in MS patients compared to unaffected individuals. MicroRNAs (miRNAs) are small non-coding nucleic acids that are involved in the control of gene expression. Their potential role in T cell activation and neurodegenerative disease has recently been recognised and they are therefore excellent candidates for further studies in MS. We investigated the transcriptome of currently known miRNAs using miRNA microarray analysis in peripheral blood samples of 59 treatment naïve MS patients and 37 controls. Of these 59, 18 had a primary progressive, 17 a secondary progressive and 24 a relapsing remitting disease course. In all MS subtypes miR-17 and miR-20a were significantly under-expressed in MS, confirmed by RT-PCR. We demonstrate that these miRNAs modulate T cell activation genes in a knock-in and knock-down T cell model. The same T cell activation genes are also up-regulated in MS whole blood mRNA, suggesting these miRNAs or their analogues may provide useful targets for new therapeutic approaches.
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    Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data
    Wang, JH ; Pappas, D ; De Jager, PL ; Pelletier, D ; de Bakker, PIW ; Kappos, L ; Polman, CH ; Chibnik, LB ; Hafler, DA ; Matthews, PM ; Hauser, SL ; Baranzini, SE ; Oksenberg, JR (BMC, 2011-01-01)
    BACKGROUND: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. METHODS: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. RESULTS: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years). CONCLUSIONS: The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.
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    A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis
    Riveros, C ; Mellor, D ; Gandhi, KS ; McKay, FC ; Cox, MB ; Berretta, R ; Vaezpour, SY ; Inostroza-Ponta, M ; Broadley, SA ; Heard, RN ; Vucic, S ; Stewart, GJ ; Williams, DW ; Scott, RJ ; Lechner-Scott, J ; Booth, DR ; Moscato, P ; Rattray, M (PUBLIC LIBRARY SCIENCE, 2010-12-01)
    BACKGROUND: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5). CONCLUSIONS/SIGNIFICANCE: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.
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    Optic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes
    van der Walt, A ; Kolbe, SC ; Wang, YE ; Klistorner, A ; Shuey, N ; Ahmadi, G ; Paine, M ; Marriott, M ; Mitchell, P ; Egan, GF ; Butzkueven, H ; Kilpatrick, TJ ; Villoslada, P (PUBLIC LIBRARY SCIENCE, 2013-12-26)
    BACKGROUND: Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS). OBJECTIVES: To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months. METHODS: Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction. RESULTS: Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated. CONCLUSIONS: These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.
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    Monitoring cognitive change in multiple sclerosis using a computerized cognitive battery.
    De Meijer, L ; Merlo, D ; Skibina, O ; Grobbee, EJ ; Gale, J ; Haartsen, J ; Maruff, P ; Darby, D ; Butzkueven, H ; Van der Walt, A (SAGE Publications, 2018-10)
    BACKGROUND: Cognitive monitoring that can detect short-term change in multiple sclerosis is challenging. Computerized cognitive batteries such as the CogState Brief Battery can rapidly assess commonly affected cognitive domains. OBJECTIVES: The purpose of this study was to establish the acceptability and sensitivity of the CogState Brief Battery in multiple sclerosis patients compared to controls. We compared the sensitivity of the CogState Brief Battery to that of the Paced Auditory Serial Addition Test over 12 months. METHODS: Demographics, Expanded Disability Status Scale scores, depression and anxiety scores were compared with CogState Brief Battery and Paced Auditory Serial Addition Test performances of 51 patients with relapsing-remitting multiple sclerosis, 19 with secondary progressive multiple sclerosis and 40 healthy controls. Longitudinal data in 37 relapsing-remitting multiple sclerosis patients were evaluated using linear mixed models. RESULTS: Both the CogState Brief Battery and the Paced Auditory Serial Addition Test discriminated between multiple sclerosis and healthy controls at baseline (p<0.001). CogState Brief Battery tasks were more acceptable and caused less anxiety than the Paced Auditory Serial Addition Test (p<0.001). In relapsing-remitting multiple sclerosis patients, reaction time slowed over 12 months (p<0.001) for the CogState Brief Battery Detection (mean change -34.23 ms) and Identification (-25.31 ms) tasks. Paced Auditory Serial Addition Test scores did not change over this time. CONCLUSIONS: The CogState Brief Battery is highly acceptable and better able to detect cognitive change than the Paced Auditory Serial Addition Test. The CogState Brief Battery could potentially be used as a practical cognitive monitoring tool in the multiple sclerosis clinic setting.
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    Prognosis in autoimmune encephalitis: Database
    Broadley, J ; Seneviratne, U ; Beech, P ; Buzzard, K ; Butzkueven, H ; O'Brien, T ; Monif, M (ELSEVIER SCIENCE BV, 2018-12-01)
    Autoimmune encephalitis is a rare and debilitating disease. An important question in clinical neurology is what factors may be correlated with outcomes in autoimmune encephalitis. There is observational data describing statistical analyses on such variables, but there are no review articles that collaborate and interpret this information. This data in brief article represents the data collection for such a review (Broadley et al., 2018). Herein we summarize clinical information from 44 research articles, in particular pertaining to outcomes and prognostic variables.
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    Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination
    Tea, F ; Lopez, JA ; Ramanathan, S ; Merheb, V ; Lee, FXZ ; Zou, A ; Pilli, D ; Patrick, E ; van der Walt, A ; Monif, M ; Tantsis, EM ; Yiu, EM ; Vucic, S ; Henderson, APD ; Fok, A ; Fraser, CL ; Lechner-Scott, J ; Reddel, SW ; Broadley, S ; Barnett, MH ; Brown, DA ; Lunemann, JD ; Dale, RC ; Brilot, F ; Sinclair, A ; Kermode, AG ; Kornberg, A ; Bye, A ; McGettigan, B ; Trewin, B ; Brew, B ; Taylor, B ; Bundell, C ; Miteff, C ; Troedson, C ; Pridmore, C ; Spooner, C ; Yiannikas, C ; O'Gorman, C ; Clark, D ; Suan, D ; Jones, D ; Kilfoyle, D ; Gill, D ; Wakefield, D ; Hofmann, D ; Mathey, E ; O'Grady, G ; Jones, HF ; Beadnall, H ; Butzkueven, H ; Joshi, H ; Andrews, I ; Sutton, I ; MacIntyre, J ; Sandbach, JM ; Freeman, J ; King, J ; O'Neill, JH ; Parratt, J ; Barton, J ; Garber, J ; Ahmad, K ; Riney, K ; Buzzard, K ; Kothur, K ; Cantrill, LC ; Menezes, MP ; Paine, MA ; Marriot, M ; Ghadiri, M ; Boggild, M ; Lawlor, M ; Badve, M ; Ryan, M ; Aaqib, M ; Shuey, N ; Jordan, N ; Urriola, N ; Lawn, N ; White, O ; McCombe, P ; Patel, R ; Leventer, R ; Webster, R ; Smith, R ; Gupta, S ; Mohammad, SS ; Pillai, S ; Hawke, S ; Simon, S ; Calvert, S ; Blum, S ; Malone, S ; Hodgkinson, S ; Nguyen, TK ; Hardy, TA ; Kalincik, T ; Ware, T ; Fung, VSC ; Huynh, W (BMC, 2019-09-03)
    Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.