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1. Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis

Author

Hilton, James B.W., Kysenius, Kai, Liddell, Jeffrey R., Mercer, Stephen W., Rautengarten, Carsten, Hare, Dominic J., Buncic, Gojko, Paul, Bence, Murray, Simon S., McLean, Catriona A., Kilpatrick, Trevor J., Beckman, Joseph S., Ayton, Scott, Bush, Ashley I., White, Anthony R., Roberts, Blaine R., Donnelly, Paul S., and Crouch, Peter J.

Published
2024
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6. Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.

Author

Jia, Xiaoming, Madireddy, Lohith, Caillier, Stacy, Santaniello, Adam, Esposito, Federica, Comi, Giancarlo, Stuve, Olaf, Zhou, Yuan, Taylor, Bruce, Kilpatrick, Trevor, Martinelli-Boneschi, Filippo, Cree, Bruce AC, Oksenberg, Jorge R, Hauser, Stephen L, and Baranzini, Sergio E

Subjects
Humans, Cysts, Multiple Sclerosis, Chronic Progressive, Hereditary Central Nervous System Demyelinating Diseases, Paraplegia, Kinesin, Membrane Transport Proteins, Membrane Proteins, Cohort Studies, Genotype, Phenotype, Mutation, Adolescent, Adult, Aged, Middle Aged, Child, Child, Preschool, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Young Adult, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

ObjectivePrimary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.MethodsWe examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.ResultsWGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.InterpretationThis study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.

Published
2018

9. Nanodiamonds with silicon vacancy defects for non-toxic photostable fluorescent labeling of neural precursor cells

Author

Merson, Tobias D., Castelletto, Stefania, Aharonovich, Igor, Turbic, Alisa, Kilpatrick, Trevor J., and Turnley, Ann M.

Subjects
Physics - Biological Physics, Condensed Matter - Materials Science, Quantitative Biology - Biomolecules
Abstract

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

Published
2013
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11. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Author

Beecham, Ashley, Patsopoulos, Nikolaos, Xifara, Dionysia, Davis, Mary, Kemppinen, Anu, Cotsapas, Chris, Shah, Tejas, Spencer, Chris, Booth, David, Goris, An, Oturai, Annette, Saarela, Janna, Fontaine, Bertrand, Hemmer, Bernhard, Martin, Claes, Zipp, Frauke, DAlfonso, Sandra, Martinelli-Boneschi, Filippo, Taylor, Bruce, Harbo, Hanne, Kockum, Ingrid, Hillert, Jan, Olsson, Tomas, Ban, Maria, Barizzone, Nadia, Barrett, Jeffrey, Bellenguez, Céline, Bergamaschi, Laura, Bernardinelli, Luisa, Berthele, Achim, Biberacher, Viola, Binder, Thomas, Blackburn, Hannah, Bomfim, Izaura, Brambilla, Paola, Broadley, Simon, Brochet, Bruno, Brundin, Lou, Buck, Dorothea, Butzkueven, Helmut, Caillier, Stacy, Camu, William, Carpentier, Wassila, Cavalla, Paola, Celius, Elisabeth, Coman, Irène, Comi, Giancarlo, Corrado, Lucia, Cosemans, Leentje, Cournu-Rebeix, Isabelle, Cusi, Daniele, Damotte, Vincent, Defer, Gilles, Delgado, Silvia, Deloukas, Panos, di Sapio, Alessia, Dilthey, Alexander, Donnelly, Peter, Dubois, Bénédicte, Duddy, Martin, Edkins, Sarah, Elovaara, Irina, Esposito, Federica, Evangelou, Nikos, Fiddes, Barnaby, Field, Judith, Franke, Andre, Freeman, Colin, Frohlich, Irene, Galimberti, Daniela, Gieger, Christian, Graetz, Christiane, Graham, Andrew, Grummel, Verena, Guaschino, Clara, Hadjixenofontos, Athena, Hakonarson, Hakon, Halfpenny, Christopher, Hall, Gillian, Hall, Per, Hamsten, Anders, Harley, James, Harrower, Timothy, Hawkins, Clive, Hellenthal, Garrett, Hillier, Charles, Hobart, Jeremy, Hoshi, Muni, Hunt, Sarah, Jagodic, Maja, Jelčić, Ilijas, Jochim, Angela, Kendall, Brian, Kermode, Allan, Kilpatrick, Trevor, Koivisto, Keijo, Konidari, Ioanna, Korn, Thomas, Kronsbein, Helena, and Langford, Cordelia

Subjects
Chromosome Mapping, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, White People
Abstract

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

Published
2013

12. Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis

Author

Xavier, Alexandre, primary, Campagna, Maria Pia, additional, Maltby, Vicki E., additional, Kilpatrick, Trevor, additional, Taylor, Bruce V., additional, Butzkueven, Helmut, additional, Ponsonby, Anne-Louise, additional, Scott, Rodney J., additional, Jokubaitis, Vilija G., additional, Lea, Rodney A., additional, and Lechner-Scott, Jeannette, additional

Published
2023
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13. The Patient‐Determined Disease Steps scale is not interchangeable with the Expanded Disease Status Scale in mild to moderate multiple sclerosis.

Author

Foong, Yi Chao, Merlo, Daniel, Gresle, Melissa, Zhu, Chao, Buzzard, Katherine, Lechner‐Scott, Jeannette, Barnett, Michael, Taylor, Bruce, Kalincik, Tomas, Kilpatrick, Trevor, Darby, David, Dobay, Pamela, van Beek, Johan, Hyde, Robert, Butzkueven, Helmut, and van der Walt, Anneke

Subjects
MULTIPLE sclerosis, STATISTICAL reliability, DISABILITIES, PSYCHOMETRICS, PANEL analysis
Abstract

Background and purpose: The validity, reliability, and longitudinal performance of the Patient‐Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. Methods: We included relapsing–remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test–retest reliability was examined. Longitudinal data were analysed with mixed‐effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). Results: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient‐reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test–retest reliability was good to excellent (concordance correlation coefficient = 0.73–0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. Conclusion: The PDDS has greater correlation with other PROs but less correlation with other MS‐related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Changes in employment status over time in multiple sclerosis following a first episode of central nervous system demyelination, a Markov multistate model study.

Author

Zarghami, Amin, Fuh‐Ngwa, Valery, Claflin, Suzi B., van der Mei, Ingrid, Ponsonby, Anne‐Louise, Broadley, Simon, Simpson‐Yap, Steve, Lucas, Robyn, Dear, Keith, Blizzard, Leigh, Taylor, Bruce V., Kilpatrick, Trevor, Williams, David, Lechner‐Scott, Jeannette, Shaw, Cameron, Chapman, Caron, Coulthard, Alan, and Valery, Patricia

Subjects
EMPLOYMENT changes, CENTRAL nervous system, MARKOV processes, EMPLOYMENT statistics, MULTIPLE sclerosis, CANCER fatigue
Abstract

Background and purpose: Understanding predictors of changes in employment status among people living with multiple sclerosis (MS) can assist health care providers to develop appropriate work retention/rehabilitation programs. We aimed to model longitudinal transitions of employment status in MS and estimate the probabilities of retaining employment status or losing or gaining employment over time in individuals with a first clinical diagnosis of central nervous system demyelination (FCD). Methods: This prospective cohort study comprised adults (aged 18–59 years) diagnosed with FCD (n = 237) who were followed for more than 11 years. At each review, participants were assigned to one of three states: unemployed, part‐time, or full‐time employed. A Markov multistate model was used to examine the rate of state‐to‐state transitions. Results: At the time of FCD, participants with full‐time employment had an 89% chance of being in the same state over a 1‐year period, but this decreased to 42% over the 10‐year follow‐up period. For unemployed participants, there was a 92% likelihood of remaining unemployed after 1 year, but this probability decreased to 53% over 10 years. Females, those who progressed to clinically definite MS, those with a higher relapse count, and those with a greater level of disability were at increased risk of transitioning to a deteriorated employment state. In addition, those who experienced clinically significant fatigue over the follow‐up period were less likely to gain employment after being unemployed. Conclusions: In our FCD cohort, we found a considerable rate of employment transition during the early years post‐diagnosis. Over more than a decade of follow‐up post‐FCD, we found that females and individuals with a greater disability and a higher relapse count are at higher risk of losing employment. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity

Author

Multiple Sclerosis Research Australia, Royal Melbourne Hospital, Multiple Sclerosis Society (UK), MSBase Foundation, Monash University, Jokubaitis, Vilija G., Campagna, Maria Pia, Ibrahim, Omar A., Stankovich, JIm, Kleinova, Pavlina, Matesanz, Fuencisla, Hui, Daniel, Eichau, Sara, Slee, Mark, Lechner-Scott, Jeannette, Lea, Rodney, Kilpatrick, Trevor J., Kalincik, Tomas, De Jager, Philip L., Beecham, Ashley, McCauley, Jacob L., Taylor, Bruce V., Vucic, Steve, Laverick, Louise, Vodehnalova, Karolina, García-Sánchez, María Isabel, Alcina, Antonio, van der Walt, Anneke, Kubala Havrdova, Eva, Izquierdo, Guillermo, Patsopoulos, Nikolaos, Horakova, Dana, Butzkueven, Helmut, Multiple Sclerosis Research Australia, Royal Melbourne Hospital, Multiple Sclerosis Society (UK), MSBase Foundation, Monash University, Jokubaitis, Vilija G., Campagna, Maria Pia, Ibrahim, Omar A., Stankovich, JIm, Kleinova, Pavlina, Matesanz, Fuencisla, Hui, Daniel, Eichau, Sara, Slee, Mark, Lechner-Scott, Jeannette, Lea, Rodney, Kilpatrick, Trevor J., Kalincik, Tomas, De Jager, Philip L., Beecham, Ashley, McCauley, Jacob L., Taylor, Bruce V., Vucic, Steve, Laverick, Louise, Vodehnalova, Karolina, García-Sánchez, María Isabel, Alcina, Antonio, van der Walt, Anneke, Kubala Havrdova, Eva, Izquierdo, Guillermo, Patsopoulos, Nikolaos, Horakova, Dana, and Butzkueven, Helmut

Abstract

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = ¿0.4882, P = 2.73 × 10¿7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79¿0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48¿0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10¿8), the other in males (rs698805; ßmale = ¿1.5395, P = 4.35 × 10¿8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrich

Published
2023

18. DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes.

Author

Xavier, Alexandre, Maltby, Vicki E., Ewing, Ewoud, Campagna, Maria Pia, Burnard, Sean M., Tegner, Jesper N., Slee, Mark, Butzkueven, Helmut, Kockum, Ingrid, Kular, Lara, Jokubaitis, Vilija G., Kilpatrick, Trevor, Alfredsson, Lars, Jagodic, Maja, Ponsonby, Anne-Louise, Taylor, Bruce V., Scott, Rodney J., Lea, Rodney A., and Lechner-Scott, Jeannette

Subjects
DNA methylation, MULTIPLE sclerosis, MONOCYTES, ETIOLOGY of diseases, NATALIZUMAB, METHYLATION, B cells
Abstract

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS. [ABSTRACT FROM AUTHOR]

Published
2023
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19. Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity

Author

Jokubaitis, Vilija G, primary, Campagna, Maria Pia, additional, Ibrahim, Omar, additional, Stankovich, Jim, additional, Kleinova, Pavlina, additional, Matesanz, Fuencisla, additional, Hui, Daniel, additional, Eichau, Sara, additional, Slee, Mark, additional, Lechner-Scott, Jeannette, additional, Lea, Rodney, additional, Kilpatrick, Trevor J, additional, Kalincik, Tomas, additional, De Jager, Philip L, additional, Beecham, Ashley, additional, McCauley, Jacob L, additional, Taylor, Bruce V, additional, Vucic, Steve, additional, Laverick, Louise, additional, Vodehnalova, Karolina, additional, García-Sanchéz, Maria-Isabel, additional, Alcina, Antonio, additional, van der Walt, Anneke, additional, Havrdova, Eva Kubala, additional, Izquierdo, Guillermo, additional, Patsopoulos, Nikolaos, additional, Horakova, Dana, additional, and Butzkueven, Helmut, additional

Published
2022
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20. Comparative effectiveness of autologous hematopoietic stem cell transplant vs Fingolimod, Natalizumab, and Ocrelizumab in highly active relapsing-remitting multiple sclerosis

Author

Kalincik, Tomas, Sharmin, Sifat, Roos, Izanne, Freedman, Mark S., Atkins, Harold, Burman, Joachim, Massey, Jennifer, Sutton, Ian, Withers, Barbara, Macdonell, Richard, Grigg, Andrew, Torkildsen, Øivind, Bo, Lars, Lehmann, Anne Kristine, Havrdova, Eva Kubala, Krasulova, Eva, Trněný, Marek, Kozak, Tomas, van der Walt, Anneke, Butzkueven, Helmut, McCombe, Pamela, Skibina, Olga, Lechner-Scott, Jeannette, Willekens, Barbara, Cartechini, Elisabetta, Ozakbas, Serkan, Alroughani, Raed, Kuhle, Jens, Patti, Francesco, Duquette, Pierre, Lugaresi, Alessandra, Khoury, Samia J., Slee, Mark, Turkoglu, Recai, Hodgkinson, Suzanne, John, Nevin, Maimone, Davide, Sa, Maria Jose, van Pesch, Vincent, Gerlach, Oliver, Laureys, Guy, Van Hijfte, Liesbeth, Karabudak, Rana, Spitaleri, Daniele, Csepany, Tunde, Gouider, Riadh, Castillo-Triviño, Tamara, Taylor, Bruce, Sharrack, Basil, Snowden, John A., Horakova, Dana, Buzzard, Katherine, Terzi, Murat, Prat, Alexandre, Girard, Marc, Grammond, Pierre, Barnett, Michael, Stewart, Grace, Onofrj, Marco, Izquierdo, Guillermo, Eichau, Sara, Grand'Maison, Francois, Prevost, Julie, Van Wijmeersch, Bart, Amato, Maria Pia, Shaygannejad, Vahid, Boz, Cavit, Bolaños, Ricardo Fernandez, Soysal, Aysun, Ramo-Tello, Cristina, Solaro, Claudio, Gobbi, Claudio, Cabrera-Gomez, Jose Antonio, Roullet, Etienne, Zwanikken, Cees, Den braber-Moerland, Leontien, Deri, Norma, Saladino, Maria Laura, Cristiano, Edgardo, Rojas, Juan Ignacio, Vrech, Carlos, Shaw, Cameron, Shuey, Neil, Boggild, Mike, Tan, Ik Lin, Hardy, Todd, Decoo, Danny, Moore, Fraser, Oh, Jiwon, Lalive, Patrice, Ampapa, Radek, Petersen, Thor, Oreja-Guevara, Celia, Perez Sempere, Angel, Dominguez, Jose Andres, Besora, Sarah, Hughes, Stella, Gray, Orla, Grigoriadis, Nikolaos, Piroska, Imre, Rozsa, Csilla, Kasa, Krisztian, Simo, Magdolna, Kovacs, Krisztina, Sas, Attila, Dobos, Eniko, Rajda, Cecilia, McGuigan, Chris, Mason, Deborah, Schepel, Jan, Alkhaboori, Jabir, Rio, Maria Edite, Mihaela, Simu, Al-Harbi, Talal, Altintas, Ayse, Kister, Ilya, Marriott, Mark, Kilpatrick, Trevor, King, John, Nguyen, Ai-Lan, Dwyer, Chris, Monif, Mastura, Taylor, Lisa, Diamanti, Matteo, Chisari, Clara, Toscano, Simona, Salvatore, Lo Fermo, Larochelle, Catherine, De Luca, Giovanna, Di Tommaso, Valeria, Travaglini, Daniela, Pietrolongo, Erika, di Ioia, Maria, Farina, Deborah, Mancinelli, Luca, Hupperts, Raymond, Olascoaga, Javier, Saiz, Albert, Zivadinov, Robert, Benedict, Ralph, Verheul, Freek, Fabis-Pedrini, Marzena, Mrabet, Saloua, Garber, Justin, Sanchez-Menoyo, Jose Luis, Aguera-Morales, Eduardo, Blanco, Yolanda, Al-Asmi, Abdullah, Weinstock-Guttman, Bianca, Fragoso, Yara, de Gans, Koen, and Kermode, Allan

Subjects
Human medicine
Abstract

you are agreeing to our Cookie Policy | Continue JAMA Network HomeJAMA Neurology This Issue Views 2,357 Citations 0 60 Full Text Share Comment Original Investigation May 15, 2023 Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis Tomas Kalincik, MD, PhD1,2; Sifat Sharmin, PhD1,2; Izanne Roos, MBChB, PhD1,2; Mark S. Freedman, MD3; Harold Atkins, MD4; Joachim Burman, MD, PhD5; Jennifer Massey, MBBS, PhD6,7; Ian Sutton, MBBS, PhD6,8; Barbara Withers, MD, PhD7,9; Richard Macdonell, MD, PhD10,11; Andrew Grigg, MD, PhD11,12; Øivind Torkildsen, MD, PhD13; Lars Bo, MD, PhD13; Anne Kristine Lehmann, MD, PhD14; Eva Kubala Havrdova, MD, PhD15; Eva Krasulova, MD, PhD15; Marek Trněný, MD, PhD16; Tomas Kozak, MD, PhD17; Anneke van der Walt, MBBS, PhD18,19; Helmut Butzkueven, MBBS, PhD18,19; Pamela McCombe, MBBS20,21; Olga Skibina, MBBS18,22,23; Jeannette Lechner-Scott, MD, PhD24,25; Barbara Willekens, MD, PhD26,27; Elisabetta Cartechini, MD28; Serkan Ozakbas, MD29; Raed Alroughani, MD30; Jens Kuhle, MD, PhD31; Francesco Patti, MD32,33; Pierre Duquette, MD34; Alessandra Lugaresi, MD, PhD35,36; Samia J. Khoury, MD, PhD37; Mark Slee, MD, PhD38; Recai Turkoglu, MD39; Suzanne Hodgkinson, MD40; Nevin John, MD, PhD41,42; Davide Maimone, MD43; Maria Jose Sa, MD44; Vincent van Pesch, MD, PhD45,46; Oliver Gerlach, MD, PhD47,48; Guy Laureys, MD49; Liesbeth Van Hijfte, MD49; Rana Karabudak, MD50; Daniele Spitaleri, MD51; Tunde Csepany, MD, PhD52; Riadh Gouider, MD53,54; Tamara Castillo-Triviño, MD55; Bruce Taylor, MD, PhD56,57; Basil Sharrack, MD, PhD58; John A. Snowden, MD, PhD59; and the MSBase Study Group Collaborators; and the MSBase Study Group Authors Author Affiliations JAMA Neurol. 2023;80(7):702-713. doi:10.1001/jamaneurol.2023.1184 editorial comment iconEditorial Comment Key Points Question What is the comparative effectiveness of autologous hematopoietic stem cell transplant (AHSCT) vs individual most potent disease-modifying therapies for relapsing-remitting multiple sclerosis (MS), such as natalizumab or ocrelizumab? Findings In this observational comparative effectiveness study of 4915 individuals using a composite cohort from specialized MS centers and the MSBase international registry, the effectiveness of AHSCT was compared with 1 medium-efficacy and 2 high-efficacy disease-modifying therapies (fingolimod, natalizumab, and ocrelizumab) in patients with relapsing-remitting MS, high frequency of relapses, and moderate disability. Over 5 years, AHSCT was associated with substantially lower relapse rate than fingolimod and marginally lower relapse rate than natalizumab and was also associated with a higher rate of recovery from disability compared with fingolimod and natalizumab, but no evidence of difference in clinical outcomes between AHSCT and ocrelizumab was found at 3-year follow-up. Meaning The results indicate that in relapsing-remitting MS, the clinical effectiveness of AHSCT is considerably superior to fingolimod and marginally superior to natalizumab. Abstract Importance Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Published
2023

23. Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity.

Author

Jokubaitis, Vilija G, Campagna, Maria Pia, Ibrahim, Omar, Stankovich, Jim, Kleinova, Pavlina, Matesanz, Fuencisla, Hui, Daniel, Eichau, Sara, Slee, Mark, Lechner-Scott, Jeannette, Lea, Rodney, Kilpatrick, Trevor J, Kalincik, Tomas, Jager, Philip L De, Beecham, Ashley, McCauley, Jacob L, Taylor, Bruce V, Vucic, Steve, Laverick, Louise, and Vodehnalova, Karolina

Subjects
MULTIPLE sclerosis, DELAYED onset of disease, SINGLE nucleotide polymorphisms, MACHINE learning, MEDICAL registries, GENOME-wide association studies, IMMUNE system
Abstract

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale =0.8289, P = 3.52 × 10-08), the other in males (rs698805; βmale = -1.5395, P = 4.35 × 10-08), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in central nervous system compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and g-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Cladribine Treatment for MS Preserves the Differentiative Capacity of Subsequently Generated Monocytes, Whereas Its Administration In Vitro Acutely Influences Monocyte Differentiation but Not Microglial Activation

Author

Medeiros-Furquim, Tiago, Ayoub, Sinan, Johnson, Laura J., Aprico, Andrea, Nwoke, Eze, Binder, Michele D., and Kilpatrick, Trevor J.

Subjects
PHARMACOKINETICS, IMMUNOPATHOLOGY, POLARIZATION, CLEARANCE, Immunology, microglia, GM-CSF, cladribine, macrophage, MULTIPLE-SCLEROSIS, multiple sclerosis, neuroinflammation, MECHANISMS, monocyte, CELLS, Immunology and Allergy, 2-chlorodeoxyadenosine (2-CdA), MACROPHAGES, 2-CHLORODEOXYADENOSINE, innate immunity
Abstract

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS.

Published
2022

26. Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation

Author

Jonas, Anna, Thiem, Stefan, Kuhlmann, Tanja, Wagener, Raimund, Aszodi, Attila, Nowell, Cameron, Hagemeier, Karin, Laverick, Louise, Perreau, Victoria, Jokubaitis, Vilija, Emery, Ben, Kilpatrick, Trevor, Butzkueven, Helmut, and Gresle, Melissa

Subjects
Genes -- Physiological aspects -- Research, Axons -- Physiological aspects -- Research -- Genetic aspects, Encephalomyelitis -- Risk factors -- Genetic aspects -- Research, Health care industry
Abstract

In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), inflammatory axonal injury is a major determinant of disability; however, the drivers of this injury are incompletely understood. Here, we used the EAE model and determined that the extracellular matrix protein matrilin-2 (MATN2) is an endogenous neuronal molecule that is regulated in association with inflammatory axonal injury. Compared with WT mice, mice harboring a deletion of Matn2 exhibited reduced disease severity and axon damage following induction of EAE. Evaluation of neuron-macrophage cocultures revealed that exogenous MATN2 specifically signals through TLR4 and directly induces expression of proinflammatory genes in macrophages, promoting axonal damage. Moreover, the MATN2-induced proinflammatory response was attenuated greatly in macrophages from Myd88 KO mice. Examination of brain sections from patients with MS revealed that MATN2 is expressed in lesions but not in normal-appearing white matter. Together, our results indicate that MATN2 is a deleterious endogenous neuroaxonal injury response signal that activates innate immune cells and could contribute to early axonal damage in CNS inflammatory diseases like MS., Introduction Axonal injury is an important pathological feature of acute and chronic multiple sclerosis (MS) lesions. It is now widely accepted that immune-mediated axonal damage and loss are major determinants [...]

Published
2014
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28. A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Author

Gu, Ben J., Field, Judith, Dutertre, Sébastien, Ou, Amber, Kilpatrick, Trevor J., Lechner-Scott, Jeannette, Scott, Rodney, Lea, Rodney, Taylor, Bruce V., Stankovich, Jim, Butzkueven, Helmut, Gresle, Melissa, Laws, Simon M., Petrou, Steven, Hoffjan, Sabine, Akkad, Denis A., Graham, Colin A., Hawkins, Stanley, Glaser, Anna, Bedri, Sahl Khalid, Hillert, Jan, Matute, Carlos, Antiguedad, Alfredo, Wiley, James S., Baxter, Alan G., Kermode, Allan G., Taylor, Bruce V., Booth, David R., Mason, Deborah F., Stewart, Graeme J., Butzkueven, Helmut, Charlesworth, Jac C., Wiley, James S., Lechner-Scott, Jeannette S., Field, Judith, Tajouri, Lotti, Griffiths, Lyn R., Slee, Mark, Brown, Matthew A., Moscato, Pablo, Scott, Rodney J., Broadley, Simon A., Vucic, Steve, Kilpatrick, Trevor J., Carroll, William M., and Barnett, Michael H.

Published
2015
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31. MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis

Author

Clarke, Laura, primary, Arnett, Simon, additional, Bukhari, Wajih, additional, Khalilidehkordi, Elham, additional, Jimenez Sanchez, Sofia, additional, O'Gorman, Cullen, additional, Sun, Jing, additional, Prain, Kerri M., additional, Woodhall, Mark, additional, Silvestrini, Roger, additional, Bundell, Christine S., additional, Abernethy, David A., additional, Bhuta, Sandeep, additional, Blum, Stefan, additional, Boggild, Mike, additional, Boundy, Karyn, additional, Brew, Bruce J., additional, Brownlee, Wallace, additional, Butzkueven, Helmut, additional, Carroll, William M., additional, Chen, Cella, additional, Coulthard, Alan, additional, Dale, Russell C., additional, Das, Chandi, additional, Fabis-Pedrini, Marzena J., additional, Gillis, David, additional, Hawke, Simon, additional, Heard, Robert, additional, Henderson, Andrew P. D., additional, Heshmat, Saman, additional, Hodgkinson, Suzanne, additional, Kilpatrick, Trevor J., additional, King, John, additional, Kneebone, Christopher, additional, Kornberg, Andrew J., additional, Lechner-Scott, Jeannette, additional, Lin, Ming-Wei, additional, Lynch, Christopher, additional, Macdonell, Richard A. L., additional, Mason, Deborah F., additional, McCombe, Pamela A., additional, Pereira, Jennifer, additional, Pollard, John D., additional, Ramanathan, Sudarshini, additional, Reddel, Stephen W., additional, Shaw, Cameron P., additional, Spies, Judith M., additional, Stankovich, James, additional, Sutton, Ian, additional, Vucic, Steve, additional, Walsh, Michael, additional, Wong, Richard C., additional, Yiu, Eppie M., additional, Barnett, Michael H., additional, Kermode, Allan G. K., additional, Marriott, Mark P., additional, Parratt, John D. E., additional, Slee, Mark, additional, Taylor, Bruce V., additional, Willoughby, Ernest, additional, Brilot, Fabienne, additional, Vincent, Angela, additional, Waters, Patrick, additional, and Broadley, Simon A., additional

Published
2021
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34. Axonal loss in major sensorimotor tracts is associated with impaired motor performance in minimally disabled multiple sclerosis patients

Author

Strik, Myrte, primary, Cofré Lizama, L Eduardo, additional, Shanahan, Camille J, additional, van der Walt, Anneke, additional, Boonstra, Frederique M C, additional, Glarin, Rebecca, additional, Kilpatrick, Trevor J, additional, Geurts, Jeroen J G, additional, Cleary, Jon O, additional, Schoonheim, Menno M, additional, Galea, Mary P, additional, and Kolbe, Scott C, additional

Published
2021
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35. Functional correlates of motor control impairments in multiple sclerosis: A 7 Tesla task functional MRI study

Author

Strik, Myrte, primary, Shanahan, Camille J., additional, Walt, Anneke, additional, Boonstra, Frederique M. C., additional, Glarin, Rebecca, additional, Galea, Mary P., additional, Kilpatrick, Trevor J., additional, Geurts, Jeroen J. G., additional, Cleary, Jon O., additional, Schoonheim, Menno M., additional, and Kolbe, Scott C., additional

Published
2021
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36. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis

Author

Kalincik, Tomas, Vivek, Vino, Jokubaitis, Vilija, Lechner-Scott, Jeannette, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Grand’Maison, Francois, Hupperts, Raymond, Oreja-Guevara, Celia, Bergamaschi, Roberto, Iuliano, Gerardo, Alroughani, Raed, Van Pesch, Vincent, Amato, Maria Pia, Slee, Mark, Verheul, Freek, Fernandez-Bolanos, Ricardo, Fiol, Marcela, Spitaleri, Daniele La, Cristiano, Edgardo, Gray, Orla, Cabrera-Gomez, Jose Antonio, Shaygannejad, Vahid, Herbert, Joseph, Vucic, Steve, Needham, Merilee, Petkovska-Boskova, Tatjana, Sirbu, Carmen-Adella, Duquette, Pierre, Girard, Marc, Grammond, Pierre, Boz, Cavit, Giuliani, Giorgio, Rio, Maria Edite, Barnett, Michael, Flechter, Shlomo, Moore, Fraser, Singhal, Bhim, Bacile, Elizabeth Alejandra, Saladino, Maria Laura, Shaw, Cameron, Skromne, Eli, Poehlau, Dieter, Vella, Norbert, Spelman, Timothy, Liew, Danny, Kilpatrick, Trevor J., and Butzkueven, Helmut

Published
2013
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37. MOESM1 of Comparison of the effectiveness of a tailored cognitive behavioural therapy with a supportive listening intervention for depression in those newly diagnosed with multiple sclerosis (the ACTION-MS trial): protocol of an assessor-blinded, active comparator, randomised controlled trial

Author

Litza Kiropoulos, Kilpatrick, Trevor, Kalincek, Tomas, Cherulov, Leonid, McDonald, Elizabeth, Tissa Wijeratne, Threader, Jennifer, Rozenblat, Vanja, Simpson-O’Brien, Neil, Walt, Anneke, and Taylor, Lisa

Abstract

Additional file 1. SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents.

Published
2020
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38. Erratum: A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))

Author

Carter, Adrian, Richards, Linda J., Apthorp, Deborah, Azghadi, Mostafa Rahimi, Badcock, David R., Balleine, Bernard, Bekkers, John M., Berk, Michael, Bourne, James A., Bradley, Andrew P., Breakspear, Michael, Brichta, Alan, Carter, Olivia, Castles, Anne, Chakli, Khaled, Cohen-Woods, Sarah, Conn, Simon J., Cornish, Jennifer, Cornish, Kim, de Zubicaray, Greg, Egan, Gary F., Enticott, Peter G., Fitzgibbon, Bernadette M., Forlini, Cynthia, Fornito, Alex, Griffiths, Lyn, Gullifer, Judith, Hall, Wayne, Halliday, Glenda, Hannan, Anthony J., Harrer, Stefan, Harvey, Alan, Hatherly, Chris, Hickie, Ian B., Kennett, Jeanette, Kiernan, Matthew, Kilpatrick, Trevor, Kiral-Kornek, Isabell, Korgaonkar, Mayuresh S., Lawrence, Andrew J., Leventer, Rick, Levy, Neil, Licinio, Julio, Lovell, Nigel, Mackellar, Geoff, Malcolm, Lynne, Mason, Alice, Mattingley, Jason B., Medland, Sarah E., Michie, Patricia T., Nithianantharajah, Jess, Parker, John, Payne, Jonathan M., Poole-Warren, Laura, Sah, Pankaj, Sarnyai, Zoltan, Schofield, Peter R., Shimoni, Olga, Shum, David H.K., Silk, Tim, Slee, Mark, Smith, Ashleigh E., Soulis, Tina, Sriram, Sharath, Stuart, Greg J., Tapson, Jonathan, Thompson, Matthew B., van Schaik, André, Vincent, Nicole A., Vissel, Bryce, Waters, Allison, other, and, Carter, Adrian, Richards, Linda J., Apthorp, Deborah, Azghadi, Mostafa Rahimi, Badcock, David R., Balleine, Bernard, Bekkers, John M., Berk, Michael, Bourne, James A., Bradley, Andrew P., Breakspear, Michael, Brichta, Alan, Carter, Olivia, Castles, Anne, Chakli, Khaled, Cohen-Woods, Sarah, Conn, Simon J., Cornish, Jennifer, Cornish, Kim, de Zubicaray, Greg, Egan, Gary F., Enticott, Peter G., Fitzgibbon, Bernadette M., Forlini, Cynthia, Fornito, Alex, Griffiths, Lyn, Gullifer, Judith, Hall, Wayne, Halliday, Glenda, Hannan, Anthony J., Harrer, Stefan, Harvey, Alan, Hatherly, Chris, Hickie, Ian B., Kennett, Jeanette, Kiernan, Matthew, Kilpatrick, Trevor, Kiral-Kornek, Isabell, Korgaonkar, Mayuresh S., Lawrence, Andrew J., Leventer, Rick, Levy, Neil, Licinio, Julio, Lovell, Nigel, Mackellar, Geoff, Malcolm, Lynne, Mason, Alice, Mattingley, Jason B., Medland, Sarah E., Michie, Patricia T., Nithianantharajah, Jess, Parker, John, Payne, Jonathan M., Poole-Warren, Laura, Sah, Pankaj, Sarnyai, Zoltan, Schofield, Peter R., Shimoni, Olga, Shum, David H.K., Silk, Tim, Slee, Mark, Smith, Ashleigh E., Soulis, Tina, Sriram, Sharath, Stuart, Greg J., Tapson, Jonathan, Thompson, Matthew B., van Schaik, André, Vincent, Nicole A., Vissel, Bryce, Waters, Allison, and other, and

Abstract

(Neuron 101, 365–369; February 6, 2019) In the original publication of this NeuroView, the member list for the Australian Brain Alliance was omitted. This has now been corrected online. Neuron apologizes for the error.

Published
2020

39. Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation

Author

Khalilidehkordi, Elham, Clarke, Laura, Arnett, Simon, Bukhari, Wajih, Jimenez Sanchez, Sofia, O'Gorman, Cullen, Sun, Jing, Prain, Kerri M., Woodhall, Mark, Silvestrini, Roger, Bundell, Christine S., Abernethy, David, Bhuta, Sandeep, Blum, Stefan, Boggild, Mike, Boundy, Karyn, Brew, Bruce J., Brown, Matthew, Brownlee, Wallace, Butzkueven, Helmut, Carroll, William M., Chen, Celia, Coulthard, Alan, Dale, Russell C., Das, Chandi, Fabis-Pedrini, Marzena J., Fulcher, David, Gillis, David, Hawke, Simon, Heard, Robert, Henderson, Andrew P.D., Heshmat, Saman, Hodgkinson, Suzanne, Kilpatrick, Trevor J., King, John, Kneebone, Chris, Kornberg, Andrew J., Lechner-Scott, Jeannette, Lin, Ming Wei, Lynch, Christopher, Macdonell, Richard A.L., Mason, Deborah F., McCombe, Pamela A., Pereira, Jennifer, Pollard, John D., Ramanathan, Sudarshini, Reddel, Stephen W., Shaw, Cameron, Spies, Judith, Stankovich, James, Sutton, Ian, Vucic, Steve, Walsh, Michael, Wong, Richard C., Yiu, Eppie M., Barnett, Michael H., Kermode, Allan G., Marriott, Mark P., Parratt, John, Slee, Mark, Taylor, Bruce V., Willoughby, Ernest, Brilot, Fabienne, Vincent, Angela, Waters, Patrick, Broadley, Simon A., Khalilidehkordi, Elham, Clarke, Laura, Arnett, Simon, Bukhari, Wajih, Jimenez Sanchez, Sofia, O'Gorman, Cullen, Sun, Jing, Prain, Kerri M., Woodhall, Mark, Silvestrini, Roger, Bundell, Christine S., Abernethy, David, Bhuta, Sandeep, Blum, Stefan, Boggild, Mike, Boundy, Karyn, Brew, Bruce J., Brown, Matthew, Brownlee, Wallace, Butzkueven, Helmut, Carroll, William M., Chen, Celia, Coulthard, Alan, Dale, Russell C., Das, Chandi, Fabis-Pedrini, Marzena J., Fulcher, David, Gillis, David, Hawke, Simon, Heard, Robert, Henderson, Andrew P.D., Heshmat, Saman, Hodgkinson, Suzanne, Kilpatrick, Trevor J., King, John, Kneebone, Chris, Kornberg, Andrew J., Lechner-Scott, Jeannette, Lin, Ming Wei, Lynch, Christopher, Macdonell, Richard A.L., Mason, Deborah F., McCombe, Pamela A., Pereira, Jennifer, Pollard, John D., Ramanathan, Sudarshini, Reddel, Stephen W., Shaw, Cameron, Spies, Judith, Stankovich, James, Sutton, Ian, Vucic, Steve, Walsh, Michael, Wong, Richard C., Yiu, Eppie M., Barnett, Michael H., Kermode, Allan G., Marriott, Mark P., Parratt, John, Slee, Mark, Taylor, Bruce V., Willoughby, Ernest, Brilot, Fabienne, Vincent, Angela, Waters, Patrick, and Broadley, Simon A.

Abstract

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

Published
2020

43. Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes

Author

Cortes, Adrian, Field, Judith, Glazov, Evgeny A., Hadler, Johanna, Stankovich, Jim, Brown, Matthew A., Baxter, Alan, Kermode, Allan G, Taylor, Bruce, Booth, David R, Mason, Deborah, Stewart, Graeme J, Butzkueven, Helmut, Charlesworth, Jac, Wiley, James, Lechner-Scott, Jeannette, Field, Judith, Tajouri, Lotti, Griffiths, Lyn, Slee, Mark, Brown, Matthew A, Moscato, Pablo, Scott, Rodney J, Broadley, Simon, Vucic, Steve, Kilpatrick, Trevor J, and Carroll, William M

Published
2013
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44. Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis

Author

Rubio, Justin P., Bahlo, Melanie, Butzkueven, Helmut, van der Mei, Ingrid A.F., Sale, Michele M., Dickinson, Joanne L., Groom, Patricia, Johnson, Laura J., Simmons, Rex D., Tait, Brian, Varney, Mike, Taylor, Bruce, Dwyer, Terence, Williamson, Robert, Gough, Nicholas M., Kilpatrick, Trevor J., Speed, Terence P., and Foote, Simon J.

Subjects
Tasmanian aborigines -- Diseases, Genetic disorders -- Demographic aspects, Antigens -- Analysis, Multiple sclerosis -- Demographic aspects, Biological sciences
Published
2002

46. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris C. A., Patsopoulos, Nikolaos A., Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E., Edkins, Sarah, Gray, Emma, Booth, David R., Potter, Simon C., Goris, An, Band, Gavin, Bang Oturai, Annette, Strange, Amy, Saarela, Janna, Bellenguez, Céline, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D’alfonso, Sandra, Blackburn, Hannah, Martinelli Boneschi, Filippo, Liddle, Jennifer, Harbo, Hanne F., Perez, Marc L., Spurkland, Anne, Waller, Matthew J., Mycko, Marcin P., Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T., Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J., Barcellos, Lisa F., Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E., Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P., Brassat, David, Broadley, Simon A., Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M., Cavalla, Paola, Celius, Elisabeth G., Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Françoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B., Cozen, Wendy, Cree, Bruce A. C., Cross, Anne H., Cusi, Daniele, Daly, Mark J., Davis, Emma, de Bakker, Paul I. W., Debouverie, Marc, D’hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Bénédicte, Ellinghaus, David, Elovaara, Irina, Esposito, Federica, Fontenille, Claire, Foote, Simon, Franke, Andre, Galimberti, Daniela, Ghezzi, Angelo, Glessner, Joseph, Gomez, Refujia, Gout, Olivier, Graham, Colin, Grant, Struan F. A., Rosa Guerini, Franca, Hakonarson, Hakon, Hall, Per, Hamsten, Anders, Hartung, Hans-Peter, Heard, Rob N., Heath, Simon, Hobart, Jeremy, Hoshi, Muna, Infante-Duarte, Carmen, Ingram, Gillian, Ingram, Wendy, Islam, Talat, Jagodic, Maja, Kabesch, Michael, Kermode, Allan G., Kilpatrick, Trevor J., Kim, Cecilia, Klopp, Norman, Koivisto, Keijo, Larsson, Malin, Lathrop, Mark, Lechner-Scott, Jeannette S., Leone, Maurizio A., Leppä, Virpi, Liljedahl, Ulrika, Lima Bomfim, Izaura, Lincoln, Robin R., Link, Jenny, Liu, Jianjun, Lorentzen, Åslaug R., Lupoli, Sara, Macciardi, Fabio, Mack, Thomas, Marriott, Mark, Martinelli, Vittorio, Mason, Deborah, McCauley, Jacob L., Mentch, Frank, Mero, Inger-Lise, Mihalova, Tania, Montalban, Xavier, Mottershead, John, Myhr, Kjell-Morten, Naldi, Paola, Ollier, William, Page, Alison, Palotie, Aarno, Pelletier, Jean, Piccio, Laura, Pickersgill, Trevor, Piehl, Fredrik, Pobywajlo, Susan, Quach, Hong L., Ramsay, Patricia P., Reunanen, Mauri, Reynolds, Richard, Rioux, John D., Rodegher, Mariaemma, Roesner, Sabine, Rubio, Justin P., Rückert, Ina-Maria, Salvetti, Marco, Salvi, Erika, Santaniello, Adam, Schaefer, Catherine A., Schreiber, Stefan, Schulze, Christian, Scott, Rodney J., Sellebjerg, Finn, Selmaj, Krzysztof W., Sexton, David, Shen, Ling, Simms-Acuna, Brigid, Skidmore, Sheila, Sleiman, Patrick M. A., Smestad, Cathrine, Sørensen, Per Soelberg, Søndergaard, Helle Bach, Stankovich, Jim, Strange, Richard C., Sulonen, Anna-Maija, Sundqvist, Emilie, Syvänen, Ann-Christine, Taddeo, Francesca, Taylor, Bruce, Blackwell, Jenefer M., Tienari, Pentti, Bramon, Elvira, Tourbah, Ayman, Brown, Matthew A., Tronczynska, Ewa, Casas, Juan P., Tubridy, Niall, Corvin, Aiden, Vickery, Jane, Jankowski, Janusz, Villoslada, Pablo, Markus, Hugh S., Wang, Kai, Mathew, Christopher G., Wason, James, Palmer, Colin N. A., Wichmann, H-Erich, Plomin, Robert, Willoughby, Ernest, Rautanen, Anna, Winkelmann, Juliane, Wittig, Michael, Trembath, Richard C., Yaouanq, Jacqueline, Viswanathan, Ananth C., Zhang, Haitao, Wood, Nicholas W., Zuvich, Rebecca, Deloukas, Panos, Langford, Cordelia, Duncanson, Audrey, Oksenberg, Jorge R., Pericak-Vance, Margaret A., Haines, Jonathan L., Olsson, Tomas, Hillert, Jan, Ivinson, Adrian J., De Jager, Philip L., Peltonen, Leena, Stewart, Graeme J., Hafler, David A., Hauser, Stephen L., McVean, Gil, Donnelly, Peter, and Compston, Alastair

Published
2011
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49. Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation

Author

Khalilidehkordi, Elham, primary, Clarke, Laura, additional, Arnett, Simon, additional, Bukhari, Wajih, additional, Jimenez Sanchez, Sofia, additional, O'Gorman, Cullen, additional, Sun, Jing, additional, Prain, Kerri M., additional, Woodhall, Mark, additional, Silvestrini, Roger, additional, Bundell, Christine S., additional, Abernethy, David, additional, Bhuta, Sandeep, additional, Blum, Stefan, additional, Boggild, Mike, additional, Boundy, Karyn, additional, Brew, Bruce J., additional, Brown, Matthew, additional, Brownlee, Wallace, additional, Butzkueven, Helmut, additional, Carroll, William M., additional, Chen, Celia, additional, Coulthard, Alan, additional, Dale, Russell C., additional, Das, Chandi, additional, Fabis-Pedrini, Marzena J., additional, Fulcher, David, additional, Gillis, David, additional, Hawke, Simon, additional, Heard, Robert, additional, Henderson, Andrew P. D., additional, Heshmat, Saman, additional, Hodgkinson, Suzanne, additional, Kilpatrick, Trevor J., additional, King, John, additional, Kneebone, Chris, additional, Kornberg, Andrew J., additional, Lechner-Scott, Jeannette, additional, Lin, Ming-Wei, additional, Lynch, Christopher, additional, Macdonell, Richard A. L., additional, Mason, Deborah F., additional, McCombe, Pamela A., additional, Pereira, Jennifer, additional, Pollard, John D., additional, Ramanathan, Sudarshini, additional, Reddel, Stephen W., additional, Shaw, Cameron, additional, Spies, Judith, additional, Stankovich, James, additional, Sutton, Ian, additional, Vucic, Steve, additional, Walsh, Michael, additional, Wong, Richard C., additional, Yiu, Eppie M., additional, Barnett, Michael H., additional, Kermode, Allan G., additional, Marriott, Mark P., additional, Parratt, John, additional, Slee, Mark, additional, Taylor, Bruce V., additional, Willoughby, Ernest, additional, Brilot, Fabienne, additional, Vincent, Angela, additional, Waters, Patrick, additional, and Broadley, Simon A., additional

Published
2020
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