43 results on '"McCombe, Pamela"'
Search Results
2. Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis
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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, Trnený, 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., 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
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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.
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- 2023
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3. Disability accrual in primary and secondary progressive multiple sclerosis
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Harding-Forrester, Sam, Roos, Izanne, Nguyen, Ai-Lan, Malpas, Charles B, Diouf, Ibrahima, Moradi, Nahid, Sharmin, Sifat, Izquierdo, Guillermo, Eichau, Sara, Patti, Francesco, Horakova, Dana, Kubala Havrdova, Eva, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grand'Maison, Francois, Onofrj, Marco, Lugaresi, Alessandra, Grammond, Pierre, Ozakbas, Serkan, Amato, Maria Pia, Gerlach, Oliver, Sola, Patrizia, Ferraro, Diana, Buzzard, Katherine, Skibina, Olga, Lechner-Scott, Jeannette, Alroughani, Raed, Boz, Cavit, Van Pesch, Vincent, Cartechini, Elisabetta, Terzi, Murat, Maimone, Davide, Ramo-Tello, Cristina, Yamout, Bassem, Khoury, Samia Joseph, La Spitaleri, Daniele, Sa, Maria Jose, Blanco, Yolanda, Granella, Franco, Slee, Mark, Butler, Ernest, Sidhom, Youssef, Gouider, Riadh, Bergamaschi, Roberto, Karabudak, Rana, Ampapa, Radek, Sánchez-Menoyo, José Luis, Prevost, Julie, Castillo-Trivino, Tamara, McCombe, Pamela A, Macdonell, Richard, Laureys, Guy, Van Hijfte, Liesbeth, Oh, Jiwon, Altintas, Ayse, de Gans, Koen, Turkoglu, Recai, van der Walt, Anneke, Butzkueven, Helmut, Vucic, Steve, Barnett, Michael, Cristiano, Edgardo, Hodgkinson, Suzanne, Iuliano, Gerardo, Kappos, Ludwig, Kuhle, Jens, Shaygannejad, Vahid, Soysal, Aysun, Weinstock-Guttman, Bianca, Van Wijmeersch, Bart, and Kalincik, Tomas
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BackgroundSome studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS.MethodsWe compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS.ResultsIncluded patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2–47.3) vs 43.9 (43.3–44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78–0.94); p<0.001) and similar age at wheelchair dependence.ConclusionsWe demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
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- 2023
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4. Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial
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Diouf, Ibrahima, Malpas, Charles B, Sharmin, Sifat, Roos, Izanne, Horakova, Dana, Kubala Havrdova, Eva, Patti, Francesco, Shaygannejad, Vahid, Ozakbas, Serkan, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Alroughani, Raed, Prat, Alexandre, Duquette, Pierre, Terzi, Murat, Boz, Cavit, Grand'Maison, Francois, Sola, Patrizia, Ferraro, Diana, Grammond, Pierre, Yamout, Bassem, Altintas, Ayse, Gerlach, Oliver, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Karabudak, Rana, Iuliano, Gerardo, McGuigan, Christopher, Cartechini, Elisabetta, Hughes, Stella, Sa, Maria Jose, Solaro, Claudio, Kappos, Ludwig, Hodgkinson, Suzanne, Slee, Mark, Granella, Franco, de Gans, Koen, McCombe, Pamela A, Ampapa, Radek, van der Walt, Anneke, Butzkueven, Helmut, Sánchez-Menoyo, José Luis, Vucic, Steve, Laureys, Guy, Sidhom, Youssef, Gouider, Riadh, Castillo-Trivino, Tamara, Gray, Orla, Aguera-Morales, Eduardo, Al-Asmi, Abdullah, Shaw, Cameron, Al-Harbi, Talal M, Csepany, Tunde, Sempere, Angel P, Treviño Frenk, Irene, Stuart, Elizabeth A, and Kalincik, Tomas
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BackgroundSimultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years.MethodsData from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement.Results23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability.ConclusionsThe effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
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- 2023
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5. Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network
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Signori, Alessio, Lorscheider, Johannes, Vukusic, Sandra, Trojano, Maria, Iaffaldano, Pietro, Hillert, Jan, Hyde, Robert, Pellegrini, Fabio, Magyari, Melinda, Koch-Henriksen, Nils, Sørensen, Per Soelberg, Spelman, Tim, van der Walt, Anneke, Horakova, Dana, Havrdova, Eva, Girard, Marc, Eichau, Sara, Grand'Maison, Francois, Gerlach, Oliver, Terzi, Murat, Ozakbas, Serkan, Skibina, Olga, Van Pesch, Vincent, Sa, Maria Jose, Prevost, Julie, Alroughani, Raed, McCombe, Pamela A, Gouider, Riadh, Mrabet, Saloua, Castillo-Trivino, Tamara, Zhu, Chao, de Gans, Koen, Sánchez-Menoyo, José Luis, Yamout, Bassem, Khoury, Samia, Sormani, Maria Pia, Kalincik, Tomas, and Butzkueven, Helmut
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BackgroundOver the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time.MethodsAll patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3–4.ResultsA total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria.ConclusionsContrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.
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- 2023
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6. Effect of immunotherapy on intracranial EEG in patients with seronegative autoimmune‐associated epilepsy
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Gillinder, Lisa, Papacostas, Jason, McCombe, Pamela, and Chauvel, Patrick
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Objective. Immunity is increasingly implicated in the aetiology of certain types of epilepsy, however, the clinical and EEG features in such cases remain poorly defined. We present stereo‐electroencephalography (SEEG) findings in patients who were thought to have autoantibody‐mediated epilepsy on the basis of clinical improvement after administration of immunotherapy (IT). Methods. All patients undergoing SEEG implantation in our service were reviewed and those receiving immunotherapy, either before, during, or after SEEG evaluation, were identified. Response to immunotherapy was defined as greater than 50% seizure reduction. We compared the clinical features and SEEG findings between those who responded to immunotherapy and those who did not. Results. Sixty‐two cases underwent SEEG evaluation. Of these, 11 received immunotherapy and three cases demonstrated a positive clinical benefit. The three responsive patients had multifocal seizure onset, repetitive spiking interictally and ictally, perisylvian semiology, seizure onset in the posterior perisylvian regions, and normal neuroimaging. Significance. Seronegative immunotherapy responders exist in epilepsy populations, therefore the diagnosis of autoimmune‐associated epilepsy should be considered before proceeding to epilepsy surgery. Possible features of an electroclinical syndrome associated with autoimmunity may include multifocal seizure onset, perisylvian involvement, and normal neuroimaging.
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- 2022
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7. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis
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Roos, Izanne, Malpas, Charles, Leray, Emmanuelle, Casey, Romain, Horakova, Dana, Havrdova, Eva Kubala, Debouverie, Marc, Patti, Francesco, De Seze, Jerome, Izquierdo, Guillermo, Eichau, Sara, Edan, Gilles, Prat, Alexandre, Girard, Marc, Ozakbas, Serkan, Grammond, Pierre, Zephir, Helene, Ciron, Jonathan, Maillart, Elisabeth, Moreau, Thibault, Amato, Maria Pia, Labauge, Pierre, Alroughani, Raed, Buzzard, Katherine, Skibina, Olga, Terzi, Murat, Laplaud, David Axel, Berger, Eric, Grand'Maison, Francois, Lebrun-Frenay, Christine, Cartechini, Elisabetta, Boz, Cavit, Lechner-Scott, Jeannette, Clavelou, Pierre, Stankoff, Bruno, Prevost, Julie, Kappos, Ludwig, Pelletier, Jean, Shaygannejad, Vahid, Yamout, Bassem I., Khoury, Samia J., Gerlach, Oliver, Spitaleri, Daniele L.A., Van Pesch, Vincent, Gout, Olivier, Turkoglu, Recai, Heinzlef, Olivier, Thouvenot, Eric, McCombe, Pamela Ann, Soysal, Aysun, Bourre, Bertrand, Slee, Mark, Castillo-Trivino, Tamara, Bakchine, Serge, Ampapa, Radek, Butler, Ernest Gerard, Wahab, Abir, Macdonell, Richard A., Aguera-Morales, Eduardo, Cabre, Philippe, Ben, Nasr Haifa, Van der Walt, Anneke, Laureys, Guy, Van Hijfte, Liesbeth, Ramo-Tello, Cristina M., Maubeuge, Nicolas, Hodgkinson, Suzanne, Sánchez-Menoyo, José Luis, Barnett, Michael H., Labeyrie, Celine, Vucic, Steve, Sidhom, Youssef, Gouider, Riadh, Csepany, Tunde, Sotoca, Javier, de Gans, Koen, Al-Asmi, Abdullah, Fragoso, Yara Dadalti, Vukusic, Sandra, Butzkueven, Helmut, and Kalincik, Tomas
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- 2022
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8. Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis
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Vitkova, Marianna, Diouf, Ibrahima, Malpas, Charles, Horakova, Dana, Kubala Havrdova, Eva, Patti, Francesco, Ozakbas, Serkan, Izquierdo, Guillermo, Eichau, Sara, Shaygannejad, Vahid, Onofrj, Marco, Lugaresi, Alessandra, Alroughani, Raed, Prat, Alexandre, Larochelle, Catherine, Girard, Marc, Duquette, Pierre, Terzi, Murat, Boz, Cavit, Grand'Maison, Francois, Sola, Patrizia, Ferraro, Diana, Grammond, Pierre, Butzkueven, Helmut, Buzzard, Katherine, Skibina, Olga, Yamout, Bassem I., Karabudak, Rana, Gerlach, Oliver, Lechner-Scott, Jeannette, Maimone, Davide, Bergamaschi, Roberto, Van Pesch, Vincent, Iuliano, Gerardo, Cartechini, Elisabetta, José Sà, Maria, Ampapa, Radek, Barnett, Michael, Hughes, Stella E., Ramo-Tello, Cristina M., Hodgkinson, Suzanne, Spitaleri, Daniele L.A., Petersen, Thor, Butler, Ernest Gerard, Slee, Mark, McGuigan, Chris, McCombe, Pamela Ann, Granella, Franco, Cristiano, Edgardo, Prevost, Julie, Taylor, Bruce V., Sãnchez-Menoyo, Josã Luis, Laureys, Guy, Van Hijfte, Liesbeth, Vucic, Steve, Macdonell, Richard A., Gray, Orla, Olascoaga, Javier, Deri, Norma, Fragoso, Yara Dadalti, Shaw, Cameron, and Kalincik, Tomas
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- 2022
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9. Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia
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Restuadi, Restuadi, Garton, Fleur C., Benyamin, Beben, Lin, Tian, Williams, Kelly L., Vinkhuyzen, Anna, van Rheenen, Wouter, Zhu, Zhihong, Laing, Nigel G., Mather, Karen A., Sachdev, Perminder S., Ngo, Shyuan T., Steyn, Frederik J., Wallace, Leanne, Henders, Anjali K., Visscher, Peter M., Needham, Merrilee, Mathers, Susan, Nicholson, Garth, Rowe, Dominic B., Henderson, Robert D., McCombe, Pamela A., Pamphlett, Roger, Blair, Ian P., Wray, Naomi R., and McRae, Allan F.
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Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R2) of the case–control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R2) of 0.027 (Pvalue = 4.6 × 10−8), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96–5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS.
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- 2022
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10. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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- 2021
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11. Natalizumab, Fingolimod, and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis
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Yeh, Wei Zhen, Widyastuti, Putu Ayu, Van der Walt, Anneke, Stankovich, Jim, Havrdova, Eva, Horakova, Dana, Vodehnalova, Karolina, Ozakbas, Serkan, Eichau, Sara, Duquette, Pierre, Kalincik, Tomas, Patti, Francesco, Boz, Cavit, Terzi, Murat, Yamout, Bassem I., Lechner-Scott, Jeannette, Sola, Patrizia, Skibina, Olga G., Barnett, Michael, Onofrj, Marco, Sá, Maria José, McCombe, Pamela Ann, Grammond, Pierre, Ampapa, Radek, Grand'Maison, Francois, Bergamaschi, Roberto, Spitaleri, Daniele L.A., Van Pesch, Vincent, Cartechini, Elisabetta, Hodgkinson, Suzanne, Soysal, Aysun, Saiz, Albert, Gresle, Melissa, Uher, Tomas, Maimone, Davide, Turkoglu, Recai, Hupperts, Raymond M.M., Amato, Maria Pia, Granella, Franco, Oreja-Guevara, Celia, Altintas, Ayse, Macdonell, Richard A., Castillo-Trivino, Tamara, Butzkueven, Helmut, Alroughani, Raed, and Jokubaitis, Vilija G.
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- 2021
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12. The spectrum of language impairments in amyotrophic lateral sclerosis
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Ceslis, Amelia, Argall, Rosemary, Henderson, Robert D., McCombe, Pamela A., and Robinson, Gail A.
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Language disorders are increasingly recognised in Amyotrophic lateral sclerosis (ALS), supporting the view of ALS as a multi-system disorder, impacting cognitive and motor function. However, the language impairments are heterogeneous and recent focus has been on determining the language profile across the ALS spectrum with little focus on spontaneous speech. The current study systematically investigated a wide range of language abilities in an unselected ALS sample (N = 22), including spontaneous speech. We analysed the ALS patients' performance as a group, compared to age-, education- and IQ-matched healthy controls (N = 21), and as a case series to identify dementia and specific language profiles. The ALS group was impaired on measures of spontaneous speech, word fluency and action naming. By contrast, object naming, semantic memory (object and actions), sentence comprehension and repetition (word and sentences) were comparable to healthy controls. In line with recent suggestions, our ALS patients’ action naming (but not action semantic) deficit does not support the notion that action processing may be selectively impaired in ALS. The case series demonstrated that 14% of patients had probable dementia, 31% showed significant cognitive and/or language impairment and 55% were unimpaired, consistent with the spectrum of cognitive and language impairments reported in the literature. In addition, 36% of ALS patients produced significantly fewer words per minute on a spontaneous speech task than the control group, with this difference remaining when the ALS patients with frontotemporal dementia were excluded from the analysis. This pattern was observed across the ALS spectrum and in both limb and bulbar onset patients. The pattern of performance observed in the present study suggests that spontaneous speech is reduced across the ALS spectrum even in those with intact core language abilities.
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- 2020
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13. Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study
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Nguyen, Ai-Lan, Havrdova, Eva Kubala, Horakova, Dana, Izquierdo, Guillermo, Kalincik, Tomas, van der Walt, Anneke, Terzi, Murat, Alroughani, Raed, Duquette, Pierre, Girard, Marc, Prat, Alexandre, Boz, Cavit, Sola, Patrizia, Ferraro, Diana, Lugaresi, Alessandra, Lechner-Scott, Jeannette, Barnett, Michael, Grand'Maison, Francois, Grammond, Pierre, Ramo-Tello, Cristina, Turkoglu, Recai, McCombe, Pamela, Pucci, Eugenio, Trojano, Maria, Granella, Franco, Spitaleri, Daniele, Van Pesch, Vincent, Soysal, Aysun, Oreja-Guevara, Celia, Verheul, Freek, Vucic, Steve, Hodgkinson, Suzanne, Slee, Mark, Ampapa, Radek, Prevost, Julie, Menoyo, Jose Luis Sanchez, Skibina, Olga, Solaro, Claudio, Olascoaga, Javier, Shaw, Cameron, Madsen, Klaus Gregaard, Naidoo, Kerisha, Hyde, Robert, Butzkueven, Helmut, and Jokubaitis, Vilija
- Abstract
Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing.
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- 2019
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14. Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis
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Kalincik, Tomas, Kubala Havrdova, Eva, Horakova, Dana, Izquierdo, Guillermo, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Grammond, Pierre, Onofrj, Marco, Lugaresi, Alessandra, Ozakbas, Serkan, Kappos, Ludwig, Kuhle, Jens, Terzi, Murat, Lechner-Scott, Jeannette, Boz, Cavit, Grand'Maison, Francois, Prevost, Julie, Sola, Patrizia, Ferraro, Diana, Granella, Franco, Trojano, Maria, Bergamaschi, Roberto, Pucci, Eugenio, Turkoglu, Recai, McCombe, Pamela A, Pesch, Vincent Van, Van Wijmeersch, Bart, Solaro, Claudio, Ramo-Tello, Cristina, Slee, Mark, Alroughani, Raed, Yamout, Bassem, Shaygannejad, Vahid, Spitaleri, Daniele, Sánchez-Menoyo, José Luis, Ampapa, Radek, Hodgkinson, Suzanne, Karabudak, Rana, Butler, Ernest, Vucic, Steve, Jokubaitis, Vilija, Spelman, Tim, and Butzkueven, Helmut
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ObjectiveOral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.MethodsWe identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).ResultsThe eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).ConclusionThe effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
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- 2019
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15. Hypermetabolism in ALS is associated with greater functional decline and shorter survival
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Steyn, Frederik J, Ioannides, Zara A, van Eijk, Ruben P A, Heggie, Susan, Thorpe, Kathryn A, Ceslis, Amelia, Heshmat, Saman, Henders, Anjali K, Wray, Naomi R, van den Berg, Leonard H, Henderson, Robert D, McCombe, Pamela A, and Ngo, Shyuan T
- Abstract
ObjectiveTo determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival.MethodsFifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment.ResultsHypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; p<0.01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7); p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (−0.68 points/month vs −0.39 points/month; p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03).Conclusions and relevanceHypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS.
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- 2018
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16. Incidence and prevalence of NMOSD in Australia and New Zealand
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Bukhari, Wajih, Prain, Kerri M, Waters, Patrick, Woodhall, Mark, O‘Gorman, Cullen M, Clarke, Laura, Silvestrini, Roger A, Bundell, Christine S, Abernethy, David, Bhuta, Sandeep, Blum, Stefan, Boggild, Mike, Boundy, Karyn, Brew, Bruce J, Brown, Matthew, Brownlee, Wallace J, Butzkueven, Helmut, Carroll, William M, Chen, Celia, Coulthard, Alan, Dale, Russell C, Das, Chandi, Dear, Keith, Fabis-Pedrini, Marzena J, Fulcher, David, Gillis, David, Hawke, Simon, Heard, Robert, Henderson, Andrew P D, Heshmat, Saman, Hodgkinson, Suzanne, Jimenez-Sanchez, Sofia, Killpatrick, Trevor, King, John, Kneebone, Christopher, Kornberg, Andrew J, Lechner-Scott, Jeannette, Lin, Ming-Wei, Lynch, Christpher, Macdonell, Richard, Mason, Deborah F, McCombe, Pamela A, Pender, Michael P, Pereira, Jennifer A, Pollard, John D, 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 D E, Slee, Mark, Taylor, Bruce V, Willoughby, Ernest, Wilson, Robert J, Vincent, Angela, and Broadley, Simon A
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ObjectivesWe have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry.BackgroundNMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established.MethodsCentres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture–recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases.ResultsNMOSD was confirmed in 81/170 (48%) cases referred. Capture–recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD.ConclusionsNMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.
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- 2017
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17. Patient with ALS with a novel TBK1 mutation, widespread brain involvement, behaviour changes and metabolic dysfunction
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McCombe, Pamela A, Ngo, Shyuan T, Guo, Christine Cong, Fazlollahi, Amir, Bollmann, Saskia, Wang, Liting, Hu, Xintao, Barth, Markus, Salvado, Olivier, Davis, Mark, Ceslis, Amelia, Robinson, Gail, Henderson, Robert D, and Steyn, Frederik J
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- 2019
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18. A Case Series of Patients With Autoimmune Myasthenia Gravis in Association With Invasive Thymoma
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McCombe, Pamela, Raj, Meenakshi, Henderson, Robert, and Blum, Stefan
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- 2016
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19. A Simple and Reliable Immunohistochemical Method for Colocalization of 2 Antigens in the Same Cells of Paraffin-embedded Tissues
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Yan, Jun, Catts, Vibeke S., Chan, Anthony, and McCombe, Pamela A.
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Immunohistochemistry (IHC) lacks an efficient technique for colocalizing multiple antigens in the same cells of a single tissue section. The development of a methodology which combines the advantage of low cost, high sensitivity, and specificity would benefit clinical diagnosis and general research. On the basis of a newly published method of visualizing 2 antigens on a single paraffin-embedded tissue section, we have further developed a novel sequential technique for colocalizing 2 different antigens in a same cell in a paraffin-embedded tissue section. In this technique, we combined the microwave heating technique (MVT) with normal IHC methods to sequentially double stain a paraffin section; and colocalize 2 antigens in a single cell through result comparison stored in a digital management system. This MVT colocalization method has a higher degree of sensitivity and specificity comparable with conventional staining of both immunofluorescence and IHC systems. The primary advantage of this method is that it is inexpensive and convenient; the antibody(s) used in this method can be generated from the same or different species; it allows colocalization or comparison of different results of cell morphology for any single cell of the section on 2 images, avoids uncertainty when overlapping 2 antigens on a single image.
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- 2013
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20. Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.
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- 2022
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21. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
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Hop, Paul J., Zwamborn, Ramona A.J., Hannon, Eilis, Shireby, Gemma L., Nabais, Marta F., Walker, Emma M., van Rheenen, Wouter, van Vugt, Joke J.F.A., Dekker, Annelot M., Westeneng, Henk-Jan, Tazelaar, Gijs H.P., van Eijk, Kristel R., Moisse, Matthieu, Baird, Denis, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Ticozzi, Nicola, Ratti, Antonia, Cooper-Knock, Jonathan, Morrison, Karen E., Shaw, Pamela J., Basak, A. Nazli, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Canosa, Antonio, Brunetti, Maura, Grassano, Maurizio, Gotkine, Marc, Lerner, Yossef, Zabari, Michal, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Mora Pardina, Jesus S., Salas, Teresa, Dion, Patrick, Ross, Jay P., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Nicholson, Garth, Rowe, Dominic B., Pamphlett, Roger, Mather, Karen A., Sachdev, Perminder S., Furlong, Sarah, Garton, Fleur C., Henders, Anjali K., Lin, Tian, Ngo, Shyuan T., Steyn, Frederik J., Wallace, Leanne, Williams, Kelly L., Neto, Miguel Mitne, Cauchi, Ruben J., Blair, Ian P., Kiernan, Matthew C., Drory, Vivian, Povedano, Monica, de Carvalho, Mamede, Pinto, Susana, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Landers, John E., Shaw, Christopher E., Andersen, Peter M., McRae, Allan F., van Es, Michael A., Pasterkamp, R. Jeroen, Wray, Naomi R., McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Tsai, Ellen, Runz, Heiko, Al-Chalabi, Ammar, van den Berg, Leonard H., Van Damme, Philip, Mill, Jonathan, Veldink, Jan H., Veldink, Jan H., van den Berg, Leonard H., Moed, Matthijs, Al-Chalabi, Ammar, Wray, Naomi R., Hardiman, Orla, Chio, Adriano, and Mill, Jonathan
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation–based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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- 2022
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22. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders
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Nabais, Marta F., Laws, Simon M., Lin, Tian, Vallerga, Costanza L., Armstrong, Nicola J., Blair, Ian P., Kwok, John B., Mather, Karen A., Mellick, George D., Sachdev, Perminder S., Wallace, Leanne, Henders, Anjali K., Zwamborn, Ramona A. J., Hop, Paul J., Lunnon, Katie, Pishva, Ehsan, Roubroeks, Janou A. Y., Soininen, Hilkka, Tsolaki, Magda, Mecocci, Patrizia, Lovestone, Simon, Kłoszewska, Iwona, Vellas, Bruno, Furlong, Sarah, Garton, Fleur C., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth, Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Anderson, Tim J., Bentley, Steven R., Dalrymple-Alford, John, Fowder, Javed, Gratten, Jacob, Halliday, Glenda, Hickie, Ian B., Kennedy, Martin, Lewis, Simon J. G., Montgomery, Grant W., Pearson, John, Pitcher, Toni L., Silburn, Peter, Zhang, Futao, Visscher, Peter M., Yang, Jian, Stevenson, Anna J., Hillary, Robert F., Marioni, Riccardo E., Harris, Sarah E., Deary, Ian J., Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, van Rheenen, Wouter, van den Berg, Leonard H., Shaw, Pamela J., Shaw, Cristopher E., Morrison, Karen E., Al-Chalabi, Ammar, Veldink, Jan H., Hannon, Eilis, Mill, Jonathan, Wray, Naomi R., and McRae, Allan F.
- Abstract
Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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- 2021
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23. Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis
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Henderson, Robert D., Agosti, Jan M., McCombe, Pamela A., Thorpe, Kathryn, Heggie, Susan, Heshmat, Saman, Appleby, Mark W., Ziegelaar, Brian W., Crowe, David T., Redlich, Garry L., and Naik., Subhashchandra
- Abstract
Supplemental Digital Content is available in the text
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- 2021
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24. Gender issues in multiple sclerosis
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McCombe, Pamela A
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Multiple sclerosis is an inflammatory demyelinating disorder of the CNS that also has features of a neurodegenerative disease. Gender influences both susceptibility to multiple sclerosis and the clinical course of disease. The basis for these differences may include genetic and immunological factors. The immunological differences between men and women may be mediated through the effects of the sex hormones. It can be speculated that there may also be gender differences in the ability of males and females to repair damage in the CNS. Multiple sclerosis is also influenced by pregnancy, with fewer relapses in pregnancy and increased numbers of relapses post-partum. This effect is likely to be mediated by the hormones produced in pregnancy, which include the steroid and other pregnancy-specific hormones. Pregnancy may also lead to a more favorable clinical course of multiple sclerosis. These observations lead to the possibility of treating multiple sclerosis patients with steroid or pregnancy hormones or the growth factors foundin pregnancy.
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- 2003
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25. The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis
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White, Catherine A, McCombe, Pamela A, and Pender, Michael P
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The selective apoptotic elimination of autoreactive T cells in the central nervous system (CNS) contributes to the resolution of inflammation and the spontaneous clinical recovery from experimental autoimmune encephalomyelitis (EAE). To assess the molecular mechanisms involved in this process, we used three-colour flow cytometry to examine the expression of apoptosis-regulating proteins by inflammatory cells isolated from the spinal cords of Lewis rats immunized with myelin basic protein (MBP) and complete Freund's adjuvant. Throughout the course of the disease, which peaked 12–14 days after inoculation and was followed by clinical recovery, we analyzed the DNA content of the spinal cord inflammatory cells to assess apoptosis and, simultaneously, we measured the expression of five proteins (Fas, Fas ligand (Fas-L), Bcl-2, Bcl-x and Bax) which modulate the apoptotic process. Cells expressing the death effector molecules Fas and Fas-L were particularly prone to undergo apoptosis, and were over-represented in the apoptotic population. Of the cells expressing the cell death inhibitor Bcl-2, a low proportion were undergoing apoptosis compared to the proportion of the total inflammatory cell population undergoing apoptosis, indicating that expression of Bcl-2 protects against T cell apoptosis in this disease. There was no evidence, however, that the apoptotic regulators Bcl-x and Bax influenced the susceptibility to apoptosis. We also found that Vβ8.2+T cells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat, have a high frequency of Fas and Fas-L expression compared to other inflammatory cells. This would account for the previously demonstrated susceptibility of Vβ8.2+T cells to apoptosis in the CNS in EAE. These findings support the hypothesis that autoreactive T cells are eliminated from the CNS during spontaneous recovery from EAE by activation-induced apoptosis involving the Fas pathway.
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- 1998
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26. Macrophage Apoptosis in the Central Nervous System in Experimental Autoimmune Encephalomyelitis
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Nguyen, Kim B., McCombe, Pamela A., and Pender, Michael P.
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Using light and electron microscopy, we have demonstrated that macrophage apoptosis (programmed cell death) occurs in the central nervous system (CNS) in Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) and chronic relapsing EAE. Apoptotic macrophages were identified by the presence of an apoptotic nucleus in a cell with cytoplasm containing myelin debris but no intermediate filaments. They were found in the meninges, perivascular spaces and in the parenchyma of the white and grey matter of the spinal cord. In acute EAE the apoptotic macrophages were most frequently seen at the time of maximal neurological signs and during the early stages of clinical recovery. Several possible mechanisms may be responsible for the macrophage apoptosis: the release or withdrawal of cytokines; T-cell cytotoxicity; the effect of activated macrophage products, such as nitric oxide; and a direct effect of endogenous glucocorticoids. Macrophage apoptosis, together with the T-cell apoptosis we have previously described in the CNS in EAE, may contribute to the down-regulation of this autoimmune disease. Copyright 1994, 1999 Academic Press
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- 1994
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27. The proximal peripheral nervous system is a major site of demyelination in experimental autoimmune encephalomyelitis induced in the Lewis rat by a myelin basic protein-specific T cell clone
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Pender, Michael P., Tabi, Zsuzsanna, Nguyen, Kim B., and McCombe, Pamela A.
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Experimental autoimmune encephalomyelitis (EAE) was induced in the Lewis rat by the passive transfer of a cytotoxic CD4
+ T cell clone specific for the 72–89 peptide of guinea-pig myelin basic protein (MBP). Histological studies on rats with neurological signs showed that inflammation was present in the proximal peripheral nervous system (PNS), namely the spinal roots, as well as in the central nervous system (CNS). The main sites of demyelination were the spinal roots in the PNS, and the spinal cord root entry and exit zones in the CNS. The major involvement of the proximal PNS in autoimmune disease directed at MBP is in marked contrast to EAE induced by immunisation with myelin proteolipid protein, where the inflammation and demyelination are restricted to the CNS. These findings may have implications for the human inflammatory demyelinating diseases including multiple sclerosis, in which MBP is a putative target antigen.- Published
- 1995
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28. Long-term follow-up of patients with myasthenia gravis treated with low-dose rituximab
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Chan, Fiona, Swayne, Andrew, Gillis, David, Walsh, Michael, Henderson, Robert D, McCombe, Pamela A, Wong, Richard C, and Blum, Stefan
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- 2019
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29. Response to treatment in NMOSD: the Australasian experience
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Clarke, Laura, Bukhari, Wajih, O'Gorman, Cullen M., Khalilidehkordi, Elham, Arnett, Simon, Woodhall, Mark, Prain, Kerri M., Parratt, John D.E., Barnett, Michael H., Marriott, Mark P., McCombe, Pamela A., Sutton, Ian, Boggild, Mike, Brownlee, Wallace, Carroll, William M., Hodgkinson, Suzanne, Macdonell, Richard A.L., Mason, Deborah F., Pereira, Jennifer, Slee, Mark, Das, Chandi, Henderson, Andrew P.D., Kermode, Allan G., Lechner-Scott, Jeannette, Waters, Patrick, Sun, Jing, and Broadley, Simon A.
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•Retrospective study of treatment outcomes in AQP4 Ab positive NMOSD.•Rituximab is associated with reduced ARR compared to no treatment, beta-interferon and standard immunosuppressive therapy.•Compared to other therapies rituximab reduces risk in time to first relapse survival analyses.•Rituximab and immunosuppressive therapy are associated with a lower final EDSS score.•Rituximab should be considered as first-line therapy in AQP4 Ab positive NMOSD.
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- 2021
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30. The effectiveness of natalizumab vs fingolimod – a comparison of international registry studies
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Andersen, Johanna B, Sharmin, Sifat, Lefort, Mathilde, Koch-Henriksen, Nils, Sellebjerg, Finn, Sørensen, Per Soelberg, Pfleger, Claudia C, Rasmussen, Peter V, Jensen, Michael B, Frederiksen, Jette L, Bramow, Stephan, Mathiesen, Henrik K, Schreiber, Karen I, Horakova, Dana, Havrdova, Eva K, Alroughani, Raed, Izquierdo, Guillermo, Eichau, Sara, Ozakbas, Serkan, Patti, Francesco, Onofrj, Marco, Lugaresi, Alessandra, Terzi, Murat, Grammond, Pierre, Grand Maison, Francois, Yamout, Bassem, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Boz, Cavit, Trojano, Maria, McCombe, Pamela, Slee, Mark, Lechner-Scott, Jeannette, Turkoglu, Recai, Sola, Patrizia, Ferraro, Diana, Granella, Franco, Shaygannejad, Vahid, Prevost, Julie, Skibina, Olga, Solaro, Claudio, Karabudak, Rana, Wijmeersch, Bart V, Csepany, Tunde, Spitaleri, Daniele, Vucic, Steve, Casey, Romain, Debouverie, Marc, Edan, Gilles, Ciron, Jonathan, Ruet, Aurélie, Sèze, Jérôme D, Maillart, Elisabeth, Zephir, Hélène, Labauge, Pierre, Defer, Gilles, Lebrun, Christine, Moreau, Thibault, Berger, Eric, Clavelou, Pierre, Pelletier, Jean, Stankoff, Bruno, Gout, Olivier, Thouvenot, Eric, Heinzlef, Olivier, Al-Khedr, Abdullatif, Bourre, Bertrand, Casez, Olivier, Cabre, Philippe, Montcuquet, Alexis, Wahab, Abir, Camdessanché, Jean-Philippe, Marousset, Aude, Patry, Ivania, Hankiewicz, Karolina, Pottier, Corinne, Maubeuge, Nicolas, Labeyrie, Céline, Nifle, Chantal, Leray, Emmanuelle, Laplaud, David A, Butzkueven, Helmut, Kalincik, Tomas, Vukusic, Sandra, and Magyari, Melinda
- Abstract
Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening.
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- 2021
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31. Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics
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Iacoangeli, Alfredo, Lin, Tian, Al Khleifat, Ahmad, Jones, Ashley R., Opie-Martin, Sarah, Coleman, Jonathan R.I., Shatunov, Aleksey, Sproviero, William, Williams, Kelly L., Garton, Fleur, Restuadi, Restuadi, Henders, Anjali K., Mather, Karen A., Needham, Merilee, Mathers, Susan, Nicholson, Garth A., Rowe, Dominic B., Henderson, Robert, McCombe, Pamela A., Pamphlett, Roger, Blair, Ian P., Schultz, David, Sachdev, Perminder S., Newhouse, Stephen J., Proitsi, Petroula, Fogh, Isabella, Ngo, Shyuan T., Dobson, Richard J.B., Wray, Naomi R., Steyn, Frederik J., and Al-Chalabi, Ammar
- Abstract
We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6with ALS (p = 8.3 × 10−9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3are identified using a gene-based analysis. ACSL5has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5and GPX3single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients’ fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: −2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: −1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
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- 2020
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32. Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years
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Oh, Jiwon, Achiron, Anat, Celius, Elisabeth G., Chambers, Christina, Derwenskus, Joy, Devonshire, Virginia, Hellwig, Kerstin, Hutton, George J., McCombe, Pamela, Moore, Marie, Rog, David, Schneider, Jean-Raphael, Simm, Renata Faria, Sousa, Livia, Vincent, Stephen G., Chung, Luke, Daizadeh, Nadia, Mitchell, Colin, and Compston, D. Alastair S.
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•Normal live birth was the most common pregnancy outcome after alemtuzumab treatment•Spontaneous abortion rates were comparable with the general population•Timing of alemtuzumab exposure had no impact on the risk of spontaneous abortion•Relapse rates in alemtuzumab-treated patients increased minimally postpartum
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- 2020
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33. Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder
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Kunchok, Amy, Malpas, Charles, Nytrova, Petra, Havrdova, Eva Kubala, Alroughani, Raed, Terzi, Murat, Yamout, Bassem, Hor, Jyh Yung, Karabudak, Rana, Boz, Cavit, Ozakbas, Serkan, Olascoaga, Javier, Simo, Magdolna, Granella, Franco, Patti, Francesco, McCombe, Pamela, Csepany, Tunde, Singhal, Bhim, Bergamaschi, Roberto, Fragoso, Yara, Al-Harbi, Talal, Turkoglu, Recai, Lechner-Scott, Jeannette, Laureys, Guy, Oreja-Guevara, Celia, Pucci, Eugenio, Sola, Patrizia, Ferraro, Diana, Altintas, Ayse, Soysal, Aysun, Vucic, Steve, Grand'Maison, Francois, Izquierdo, Guillermo, Eichau, Sara, Lugaresi, Alessandra, Onofrj, Marco, Trojano, Maria, Marriott, Mark, Butzkueven, Helmut, Kister, Ilya, and Kalincik, Tomas
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Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD.
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- 2020
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34. 044 Durable clinical efficacy of alemtuzumab in patients with active rrms in the absence of continuous treatment: 7-year follow-up of CARE-MS I patients (Topaz Study)
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McCombe, Pamela, Boyko, Alexey N, DeSeze, Jéréôme, Hartung, Hans-Peter, Havrdova, Eva, Inshasi, Jihad Said, Montalban, Xavier, Pozzilli, Carlo, Selmaj, Krzysztof W, Vermersch, Patrick, Melanson, Maria, Daizadeh, Nadia, Rodriguez, Claudio E, and Wijmeersch, Bart Van
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IntroductionIn CARE-MS I (NCT00530348), alemtuzumab 12 mg/day (baseline: 5 days; 12 months later: 3 days) improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in treatment-naive relapsing-remitting MS (RRMS) patients. Efficacy was durable in a 4-y extension (NCT00930553; 95% enrolled, 92% completed), wherein patients could receive as-needed alemtuzumab retreatment for relapse/MRI activity or other disease-modifying therapies (DMTs) per investigator’s discretion. Patients completing the extension could enrol in the 5-y TOPAZ study (NCT02255656) for further evaluation. Here we examine efficacy/safety through Y7 in alemtuzumab-treated patients from CARE-MS I.MethodsIn TOPAZ, patients can receive alemtuzumab retreatment (≥12 months apart) or other DMTs (both per investigator’s discretion). MRI scans are performed annually. Assessments: annualised relapse rate (ARR); stable/improved Expanded Disability Status Scale (EDSS) from core study baseline; 6 month confirmed disability worsening (CDW); 6 month confirmed disability improvement (CDI); no evidence of disease activity (NEDA); adverse events (AEs).Results299/321 patients (93%) completed TOPAZ Y1 (Y7 after initiating alemtuzumab). ARR remained low (Y7: 0.13); 60% were relapse-free in Y3–7. The percentage of patients with stable/improved EDSS remained high (Y7: 78%). Through Y7, 74% were free from 6 month CDW, 37% achieved 6 month CDI, and the majority achieved NEDA each year (Y7: 61%). 59% received no additional treatment (alemtuzumab or other DMT) after the initial 2 courses. Overall AE incidence, infusion-associated reactions, and infections decreased over time. Thyroid AE incidence peaked in Y3 (15%) and then declined.ConclusionAlemtuzumab efficacy was maintained for 7 years in treatment-naive patients, despite 59% receiving no additional treatment since the initial 2 courses. 37% of patients also showed disability improvement. The alemtuzumab safety profile remained consistent; overall AE incidence decreased over time. Alemtuzumab may provide a unique treatment approach for RRMS patients, offering durable efficacy in the absence of continuous treatment.Study supportSanofi and Bayer HealthCare Pharmaceuticals.
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- 2018
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35. 059 Takotsubo cardiomyopathy and myasthenic crises: a case series
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Katz, Matthew, Walsh, Stephen, Tsang, Benjamin, McCombe, Pamela, and Sabet, Arman
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IntroductionTakotsubo cardiomyopathy (TCM) is an acute, reversible cardiomyopathy that can mimic acute coronary syndrome.1It is characterised by left ventricular dysfunction, electrocardiogram (ECG) changes and transient apical ballooning in the absence of significant coronary artery disease.1It is usually triggered by acute stress with catecholamine surge but the exact pathogenesis is not known.1Takotsubo cardiomyopathy has been described in patients with myasthenic crisis. We present the first and largest case series of four patients with TCM in the setting of myasthenic crisis and discuss possible causes.MethodsTwo patients from each tertiary neurologic centre were identified by their treating neurologist for inclusion in the series. We performed a review of their case notes with respect to history, examination, investigations and management. A brief literature review was also completed.ResultsThe mean age was 78 with a 1:1 female to male ratio. Three of the patients were newly diagnosed with myasthenia gravis (MG) at the time of their TCM. All patients were AChRab positive. One patient had a previous thymectomy but the others had no evidence of thymoma.On review of the literature most cases of TCM in myasthenic crisis occurred in older females. Abnormalities of the ECG were universal. Most cases did not have a thymoma or history of thymectomy.ConclusionTakotsubo cardiomyopathy may be easily overlooked in those presenting with myasthenic crises as they share overlapping clinical features. Rigorous attention to the cardiac status of these patients, especially the ECG, may help to avoid missing this important diagnosis.ReferenceAkashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation2008;118:2754–2762.
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- 2019
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36. 047 Acute lumbosacral plexopathy after blood loss in a patient with bilateral common iliac artery occlusion
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Katz, Matthew and McCombe, Pamela
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IntroductionWe present a case of a 56 year old male with bilateral, asymmetric leg weakness from ischemic lumbosacral plexopathy. This followed acute blood loss from an episode of self-harm, which occurred in the setting of chronic thrombotic occlusion of bilateral common iliac artery (CIA) stents.MethodsA detailed history, examination and neurophysiology study were performed in addition to reviewing case notes and results of other investigations. A brief literature review was also completed.ResultsThe patient presented with acute blood loss following self-inflicted lacerations to his anterior neck and both wrists. He had asymmetric flaccid, areflexic weakness of his legs with decreased sensation over the right foot and absent distal leg pulses. Magnetic resonance imaging (MRI) of brain and whole spine was normal. Computed tomography angiogram (CTA) revealed significant distal aortic atherosclerotic disease with complete occlusion of bilateral CIA stents. The patient underwent endovascular re-stenting of both common iliac arteries with a good angiographic result. An electromyogram per-formed one month later was supportive of a lumbosacral plex-opathy, mainly on the right.Only three cases of acute ischemic lumbosacral plexopathy have been reported in the setting of aorto-iliac occlusive disease.1–3ConclusionIschemic injury to the lumbosacral plexus is rare, especially outside the surgical setting as seen in this case. It is important to consider this cause in any patient presenting with rapid onset asymmetric, bilateral leg weakness as early recognition and reperfusion may prevent further damage and reduce long-term disability.ReferencesSchreuder AH, Fennis TF, Teijink JA, Koehler PJ. Lumbosacral plexopathy associated with aortoiliac occlusive disease. J Neurol. 2007;254(6):803–5.Chhetri SK, Lekwuwa G, Seriki D, Majeed T. Acute flaccid paraparesis secondary to bilateral ischaemic lumbosacral plexopathy. QJM. 2013;106(5):463–5.Yun S. Ischaemic lumbosacral plexopathy following an acute thrombosed abdominal aortic aneurysm mimicking stroke: A case report. Hong Kong Journal of Emergency Medicine. 2016;23(2):52–6.
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- 2019
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37. 002 Therapeutic lag in relapsing multiple sclerosis
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Roos, Izanne, Frascoli, Federico, Lechner-Scott, Jeannette, McCombe, Pamela, Macdonell, Richard, Butzkueven, Helmut, Malpas, Charles, and Kalincik, Tomas
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IntroductionIn multiple sclerosis (MS), treatment start or switch is prompted disease activity, often represented by relapses. Immunomodulatory therapies have potent effects on relapse rates but the time required to attain maximal effect is unclear. We aim to develop a method that allows identification of the time to full clinically manifest effect of treatment on relapses.MethodsData from MSBase, a multinational MS registry, were used. Inclusion criteria consisted of patients with remitting relapsing MS or clinically isolated syndrome (CIS), minimum 3-year pre-treatment follow up, 1-year treatment persistence, yearly review and availability of the minimum dataset. Stratified by therapy, density curves representing relapses occurrence were created. The first local minimum of the first derivative after treatment start was identified, representing stabilisation of treatment effect. Similar method was utilised to calculate the last pre-treatment point of stabilisation. Annualised relapse rates (ARR) were compared in the pre-treatment pre stabilisation and post-treatment post stabilisation periods.Results4979 eligible patients with 6218 treatment epochs were identified for analysis. Time, in years, to treatment effect was shortest for interferon beta-1a sc (0.22, 0.19–0.22), interferon beta-1b (0.24, 0.21–0.24) and fingolimod (0.26, 0.23–0.26) and longest for dimethyl fumarate (0.54, 0.51–0.54) and glatiramer acetate (0.62, 0.60–0.62). Significant differences in pre vs post treatment ARR were present for patients on natalizumab, fingolimod and dimethyl fumarate. A sequential analysis confirmed outcome stability after approximately 1000 recorded number of events.ConclusionsWe have developed a method to objectively quantify time from commencing therapy to its full effect. Time to full effect varies among therapies.
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- 2019
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38. 134 Cladribine: a multicentre long-term efficacy biomarker australian study (CLOBAS)
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Lechner-Scott, Jeannette, Maltby, Vicky, Lyndon, Amanda, Monif, Mastura, Kilpatrick, Trevor, Butzkueven, Helmut, Taylor, Bruce, McCombe, Pamela, Hodgkinson, Suzanne, Fabis-Pedrini, Marzena, Kermode, Allan, Barnett, Michael, and Kalincik, Tomas
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IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied.MethodsThis will be a multicentre, 6-year, phase IV, low interventional trial. Subjects considered for treatment with cladribine will receive an initial treatment course in year 1 and a continuing treatment course in year 2. After year 3, patients will have the option for re-dosing, if clinically indicated or to switch to another disease modifying therapy. Throughout the duration of the study we will assess blood based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation and RNA analysis as well as MRI findings (brain volume/lesion load) and cognitive performance.ResultsThis study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. The study is due to commence on March 14th.ConclusionsThis will be the first long-term efficacy trial of cladribine which offers re-initiation of therapy after the initial two courses. We expect this study will be an indication if any of the assessed biomarkers can be used to predict treatment efficacy or the need for re-initiation of Cladribine in MS patients.
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- 2019
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39. 1127 Pregnancy outcomes in alemtuzumab trials and registry design
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Rog, David, Oh, Jiwon, Chambers, Christina, Fox, Edward J, McCombe, Pamela, Otero, Susana, Margolin, David H, Kasten, Linda, and Compston, DAlastair S
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Pregnancy outcomes in patients in the alemtuzumab MS clinical development program (CAMMS223 and NCT00050778; CARE-MS I and NCT00530348; CARE-MS II and NCT00548405; CAMMS03409 and NCT00930553) were evaluated. Patients received 2 alemtuzumab courses in core studies (baseline, 5 days; 12 months later, 3 days), and optional, as-needed retreatment during extension per investigator discretion. Pregnant/lactating patients were treatment-ineligible but remained on study for safety follow-up. By December 31, 2015, 200 pregnancies occurred in 137/972 alemtuzumab-treated women, including 182 completed with known outcomes, 11 ongoing, and 7 unknown outcomes. Of completed pregnancies, 123 (68%) were live births without congenital abnormalities or birth defects; 39 (21%) spontaneous abortions, 19 (10%) elective abortions, and 1 (0.5%) stillbirth (previously reported). There was no evidence of teratogenicity, and the spontaneous abortion rate was comparable with other MS and general populations. Women are recommended to use effective contraception during alemtuzumab infusion and for 4 months after. Real-world data are currently collected by the International Lemtrada Pregnancy Exposure Registry, a prospective, noninterventional, observational safety study enrolling patients pregnant during or within 4 months of alemtuzumab exposure in ≥19 countries. It will evaluate pregnancy outcomes, including monitoring infants for adverse events for 1 year. UK pregnancy cases can be reported to: Neuroresearch.nurse@srft.nhs.uk; phone 0161-206-0534.Study Support Sanofi and Bayer HealthCare Pharmaceuticals.
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- 2017
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40. Conduction abnormalities are restricted to the central nervous system in experimental autoimmune encephalomyelitis induced by inoculation with proteolipid protein but not with myelin basic protein
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Chalk, Jonathan B., McCombe, Pamela A., and Pender, Michael P.
- Abstract
There is an error in the dose of anaesthetic given. In the last line of the second column on page 976 the dose of ketamine should be 74 mg/kg not 15 mg/kg. The doses of xylazine and atropine are correct.
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- 1995
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41. Increased Apoptosis of T Lymphocytes and Macrophages in the Central and Peripheral Nervous Systems of Lewis Rats with Experimental Autoimmune Encephalomyelitis Treated with Dexamethasone
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Nguyen, Kim B., Mccombe, Pamela A., and Pender, Michael P.
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Using light and electron microscopic histological and immunocytochemical techniques, we investigated the effects of the glucocorticoid dexamethasone on T cell and macrophage apoptosis in the central nervous system (CNS) and peripheral nervous system (PNS) of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) induced with myelin basic protein (MBP). A single subcutaneous injection of dexamethasone markedly augmented T cell and macrophage apoptosis in the CNS and PNS and microglial apoptosis in the CNS within 6 hours (h). Pre-embedding ¡mmunolabeling revealed that dexamethasone increased the number of apoptotic CD5+ cells (T cells or activated B cells), αβ T cells, and CD11b+ cells (macrophages/microglia) in the meninges, perivascular spaces, and CNS parenchyma. The induction of increased apoptosis was dose-dependent. Daily dexamethasone treatment suppressed the neurological signs of EAE. However, the daily injection of a dose of dexamethasone (0.25 mg/kg), which, after a single dose, did not induce increased apoptosis in the CNS or PNS, was as effective in inhibiting the neurological signs of EAE as the high dose (4 mg/kg), which induced a marked increase in apoptosis. This indicates that the beneficial clinical effect of glucocorticoid therapy in EAE does not depend on the induction of increased apoptosis. The daily administration of dexamethasone for 5 days induced a relapse that commenced 5 days after cessation of treatment, with the severity of the relapse tending to increase with dexamethasone dosage.
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- 1997
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42. Conduction abnormalities are restricted to the central nervous system in experimental autoimmune encephalomyelitis induced by inoculation with proteolipid protein but not with myelin basic protein
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Chalk, Jonathan B., McCombe, Pamela A., and Pender, Michael P.
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Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) and can be induced by inoculation of animals with homogenized CNS tissue or highly purified myelin proteins such as myelin basic protein (MBP) or proteolipid protein (PLP). It is widely studied as a possible animal model of multiple sclerosis. We performed the present neurophysiological study to define the location of nerve conduction abnormalities in EAE induced by immunization with PLP (PLP-EAE) and in EAE induced by immunization with MBP (MBP-EAE) in the Lewis rat. In rats with tail weakness due to acute PLP-EAE, conduction was normal in the spinal nerve roots and peripheral nerves but there was evidence of conduction block in a high proportion of the fibres in the dorsal columns of the lumbosacral spinal cord. In contrast, in acute MBP-EAE, there was conduction block in a high proportion of fibres in the sacral dorsal and ventral roots of the peripheral nervous system (PNS) and in the dorsal columns of the lumbosacral spinal cord. The distribution of nerve conduction abnormalities is consistent with previous histological studies showing that inflammation and primary demyelination are restricted to the CNS in PLP-EAE, but are present in the CNS and in the spinal roots of the PNS in MBP-EAE. The restriction of functional abnormalities to the CNS in PLP-EAE but not in MBP-EAE may have implications for the human inflammatory demyelinating diseases, including multiple sclerosis.
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- 1994
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43. Marginal reversible jump Markov chain Monte Carlo with application to motor unit number estimation.
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Drovandi, Christopher C., Pettitt, Anthony N., Henderson, Robert D., and McCombe, Pamela A.
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MARKOV chain Monte Carlo , *MOTOR unit , *NUMBER theory , *ESTIMATION theory , *DISEASE progression , *BAYESIAN analysis - Abstract
Abstract: Motor unit number estimation (MUNE) is a method which aims to provide a quantitative indicator of progression of diseases that lead to a loss of motor units, such as motor neurone disease. However the development of a reliable, repeatable and fast real-time MUNE method has proved elusive hitherto. Previously, a reversible jump Markov chain Monte Carlo (RJMCMC) algorithm has been implemented to produce a posterior distribution for the number of motor units using a Bayesian hierarchical model that takes into account biological information about motor unit activation. However this approach can be unreliable for some datasets since it can suffer from poor cross-dimensional mixing. The focus is on improved inference by marginalising over latent variables to create the likelihood. More specifically, the emphasis is on how this marginalisation can improve the RJMCMC mixing and that alternative approaches that utilise the likelihood (e.g. DIC) can be investigated. For this model the marginalisation is over latent variables which, for a larger number of motor units, is an intractable summation over all combinations of a set of latent binary variables whose joint sample space increases exponentially with the number of motor units. A tractable and accurate approximation for this quantity is provided and also other approximations based on Monte Carlo estimates that can be incorporated into RJMCMC are investigated. [Copyright &y& Elsevier]
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- 2014
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