Pamela A. Mccombe

JAMA neurology • April 14, 2025

Jannis Müller, Sifat Sharmin, Johannes Lorscheider, Serkan Ozakbas, Rana Karabudak, Dana Horakova, Bianca Weinstock Guttman, Vahid Shaygannejad, Masoud Etemadifar, Raed Alroughani, Francesco Patti, Sara Eichau, Alexandre Prat, Alessandra Lugaresi, Valentina Tomassini, Allan Kermode, Maria Amato, Recai Turkoglu, Ayse Altintas, Katherine Buzzard, Aysun Soysal, Anneke Van Der Walt, Helmut Butzkueven, Yolanda Blanco, Oliver Gerlach, Samia Khoury, Michael Barnett, Nevin John, Jeannette Lechner Scott, Matteo Foschi, Andrea Surcinelli, Vincent Van Pesch, Julie Prevost, Maria Sa, Davide Maimone, Marie D'hooghe, Stella Hughes, Suzanne Hodgkinson, Chris Mcguigan, Elisabetta Cartechini, Bruce Taylor, Daniele Spitaleri, Mark Slee, Pamela Mccombe, Bassem Yamout, Pascal Benkert, Jens Kuhle, Ludwig Kappos, Izanne Roos, Tomas Kalincik, Marc Girard, Pierre Duquette, Marzena Fabis Pedrini, William Carroll, Olga Skibina, Riadh Gouider, Saloua Mrabet, Cristina Ramo Tello, Claudio Solaro, Mario Habek, Bart Van Wijmeersch, Radek Ampapa, Richard Macdonell, Celia Oreja Guevara, Koen De Gans, Guy Laureys, Jiwon Oh, Justin Garber, Orla Gray, Eduardo Agüera Morales, Jose Sanchez Menoyo, Tamara Castillo Triviño, Nikolaos Grigoriadis, Thor Petersen, Todd Hardy, Steve Vucic, Stephen Reddel, Sudarshini Ramanathan, Abdullah Al Asmi, Mihaela Simu, Seyed Baghbanian, Dieter Poehlau, Talal Al Harbi, Juan Rojas, Norma Deri, Patrice Lalive, Melissa Cambron, Tunde Csepany, Neil Shuey, Barbara Willekens, Cameron Shaw, Danny Decoo, Jennifer Massey, Özgür Yaldizli, Tobias Derfuss, Cristina Granziera

Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results. To compare various definitions of PIRA. This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments. Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at/above worsening score or at/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation). For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years). Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months. Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.

Computers In Biology And Medicine • March 05, 2025

Thomas Shaw, Fernanda Ribeiro, Xiangyun Zhu, Patrick Aiken, Saskia Bollmann, Steffen Bollmann, Jeryn Chang, Kali Chidley, Harriet Dempsey Jones, Zeinab Eftekhari, Jennifer Gillespie, Robert Henderson, Matthew Kiernan, Ira Ktena, Pamela Mccombe, Shyuan Ngo, Shana Taubert, Brooke-mai Whelan, Xincheng Ye, Frederik Steyn, Sicong Tu, Markus Barth

This work addresses the challenge of reliably measuring the muscles of the human tongue, which are difficult to quantify due to complex interwoven muscle types. We introduce a new semi-automated method, enabled by a manually curated dataset of MRI scans to accurately measure five key tongue muscles, combining AI-assisted, atlas-based, and manual segmentation approaches. The method was tested and validated in a dataset of 178 scans and included segmentation validation (n = 103) and clinical application (n = 132) in individuals with motor neuron disease. We show that people with speech and swallowing deficits tend to have smaller muscle volumes and present a normalisation strategy that removes confounding demographic factors, enabling broader application to large MRI datasets. As the tongue is generally covered in neuroimaging protocols, our multi-contrast pipeline will allow for the post-hoc analysis of a vast number of datasets. We expect this work to enable the investigation of tongue muscle morphology as a marker in a wide range of diseases that implicate tongue function, including neurodegenerative diseases and pathological speech disorders.

Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration • March 01, 2025

Lauren Buckett, Cory Holdom, Stephanie Howe, Pamela Mccombe, Robert Henderson, Ammar Al Chalabi, Frederik Steyn, Shyuan Ngo

Objective: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Little is known about factors that contribute to fatigue, and whether levels of fatigue change throughout disease course. We aimed to determine associations between self-reported perceived fatigue and metabolic and clinical features of ALS, and perceived fatigue over the course of disease. Methods: This prospective study was conducted between July 2017 and March 2024. Baseline measures of self-reported perceived fatigue, metabolic rate, and clinical measures of disease were assessed in 117 participants with clinically definite or probable ALS. For comparison, fatigue and metabolic rate were collected from 107 control participants. Perceived fatigue was determined using the Fatigue Severity Scale (FSS). Metabolic rate was assessed using indirect calorimetry. Functional capacity and clinical progression were assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Results: Baseline levels of perceived fatigue were greater in people living with ALS (plwALS) when compared to controls (5.44 vs. 2.55; p < 0.01). Perceived fatigue was higher in plwALS with lower ALSFRS-R scores and was not associated with measures of metabolism. For most plwALS, perceived fatigue remained high as functional capacity worsened. Conclusion: Our findings confirm higher prevalence of perceived fatigue in plwALS, with persistently high FSS scores reported by most patients during follow-up. High levels of fatigue were not associated with hypermetabolism, suggesting that metabolic rate is unlikely to be a primary contributor. Results highlight a need for further research to identify factors that contribute to fatigue in ALS, and options for improved fatigue management.

NPJ Digital Medicine • February 13, 2025

Ashkan Pirmani, Edward De Brouwer, Ádám Arany, Martijn Oldenhof, Antoine Passemiers, Axel Faes, Tomas Kalincik, Serkan Ozakbas, Riadh Gouider, Barbara Willekens, Dana Horakova, Eva Havrdova, Francesco Patti, Alexandre Prat, Alessandra Lugaresi, Valentina Tomassini, Pierre Grammond, Elisabetta Cartechini, Izanne Roos, Cavit Boz, Raed Alroughani, Maria Amato, Katherine Buzzard, Jeannette Lechner Scott, Joana Guimarães, Claudio Solaro, Oliver Gerlach, Aysun Soysal, Jens Kuhle, Jose Sanchez Menoyo, Daniele Spitaleri, Tunde Csepany, Bart Van Wijmeersch, Radek Ampapa, Julie Prevost, Samia Khoury, Vincent Van Pesch, Nevin John, Davide Maimone, Bianca Weinstock Guttman, Guy Laureys, Pamela Mccombe, Yolanda Blanco, Ayse Altintas, Abdullah Al Asmi, Justin Garber, Anneke Van Der Walt, Helmut Butzkueven, Koen De Gans, Csilla Rozsa, Bruce Taylor, Talal Al Harbi, Attila Sas, Cecilia Rajda, Orla Gray, Danny Decoo, William Carroll, Allan Kermode, Marzena Fabis Pedrini, Deborah Mason, Angel Perez Sempere, Mihaela Simu, Neil Shuey, Bhim Singhal, Marija Cauchi, Todd Hardy, Sudarshini Ramanathan, Patrice Lalive, Carmen-adella Sirbu, Stella Hughes, Tamara Castillo Trivino, Liesbet Peeters, Yves Moreau

Early prediction of disability progression in multiple sclerosis (MS) remains challenging despite its critical importance for therapeutic decision-making. We present the first systematic evaluation of personalized federated learning (PFL) for 2-year MS disability progression prediction, leveraging multi-center real-world data from over 26,000 patients. While conventional federated learning (FL) enables privacy-aware collaborative modeling, it remains vulnerable to institutional data heterogeneity. PFL overcomes this challenge by adapting shared models to local data distributions without compromising privacy. We evaluated two personalization strategies: a novel AdaptiveDualBranchNet architecture with selective parameter sharing, and personalized fine-tuning of global models, benchmarked against centralized and client-specific approaches. Baseline FL underperformed relative to personalized methods, whereas personalization significantly improved performance, with personalized FedProx and FedAVG achieving ROC-AUC scores of 0.8398 ± 0.0019 and 0.8384 ± 0.0014, respectively. These findings establish personalization as critical for scalable, privacy-aware clinical prediction models and highlight its potential to inform earlier intervention strategies in MS and beyond.

Brain : A Journal Of Neurology

Tomas Kalincik, Sifat Sharmin, Izanne Roos, Mark Freedman, Harold Atkins, Jennifer Massey, Ian Sutton, Barbara Withers, Joachim Burman, Øivind Torkildsen, Lars Bø, Anne Lehmann, Eva Havrdova, Eva Krasulova, Marek Trneny, Tomas Kozak, Richard Macdonell, J William Brown, Alasdair Coles, Anneke Van Der Walt, Helmut Butzkueven, Bart Van Wijmeersch, Jeannette Lechner Scott, Michael Barnett, Guy Laureys, Barbara Willekens, Katherine Buzzard, Olga Skibina, Maria Di Gregorio, Suzanne Hodgkinson, Serkan Ozakbas, Jose Meca Lallana, Raed Alroughani, Julie Prevost, Matteo Foschi, Andrea Surcinelli, Stefano Neri, Sara Eichau, Pamela Mccombe, Nevin John, Simón Cárdenas Robledo, Jiwon Oh, Jose Sanchez Menoyo, Francesco Patti, Oliver Gerlach, Yolanda Blanco, Pierre Grammond, Basil Sharrack, John Snowden

In the treatment of relapsing-remitting multiple sclerosis, autologous hematopoietic stem cell transplant and immune-reconstitution therapies show several similarities. These treatment strategies have not yet been compared head-to-head. This study emulated pairwise trials of comparative effectiveness of stem cell transplant vs. immune-reconstitution therapies cladribine and alemtuzumab. This cohort/registry study of comparative treatment effectiveness included data from 7 specialist multiple sclerosis centres with autologous hematopoietic stem cell programs (RESCUE-MS) and international MSBase registry during 2006-2023. The study included patients with relapsing-remitting multiple sclerosis treated with autologous hematopoietic stem cell transplant, cladribine or alemtuzumab, with a minimum of 2-month follow-up before commencing study therapy and ≥2 disability assessments after commencing the study therapy. Patients were matched on a propensity score derived from their clinical and demographic characteristics. The matched groups were compared on annualised relapse rates freedom from relapses and 6-month confirmed disability worsening and improvement (measured with Expanded Disability Status Scale). The matching of 143 (stem cell) to 283 cladribine-treated patients and of 134 (stem cell) to 562 alemtuzumab-treated patients reduced the measured differences between the groups by 98% and 96%, respectively. The matched patients had high mean disease activity (>0.8 relapses in the prior 2 years), mean Expanded Disability Status Scale scores of 3-4, and were followed-up for a mean of 3.8-3.9 (stem cell), 1.9 (cladribine) or 4.5 years (alemtuzumab). Compared to cladribine, stem cell transplant was associated with a lower risk of relapses (mean annualised relapse rate ± standard deviation 0.05±0.28 vs. 0.16±0.39, respectively; hazard ratio 0.24, 95% confidence interval 0.15-0.41), similar risk of disability worsening (hazard ratio 0.70, 95% confidence interval 0.34-1.43) and higher probability of disability improvement (hazard ratio 2.19, 95% confidence interval 1.31-3.66). Compared to alemtuzumab, stem cell transplant was associated with a lower risk of relapses (mean annualised relapse rate ± standard deviation 0.04±0.23 vs. 0.09±0.21, respectively; hazard ratio 0.52, 95% confidence interval 0.29-0.93), similar risk of disability worsening (hazard ratio 0.95, 95% confidence interval 0.53-1.72) and higher probability of disability improvement (hazard ratio 2.03, 95% confidence interval 1.23-3.34). 34% of patients treated with stem cell transplant experienced delayed complications, mainly infections. No treatment-associated deaths were reported. Among patients with active relapsing-remitting multiple sclerosis and moderate disability, autologous hematopoietic stem cell transplant is superior to cladribine and alemtuzumab at suppressing relapses and enabling recovery of neurological function. The high effectiveness of stem cell transplant is likely attributable to a complex interplay of immune suppression and reconstitution.