Title

Water T2 could predict functional decline in patients with dysferlinopathy

Authors

Ursula Moore, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Ericky Caldas de Almeida Araújo, NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology, Paris, France.
Harmen Reyngoudt, NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology, Paris, France.
Heather Gordish-Dressman, Center for Translational Science, Division of Biostatistics and Study Methodology, Children's National Health System, Washington, DC, USA.
Fiona E. Smith, Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Ian Wilson, Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Meredith James, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Anna Mayhew, The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Laura Rufibach, Jain Foundation, Seattle, WA, USA.
John W. Day, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Kristi J. Jones, The Children's Hospital at Westmead and The University of Sydney, Sydney, NSW, Australia.
Diana X. Bharucha-Goebel, Department of Neurology, Children's National Health System, Washington, DC, USA.
Emmanuelle Salort-Campana, Service des maladies neuromusculaire et de la SLA, Hôpital de La Timone, Marseille, France.
Alan Pestronk, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Maggie C. Walter, Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
Carmen Paradas, Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain.
Tanya Stojkovic, Centre de référence des maladies neuromusculaires, Institut de Myologie, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Madoka Mori-Yoshimura, Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
Elena Bravver, Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, NC, USA.
Elena Pegoraro, Department of Neuroscience, University of Padova, Padua, Italy.
Jerry R. Mendell, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Document Type

Journal Article

Publication Date

9-4-2022

Journal

Journal of cachexia, sarcopenia and muscle

DOI

10.1002/jcsm.13063

Keywords

Limb girdle muscular dystrophy; Limb girdle muscular dystrophy 2B; Limb girdle muscular dystrophy R2; Magnetic resonance imaging; Water T2

Abstract

BACKGROUND: Water T2 (T2 ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2 to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2 value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2 at baseline, age, disease duration, and baseline function. RESULTS: A higher T2 at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2 in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2 (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2 (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2 did not correlate with current functional ability. However, T2 at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2 measure at baseline. Significant challenges remain in standardizing T2 values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2 could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Department

Genomics and Precision Medicine

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