Giorgia Querin1,2,3, Timothée Lenglet4,5, Rabab Debs4, Tanya Stojkovic1, Anthony Behin1, François Salachas5, Nadine Le Forestier5,6, Maria Del Mar Amador5, Gaëlle Bruneteau5, Pascal Laforêt7,8, Sophie Blancho9, Véronique Marchand-Pauvert2, Peter Bede2,5,10, Jean-Yves Hogrel11, Pierre-François Pradat12,13,14,15. 1. Centre de Référence Maladies Neuromusculaires Paris-Est, APHP, Hôpital Pitié-Salpêtrière, Service de Neuromyologie, Paris, France. 2. Laboratoire D'Imagerie Biomédicale, Sorbonne Université, CNRS, INSERM, Paris, France. 3. Institut de Myologie, I-Motion Adultes Plateforme, Paris, France. 4. Département de Neurophysiologie, APHP, Hôpital Pitié-Salpêtrière, Paris, France. 5. APHP, Centre Référant SLA, Hôpital Pitié-Salpêtrière, Paris, France. 6. Département de Recherche en Éthique, EA 1610: Etudes Des Sciences Et Techniques, Université Paris Sud/Paris Saclay, Paris, France. 7. Neurology Department, Nord/Est/Ile de France Neuromuscular Center, Raymond-Poincaré Hospital, Garches, France. 8. INSERM U1179, END-ICAP, Versailles Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France. 9. Institut Pour La Recherche Sur La Moelle Epinière Et L'Encéphale (IRME), Paris, France. 10. Computational Neuroimaging Group, Academic Unit of Neurology, Trinity College, Dublin, Ireland. 11. Institute of Myology, Neuromuscular Investigation Center, Paris, France. 12. Laboratoire D'Imagerie Biomédicale, Sorbonne Université, CNRS, INSERM, Paris, France. pierre-francois.pradat@aphp.fr. 13. APHP, Centre Référant SLA, Hôpital Pitié-Salpêtrière, Paris, France. pierre-francois.pradat@aphp.fr. 14. Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, Altnagelvin Hospital, Derry/Londonderry, C-TRIC, UK. pierre-francois.pradat@aphp.fr. 15. Département de Neurologie, 47 Boulevard de l'sHôpital, 75634, Paris cedex 13, France. pierre-francois.pradat@aphp.fr.
Abstract
OBJECTIVE: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials. METHODS: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables. RESULTS: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials. CONCLUSIONS: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.
OBJECTIVE: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials. METHODS: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables. RESULTS: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials. CONCLUSIONS: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.
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