TY - JOUR
T1 - Longitudinal Metabolite Changes in Progressive Multiple Sclerosis
T2 - A Study of 3 Potential Neuroprotective Treatments
AU - John, Nevin A.
AU - Solanky, Bhavana S.
AU - de Angelis, Floriana
AU - Parker, Richard A.
AU - Weir, Christopher J.
AU - Stutters, Jonathan
AU - Carrasco, Ferran Prados
AU - Schneider, Torben
AU - Doshi, Anisha
AU - Calvi, Alberto
AU - Williams, Thomas
AU - Plantone, Domenico
AU - Monteverdi, Anita
AU - MacManus, David
AU - Marshall, Ian
AU - Barkhof, Frederik
AU - Gandini Wheeler-Kingshott, Claudia A. M.
AU - Chataway, Jeremy
N1 - Funding Information: The authors would like to thank all the participants of the MS‐SMART trial. Particularly, thanks to Marios Yiannakis, Almudena Garcia Gomez, Rebecca Samson, and Marcello Moccia. They would also like to thank the MS‐SMART investigators: Sebastien Ourselin, Marie Braisher, Tiggy Beyene, Vanessa Bassan, Alvin Zapata (Queen Square Multiple Sclerosis Centre, University College London and University College London Hospitals NHS Foundation Trust, London, UK); Siddharthan Chandran, Peter Connick, Dawn Lyle, James Cameron, Daisy Mollison, Shuna Colville, Baljean Dhillon (Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK); Moira Ross, Gina Cranswick, Allan Walker, Lorraine Smith (Edinburgh Clinical Trials Unit [ECTU], Usher Institute, University of Edinburgh, Edinburgh, UK); Gavin Giovannoni, Sharmilee Gnanapavan (Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, Barts Health NHS Trust, London, UK); Richard Nicholas (Imperial College Healthcare NHS Trust, London, UK); Waqar Rashid, Julia Aram (Brighton and Sussex University Hospitals NHS Trust, Brighton, UK); Helen Ford (Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK); Sue H Pavitt (Dental Translational and Clinical Research Unit, University of Leeds, Leeds, UK); James Overell (The Queen Elizabeth University Hospital Glasgow, NHS Greater Glasgow and Clyde, Glasgow, UK); Carolyn Young, Heinke Arndt (The Walton Centre NHS Foundation Trust, Liverpool, UK); Martin Duddy, Joe Guadagno (Royal Victoria Infirmary, The Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, UK); Nikolaos Evangelou (Queens Medical Centre, Nottingham University Hospital NHS Trust, Nottingham, UK); Matthew Craner, Jacqueline Palace (John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK); Jeremy Hobart (Derriford Hospital, University Hospitals Plymouth NHS Trust, Plymouth, UK); Basil Sharrack, David Paling (Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK); Clive Hawkins, Seema Kalra (Royal Stoke University Hospital, University Hospitals of North Midlands NHS Trust, Stoke‐on‐Trent, UK); Brendan McLean (Royal Cornwall Hospitals NHS Trust, Truro, UK); Nigel Stallard (Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK); and Roger Bastow (patient representative). MS‐SMART is an investigator‐led project sponsored by University College London (UCL). This independent research is awarded by the Efficacy and Mechanism Evaluation Programme (EME 11/30/11) and funded by the Medical Research Council (MRC), the UK Multiple Sclerosis Society, and the National Multiple Sclerosis Society (USA NMSS) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC‐NIHR partnership. Additional support comes from the University of Edinburgh; the National Institute for Health Research University College London Hospitals (NIHR‐UCLH), Biomedical Research Centre (BRC), and University College London; and NIHR Leeds CRF (DenTCRU). They also acknowledge the support provided the Edinburgh Clinical Trials Unit (ECTU), MS Clinical Trials Network (MS CTN), and the QSMSC NMR/MRI analysis centre. C.J.W. and R.A.P. were supported in this work by NHS Lothian via the Edinburgh Clinical Trials Unit. B.S. is funded by Wings for Life. Riluzole was provided without charge by Sanofi‐Genzyme who was not involved in either the trial design, running of the trial, or analysis. Publisher Copyright: © 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.
PY - 2023
Y1 - 2023
N2 - Background: 1H-magnetic resonance spectroscopy ( 1H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). Purpose: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1H-MRS and their association with clinical disability in SPMS. Study-Type: Longitudinal. Population: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. Field Strength/Sequence: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. Assessment: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. Statistical Tests: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. Results: In the placebo arm, tCho increased in GM (mean difference = −0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = −0.21); in the riluzole arm, GM Glx (β = −0.25) and Glx/tCr (β = −0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. Data Conclusion: 1H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. Level of Evidence: 1. Technical Efficacy: Stage 4.
AB - Background: 1H-magnetic resonance spectroscopy ( 1H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). Purpose: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1H-MRS and their association with clinical disability in SPMS. Study-Type: Longitudinal. Population: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. Field Strength/Sequence: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. Assessment: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. Statistical Tests: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. Results: In the placebo arm, tCho increased in GM (mean difference = −0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = −0.21); in the riluzole arm, GM Glx (β = −0.25) and Glx/tCr (β = −0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. Data Conclusion: 1H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. Level of Evidence: 1. Technical Efficacy: Stage 4.
KW - imaging biomarker
KW - magnetic resonance spectroscopy
KW - multiple sclerosis
KW - secondary progressive multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=85171752554&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jmri.29017
DO - https://doi.org/10.1002/jmri.29017
M3 - Article
C2 - 37787109
SN - 1053-1807
JO - Journal of magnetic resonance imaging
JF - Journal of magnetic resonance imaging
ER -