DMT54
Baseline MRI Predictors of Cognitive Processing Speed in Participants with Secondary Progressive Multiple Sclerosis from the Phase 3 Expand Study

Tuesday, October 26, 2021
Exhibit Hall (Rosen Shingle Creek)
Ralph H.B. Benedict, PhD , Jacobs Multiple Sclerosis Center, University at Buffalo, Buffalo, NY
Iris-Katharina Penner, PhD , Medical Faculty, Department of Neurology, Heinrich Heine University, COGITO Center for Applied Neurocognition and Neuropsychological Research, Dusseldorf, Germany
Ludwig Kappos, MD , Neurologic Clinic and Policlinic and Research Center for Clinical Neuroimmunology and Neuroscience, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland
Patrick Vermersch, MD, PhD , FHU Imminent, Univ. Lille, Inserm UMR U1172 LilNCog, CHU Lille, Lille, France
Bruce A.C. Cree, MD, PhD, MAS , UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA
Ralf Gold, MD , Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
Amit Bar-Or, MD , Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Daniela Piani-Meier, PhD , Novartis Pharma AG, Basel, Switzerland
Shannon Ritter, MS , Novartis Pharma AG, Basel, Switzerland
Sophie Arnould, MSc , Novartis Pharma AG, Basel, Switzerland
Goeril Karlsson, PhD , Novartis Pharma AG, Basel, Switzerland
Frank Dahlke, MD , Novartis Pharma AG, Basel, Switzerland
Thomas Hach, MD , Novartis Pharma AG, Basel, Switzerland
Robert J. Fox, MD , Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH
Douglas L. Arnold, MD , NeuroRx Research, Montreal, QC, Canada, Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada



Background:

Siponimod showed beneficial effects on magnetic resonance imaging (MRI) lesion activity, total brain and gray matter (GM) atrophy, MTR measures and cognitive processing speed in secondary progressive multiple sclerosis (SPMS) participants from the EXPAND study.

Objectives:

To explore the predictive value of a variety of MRI measures of brain tissue damage on time-to-6-month confirmed ≥4-points cognitive worsening/improvement on Symbol Digit Modalities Test (SDMT; 6mCWSDMT/6mCISDMT) in siponimod-treated SPMS EXPAND study participants over short- (Core) and long-term (Core+Extension) periods (total up-to-5 years).

Methods:

Siponimod-treated participants (MRI cohort [N=1099]; MTR cohort [n=402]) were stratified into quartiles of Baseline total normalized brain volume (NBV), cortical GM (cGM) and thalamic volume, T1-hypointense lesion volume (T1HLV), T2-lesion volume (T2LV), median normalized MTR of normal appearing brain tissue (nMTR-NABT), normal-appearing white matter (NAWM) and cGM, and by absence/presence of gadolinium-enhancing (Gd+) T1 lesions. 6mCWSDMT/6mCISDMT and absolute SDMT change from Baseline were analyzed by Cox-regression analysis with respective outcome as Baseline covariate comparing worst (WQ) vs best quartile (BQ).

Results:

Over both short- and longer-terms, thalamic and cGM volume were the strongest MRI predictors of 6mCW for participants in the worst vs best quartile (HRWQ/BQ range: 1.46–2.30, p<0.05 for both); participants in WQ of nMTR (cGM, NAWM and NABT), T1HLV, T2LV and thalamic volume were significantly less likely to experience 6mCI (HRWQ/BQ range: 0.24–0.52, p<0.0120 for all). All parameters except Gd+ T1 lesions at Baseline were significantly associated with absolute SDMT change, which showed strongest association for thalamic volume followed by T1HLV, T2LV and nMTR-NABT (delta rangeWQ/BQ: 4.19–6.15; all p≤0.0005 except nMTR-NABT p=0.0107).

Conclusions:

Baseline GM volume (especially thalamic volume), and MTR-reflected myelination were associated with clinically meaningful worsening and improvement in cognitive processing speed in siponimod-treated SPMS participants, suggesting relevance as prognostic MRI measures of decline in cognitive processing speed both in short and longer-terms.

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