Brain reserve against physical disability progression over five years in multiple sclerosis
James F. Sumowski, Ph.D.1 2
Maria A. Rocca, M.D.3 4
Victoria M. Leavitt, Ph.D.5
Alessandro Meani 3
Sarlota Mesaros, M.D.6
Jelena Drulovic, M.D.6
Paolo Preziosa, MD 3
Christian G. Habeck, Ph.D.5
Massimo Filippi, M.D.3 4
1 Department of Health and Behavior Studies, Teachers College, Columbia University, New York, NY, USA.
2 Manhattan Memory Center, New York, NY.
3 Neuroimaging Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
4 Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
5Department of Neurology, Columbia University Medical Center, New York, NY, USA.
6 Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Correspondence should be addressed to:
James F. Sumowski, Ph.D.
Department of Health and Behavior Studies
Teachers College, Columbia University
525 West 120th Street
New York, New York 10027
E-mail:
Supplemental File / Text: Appendix (appendix e-1), Tables e-1 & e-2, Figure e-1
SUPPLEMENTAL TEXT / DISCUSSION
The observed link between smaller MLBG (ICV) and increased risk for physical disability progression informs research on disability in MS, including clinical trials. Recruitment of patients at greatest risk for disability progression (smaller MLBG) into clinical trials may improve statistical power, as the efficacy of treatments to attenuate disability is assessed relative to control groups. If there is little disability progression within a control group, beneficial effects of efficacious treatments may not be observed. Differential risk for disability progression may explain mixed effects of treatments on disability outcomes (EDSS). For instance, pairs of phase-three clinical trials support beneficial effects of fingolimod,1, 2 dimethyl fumarate,3, 4 and alemtuzumab5, 6 on annualized relapse rates and lesion accumulation relative to controls; however, for each agent, one trial protected against disability progression,1, 3, 5 while the other did not.2, 4, 6 Treatments successfully protected against disability when there was more disability progression to attenuate, but not when risk for progression was lower (based on progression in control groups: 24.1%1 vs. 7.9%;2 27%3 vs 17%;4 20%5 vs. 11%6). Our Serbian sample mimics a control group, as patients were not treated with DMDs. Based on our results, recruitment of patients with smaller MLBG may increase statistical power of clinical trials by increasing risk for disability progression. Researchers may also statistically control for MLBG in data analyses, which may improve power by eliminating unexplained variance in disability outcomes.
TABLE e-1. Demographic and disease burden differences between patients with smaller versus larger MLBG (ICV). Independent t-tests and chi square tests were used as appropriate.
Smaller MLBGLarger MLBGP-Value
Age 42.9 ± 9.942.7 ± 12.0.930
Sex (F:M)19:720:6.749
Age of Diagnosis33.4 ± 10.131.5 ± 12.1.551
Education (Years)13.2 ± 2.513.4 ± 2.5.743
Disease Duration9.5 ± 9.311.1 ± 10.1.560
Phenotype (RR:SP:PP)13:5:819:2:5.212
nBV cm31533.2 ± 105.61499.9 ± 109.2.270
PBVC-4.4 ± 3.3-4.9 ± 4.4.632
T2LV cm316.0 ± 13.418.5 ± 18.1.567
T2LV cm3 Change1.4 ± 5.81.8 ± 6.4.832
TABLE e-2. Demographic and disease burden differences between patients showing disability progression versus patients who remained stable. Independent t-tests and chi square tests (sex, phenotype) were used as appropriate. By design, change in EDSS was greater within the group who progressed (1.41 ± 0.93, median change = 1.0, range: 0.5 to 3.0) than those who remained stable (-0.19 ± 0.66, median change = 0.0, range: -1.5 to 0.5). There was also a marginal difference in baseline EDSS scores (p=.059) whereby disability was worse in patients who subsequently progressed (4.0 ± 2.2, median = 3.75, range: 0.0 to 7.5) relative to patients who remained stable (3.0 ± 1.4, median = 2.5, range: 1.0 to 6.5).
StableProgressedP-Value
Age 41.2± 11.844.0± 10.2.360
Sex (F:M)19:520:8.521
Age of Diagnosis32.0± 10.232.8 ± 11.8.779
Education (Years)13.9 ± 2.312.9 ± 2.6.151
Disease Duration9.3 ± 10.711.2 ± 8.8.478
Phenotype (RR:SP:PP)20:2:112:11:6.011
nBV cm31553.4 ± 108.61487.2 ± 99.2.026
PBVC-3.0 ± 2.9-5.9 ± 4.1.006
T2LV cm310.2 ± 11.022.8 ± 17.0.003
T2LV cm3 Change0.05 ± 4.332.86 ± 6.98.097
Figure e-1. Scatterplot of EDSS change for individual patients within smaller (red) and larger (blue) MLBG groups.The red and blue lines represent the mean change for smaller and larger MLBG groups, respectively. Note that some patients with larger MLBG showed less disability at follow-up than baseline, which is consistent the idea mentioned within the Introduction that greater degrees of freedom afforded by more neurons (and synapses) may support compensatory plasticity in the face of disease-related changes (and related disability). This notion, however, requires additional attention in future research with larger samples.
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