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Useful MRI Outcome Measure in Progressive MS Clinical Trials (ACTRIMS 2016)

A variety of MRI measurement techniques may provide useful outcome measures for clinical trials in patients with progressive MS, according to a presentation at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, held February 18-20 in New Orleans.

New white matter lesions visualized with MRI are indicators for relapses in patients with relapse-remitting multiple sclerosis (MS) and have greatly enhanced the ability to measure efficacy of potential therapeutics in clinical trials. However, patients with progressive MS do not show many new white matter lesions. In progressive MS, a single MRI outcome measure has not been identified.

In progressive MS there is a slow and steady decrease in brain tissue accompanied by a small increase (0.5% per year) in cerebrospinal fluid (CSF), explained Daniel S. Reich, MD, PhD, from the National Institute of Neurological Disorders and Stroke, National Institutes of Health. Many studies have shown that this brain atrophy correlates with disability.[1]

There is a steady loss of brain gray matter volume over time, however, time there is very little concurrent change in white matter volume. Therefore, the enlargement of CSF volume could act as a surrogate for brain matter volume. Brain-free water imaging, heavily T2-weighted images, can primarily image CSF.[2] This fraction more strongly correlated with clinical measures, such as disability, compared to T1-derived results. Dr. Reich explained that “one approach to improving our ability to assessing brain volume over time might be to more specifically look at this surrogate in the CSF.” An improved ability to measure cerebral atrophy might lead to shorter clinical trials.

Dr. Reich also mentioned another approach to measuring cerebral atrophy in progressive MS patients, thalamic volume. Unpublished data from the EPIC MS study showed that mean thalamic volume decreased over time in MS patients (0.75% per year) while there were no changes in thalamic volume in healthy controls.

Next, Dr. Reich summarized clinical trial data from ongoing clinical trials that are using brain atrophy as the primary outcome measure in patients with progressive MS. All of the ongoing trials are using whole-brain measurements to assess brain atrophy. Although atrophy can demonstrate neurodegeneration, it does not provide insight into underlying mechanisms.

“When thinking about proof-of-concept trials it’s really important, at this stage in development of MS therapeutics, to favor sensitivity over specificity,” stated Dr. Reich. He suggested that proof-of-concept trials do not need to demonstrate mechanisms already established through preclinical work because it might not be possible with current clinical trial techniques. Instead he suggested that research should focus on outcomes.

Dr. Reich also described some preliminary work to improve sensitivity and reliability through lesion-based measurement.[3] There are a few ongoing and completed trials using lesion repair as the primary outcome. However, more research is necessary to determine whether lesion-based outcomes can predict efficacy in patients with progressive MS.

Dr. Reich explained that new lesions are the standard outcome measure for clinical trials in patients with relapse-remitting MS. In progressive MS, a single measure may not be achievable due to the heterogeneity of mechanisms underlying the disease. Methods and outcome measures should be tailored to the specific research questions. Dr. Reich also suggested that parallel preclinical studies using similar imaging methods in appropriate models would also be useful.

Dr. Reich concluded that there are 2 reasonable classes of outcome measures: volume-based (atrophy) and lesion-based. Additionally, there are 3 principles for designing clinical trials for progressive MS; favor sensitivity over specificity in proof-of-concept trials, consider early-phase studies in early active MS, and use MRI to identify informative trial participants.


Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014 Jan;75(1):43-9.

Gao KC, Nair G, Cortese IC, Koretsky A, Reich DS. Sub-millimeter imaging of brain-free water for rapid volume assessment in atrophic brains. Neuroimage. 2014 Oct 15;100:370-8.

Reich DS, White R, Cortese IC, Vuolo L, Shea CD, Collins TL, Petkau J. Sample-size calculations for short-term proof-of-concept studies of tissue protection and repair in multiple sclerosis lesions via conventional clinical imaging. Mult Scler. 2015 Nov;21(13):1693-704.

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About the Editors

  • Prof Timothy Vartanian

    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
  • Dr Rebecca Farber

    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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