Gray Matter Atrophy May Serve as an Effective Outcome Measure for MS Clinical Trials

According to Dr. Rudick, conventional MRI techniques almost entirely overlook gray matter pathology, even though 65% of the brain is composed of gray matter. “As a result, all of our focus has been on white matter, and the conventional MRI really just visualizes a small portion of the underlying pathology. [Gray matter pathology] is truly a Trojan horse in MS.”

Although gray matter lesions are still difficult to measure and not discernable using traditional MRI, gray matter atrophy appears to be a highly feasible metric for indirectly determining the impact of gray matter lesions. “Gray matter atrophy can be measured precisely with available techniques,” said Dr. Rudick.

Dr. Rudick described the clinical relevance of gray matter atrophy in MS, including how it correlates with lesions, disability, and whole brain atrophy, as well as its potential to mitigate complications when used as an outcome metric for MS clinical trials.

Resolving Pseudoatrophy Complications
Previous studies have attempted to use whole brain atrophy as a clinical trial measure, but these efforts have been complicated by the issue of pseudoatrophy, which occurs when MS therapies resolve edema and cause a rapid loss of tissue that resembles atrophy.

However, a recent posthoc analysis showed that pseudoatrophy was found in white matter rather than in gray matter. “So the significance of this, I believe, is that there doesn’t appear to be as much fluid shift in the gray matter as in the white matter,” Dr. Rudick commented. “And I think this [difference] would significantly simplify the design of clinical trials focused on atrophy if we were to focus on gray matter.”

Based on initial sample calculations, Dr. Rudick expects that future studies will require 60 to 80 patients per arm for moderate effect sizes.

Gray Matter Atrophy Influences Whole Brain Atrophy

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