Studies show that gray matter atrophy correlates with disability progression and drives whole brain atrophy in MS.
AMSTERDAM—Gray matter atrophy may serve as an effective outcome measure for clinical trials in multiple sclerosis (MS), said Richard A. Rudick, MD, Vice Chair of the Neurological Institute at the Cleveland Clinic. He described the latest research on gray matter atrophy at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).
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
Gray matter atrophy may serve as a valuable clinical trial metric, because it occurs early in the course of MS and increases as the disease advances, Dr. Rudick explained.
Data from an ongoing longitudinal study by Elizabeth Fisher, PhD, of the Cleveland Clinic Lerner Research Institute, and colleagues, suggest that accelerating whole brain atrophy over time is mostly driven by gray matter atrophy. The study is comparing healthy controls with patients progressing from clinically isolated syndrome to relapsing-remitting MS, as well as secondary and secondary progressive MS.
Dr. Rudick noted that white matter atrophy showed little change during the four-year study period. However, “when we look at the gray matter atrophy, it explodes, actually. It goes up to fourteenfold, compared with the healthy controls. So the accelerating atrophy over time is largely driven by increasing gray matter atrophy.”
Correlation With Disability
Gray matter atrophy also correlates with MS disability progression, according to six recent cross-sectional studies. In some of the studies, researchers analyzed multiple regression models and found that gray matter fraction, a method of quantifying gray matter atrophy, correlated with clinical outcomes better than other MRI variables, including white matter atrophy.
In addition, seven longitudinal studies have consistently demonstrated that gray matter atrophy shows a stronger correlation with disability progression than does white matter atrophy or lesions. Of the studies, two found that gray matter atrophy predicted conversion from clinically isolated syndrome to MS.
Modest Correlation With Lesions
Researchers have found that gray matter atrophy correlates somewhat with lesions as well. A three-year longitudinal study by Calabrese observed 76 patients with relapsing-remitting MS and 31 patients with secondary progressive MS. The investigators determined that cortical lesions at baseline predicted a change in gray matter volume, though the effect was modest in patients with relapsing-remitting MS and was not significant in patients with secondary progressive MS.
“My interpretation of this is that there is a connection between cortical lesions and cortical atrophy, but, at least using current techniques, this relationship is rather weak,” said Dr. Rudick. He pointed out that current methods for quantifying gray matter volume, such as gray matter fractional volume, may sometimes misclassify lesions due to their signal intensity. The potential for misclassification becomes more problematic in cases of advancing MS with numerous lesions.
In relation to quantifying gray matter atrophy, “it’s not clear whether gray matter fraction or cortical thickness or region of interest is the optimal approach,” said Dr. Rudick.