Gray Matter Atrophy May Serve as an Effective Outcome Measure for MS Clinical Trials : Neurology Reviews
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`FEATURE ARTICLE
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`Gray Matter Atrophy May Serve as an Effective Outcome Measure for MS Clinical Trials
`
`2012;20(2):8.
`
`This week's quiz:
`Clinical varieties of aphasia
`
`Studies show that gray matter atrophy correlates with disability progression and
` drives whole brain atrophy in MS.
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`More »
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`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
`
`Sponsored
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`http://www.neurologyreviews.com/specialty-focus/multiple-sclerosis-ms/article/gray-matter-atrophy-may-serve-as-an-effective-outcome-measure-for-ms-clinical-trials/5f1c2ba3adde725b8a583502b5c332e1.html?trendmd-shared=1[3/8/2016 4:12:24 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1098 PAGE 1
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`

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`Gray Matter Atrophy May Serve as an Effective Outcome Measure for MS Clinical Trials : Neurology Reviews
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` 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.”
`
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`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.
`
`Quick Poll
`Progressive MS
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` measure in progressive multiple
` sclerosis?
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`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
`http://www.neurologyreviews.com/specialty-focus/multiple-sclerosis-ms/article/gray-matter-atrophy-may-serve-as-an-effective-outcome-measure-for-ms-clinical-trials/5f1c2ba3adde725b8a583502b5c332e1.html?trendmd-shared=1[3/8/2016 4:12:24 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1098 PAGE 2
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`Gray Matter Atrophy May Serve as an Effective Outcome Measure for MS Clinical Trials : Neurology Reviews
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` 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.
`
`He also noted that the effect of drugs on gray matter atrophy might be of interest to researchers. However, not enough data are
` available to draw conclusions.
`
`Looking forward, he suggested that gray matter atrophy may play an important role in future clinical trials. “I believe gray matter
` atrophy is an attractive outcome measure for MS clinical trials, because it seems to be very important, it’s feasible, and I think it
` should be fairly straightforward,” concluded Dr. Rudick.
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`Suggested Reading
`Calabrese M, Rocca MA, Atzori M, et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol.
` 2010;67(3):376-383.
`Rudick RA, Fisher E. Brain atrophy as an outcome measure for multiple sclerosis clinical trials: a “no-brainer”? Neurology. 2009;72(7):586-587.
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`http://www.neurologyreviews.com/specialty-focus/multiple-sclerosis-ms/article/gray-matter-atrophy-may-serve-as-an-effective-outcome-measure-for-ms-clinical-trials/5f1c2ba3adde725b8a583502b5c332e1.html?trendmd-shared=1[3/8/2016 4:12:24 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1098 PAGE 3
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`http://www.neurologyreviews.com/specialty-focus/multiple-sclerosis-ms/article/gray-matter-atrophy-may-serve-as-an-effective-outcome-measure-for-ms-clinical-trials/5f1c2ba3adde725b8a583502b5c332e1.html?trendmd-shared=1[3/8/2016 4:12:24 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1098 PAGE 4
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`

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`Gray Matter Atrophy May Serve as an Effective Outcome Measure for MS Clinical Trials : Neurology Reviews
`
`http://www.neurologyreviews.com/specialty-focus/multiple-sclerosis-ms/article/gray-matter-atrophy-may-serve-as-an-effective-outcome-measure-for-ms-clinical-trials/5f1c2ba3adde725b8a583502b5c332e1.html?trendmd-shared=1[3/8/2016 4:12:24 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1098 PAGE 5