Pathology of Slowly Enlarging Lesions in Multiple Sclerosis
Abstract
Background: Multiple sclerosis (MS) is one of the leading causes of disability among young adults, affecting approximately 1 million people in the United States. Current MS drugs reduce the frequency of relapses but have less effect on progression of disability independent of disease activity, and there is an unmet need for stopping and reversing disability from MS. Sensitive markers for disability progression will greatly assist rapid evaluations of therapeutic candidates and, ultimately, development of effective drugs to stop disability in progressive MS. Overall brain lesion sizes and occurrences of new lesions on MRI have been used in relapsing-remitting MS because they are highly associated with relapses, but lesion sizes do not correlate with levels of disability in progressive MS patients. Recent MRI studies hypothesize a subset of lesions, called slowly enlarging lesions, may be a sensitive marker of disability progression. These slowly enlarging lesions are detected from routine MRI using computer software. In brain autopsy from MS patients, we find a subset of lesions, called chronic active lesions, that appear to have active tissue damage at the lesion edge, and the center has been already destroyed. Hypothesis: We hypothesize that slowly enlarging lesions show active destruction and thus may serve as a novel marker that addresses the Focus Area Correlates of Disease Activity and Progression in Multiple Sclerosis. In Specific Aim 1, we will identify slowly enlarging lesions from patients MRIs and evaluate the active destruction in their autopsy brain specimen. We will use existing post-mortem tissues along with matched in vivo serial MRIs to investigate the damage in such lesions. In Specific Aim 2, we hypothesize that the slowly enlarging lesions are a subset of lesions that exist over a long period of time and compare their lesion age to that of non-enlarging lesions. Impact: The most novel aspect of the study is that we use autopsy tissue along with those same patients in vivo MRIs. This will provide unique and conclusive insights into the mechanism of slowly enlarging lesions. We emphasize that we are comparing the slowly enlarging lesions from routine clinical MRIs without the need for advanced MRI techniques. The ability to quantify chronic active lesions from clinical MRIs will not only enhance our knowledge but also accelerate research by enabling identification of chronic active lesions from many retrospective and prospective data sets. From Aim 2, the natural history of MS lesion pathology can be obtained and the results will provide insights into the mechanism of MS evolution and may provide windows of opportunity for regenerative therapies such as remyelinating agents. Since the results provide a natural history, it will serve as a reference for future studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110787
Entities
People
- Kunio Nakamura
Organizations
- Cleveland Clinic
- United States Army