A new Mayo Clinic study has found that the type of tissue damage changes throughout the course of multiple sclerosis (MS). In early relapsing disease stages, the plaques, or areas where the nervous system is inflamed or demyelinated, are predominantly active with distinct heterogeneous patterns of myelin damage. Later in the chronic progressive phase of the disease, smoldering and inactive plaques predominate, and are characterized by a uniform pattern of tissue damage.
The study’s findings provide important information at the microscopic level regarding the dynamic changes occurring in MS white matter plaques over the course of the disease that can help inform subsequent studies that characterize the disease based on advanced imaging techniques or clinical outcomes. According to Mayo Clinic researchers, a better understanding of the pathology of MS may eventually lead to new therapeutic targets. This study will be presented at the American Academy of Neurology Annual Meeting in Toronto on April 14.
Mayo Clinic provides care for nearly 2,500 patients with MS each year. MS is a disease of the central nervous system that includes the brain, spinal cord and optic nerves. MS is called a demyelinating disease because it results from damage to myelin, the insulating covering of nerve fibers. It occurs most commonly in those between the ages of 20 and 40, and is the most common cause of non-traumatic neurological disability in young adults in North America and Europe. Approximately 330,000 people in the United States have MS. Symptoms include loss of muscle coordination, strength, vision, balance and cognition.
“We have pretty good therapies to treat and reduce the frequency of relapses in MS, but as the disease progresses and the relapses become less frequent, we need to better understand the biologic basis for that progression,” says Claudia Lucchinetti, M.D., a Mayo Clinic neurologist and author of this study. “This study showed us that smoldering MS plaques are more commonly found during progressive disease phases. These plaques, unlike active MS plaques, show a limited degree of ongoing demyelination that occurs at the expanding plaque border of an established MS lesion, and are characterized by a uniform pattern of myelin damage. By studying these plaques and attempting to understand the key mechanisms involved in their formation, we can begin thinking of alternative therapies that might better target the processes that contribute to disease progression.”
Dr. Lucchinetti and a team of Mayo Clinic researchers and collaborators studied tissue from the autopsies of 143 individuals with multiple sclerosis. The tissue was analyzed and 2,479 plaques were classified as active (new lesion in which myelin is being stripped), smoldering (limited degree of ongoing myelin damage in an established plaque), inactive (no evidence for ongoing myelin breakdown) or shadow (evidence of remyelination). The team found that the tissue damage changes over the duration of disease. Early in the disease when relapses are common, numerous active plaques with distinct heterogeneous patterns were readily identified. This study confirms data in previous Mayo Clinic studies that found distinct, heterogeneous patterns in which white matter plaques are formed, and that the pattern is similar among all active plaques in a given patient. According to Dr. Lucchinetti, these active plaques likely represent the pathologic basis of clinical relapses in MS, and are thought to reflect distinct immune mechanisms of demyelination operating in different subgroups of MS patients. The findings suggest therapies that target MS relapses need to be individualized in order to address the heterogeneity in plaque formation observed early in the disease, however, as the disease progresses, these diverse patterns are less commonly found, given the rarity of active plaques in later disease stages, she explains.
According to Dr. Lucchinetti, there is a very low likelihood of having any active plaques when the disease is beyond 20 years. Rather, there is a predominance of inactive or smoldering plaques that demonstrate a uniform pattern of tissue injury. The study suggests that when the disease is more chronic and progressive in nature, the progression may in part be driven by the accumulation of smoldering plaques in which a low degree of ongoing demyelination is occurring at the plaque edge. Since active new MS plaques show up more readily on gadolinium-enhanced MRI, Dr. Lucchinetti says this might explain why a patient goes to the doctor and feels that his or her disease is progressing, but an MRI shows no new lesions.
“We recognize that there’s not just one therapy that works for everyone with MS; patients already know this. We need to better understand why that might be, study it, model it in the laboratory, and then hopefully translate it into something that makes a difference in patients’ lives,” says Dr. Lucchinetti. According to Dr. Lucchinetti, the next step with this research is examining what other factors contribute to progression and irreversible disability in multiple sclerosis, with a particular focus on understanding how the cortex is involved in the disease. To date, most MS research has focused on the white matter plaque. Although the presence of new active white matter plaques likely account for MS relapses, researchers are increasingly recognizing that in addition to smoldering MS plaques, cortical demyelination is also an important pathologic substrate of progression and disability in the disease. A better understanding of the relationship between white matter and cortical demyelination in MS is necessary in order to target the many processes that contribute to disease progression, explains Dr. Lucchinetti.
“At first glance, it might seem that we’re making everything more complicated, but that’s really the only way that you can start to break down a disease. If we accept it to be a simple, linear straightforward disease, I don’t think we’re going to get very far in knowing how to treat the different aspects that are causing the relapses and progression of MS,” says Dr. Lucchinetti. This study was part of the MS Lesion Project funded by the National Multiple Sclerosis Society and National Institutes of Health. The Mayo Clinic research team also included Joseph Parisi, M.D.; Stephen Weigand, Kristine Thomsen and Jay Mandrekar, Ph.D. Other collaborators included Josa Frischer, M.D., and Hans Lassmann, M.D., of Medical University of Vienna in Austria; and Wolfgang Brueck, M.D., of University of Goettingen, Germany.
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