Multiple Sclerosis

Multiple sclerosis (MS) affects about 350,000 people in the United States. MS is a chronic disease of the central nervous system that results from injury to the myelin sheath (the fatty insulation that surrounds most nerves in the brain and spinal cord) with the nerves remaining relatively intact. As a result of myelin destruction, the function of the nerves is impaired, resulting in neurologic deficits.

Research in MS at Mayo Clinic is a major component of the Division of Neurology. The goals of the MS research program include promoting remyelination in MS patients, investigating heterogeneous mechanisms of tissue injury, clinical trials that correlate with disease subtypes, genetic factors in cause and course of the disease, and developing new treatments for MS symptoms, including chronic pain, fatigue, spasticity, bladder incontinence, sexual dysfunction, and osteoporosis. Mayo Clinic physicians evaluate over 1,500 new cases of MS a year, more than any other institution in the world, providing Mayo researchers with valuable research data and information. Mayo neurologists are conducting many research projects in MS and related demyelinating diseases such as:

• Neuromyelitis optica (Devic's disease)
• Acute disseminated encephalomyelitis
• Transverse myelitis

Ongoing Research

Nerve Regeneration and Repair

The demyelination that occurs in multiple sclerosis impairs normal nerve function. Spontaneous remyelination can occur, leading to recovery of motor function. Understanding and promoting spontaneous remyelination is a goal of several Mayo initiatives. Researchers are:

• Investigating the genetic basis of remyelination in mice with and without a "reparative phenotype," (i.e., reparative trait or characteristic).
• Using genetic mapping techniques to identify the genes involved in the remyelination response. These genes may suggest gene targets for future treatments in MS patients.
• Exploring the mechanisms of nerve death following demyelination and nerve injury.

A major cause of long-term disability in MS patients is damage to the axon, the part of the nerve that carries information from the cell body to the muscles or to other nerves. Mayo researchers have concluded that when the axon is no longer protected by the myelin sheath, it may be more susceptible to immune-mediated attack. They have identified a likely mechanism for that response and are working on biologic interventions that can inhibit it. They are investigating immune factors such as interleukin-6, TNF, and interferon gamma, previously thought to be damaging to the CNS, as potentially beneficial in preserving neurons and axons from damage in demyelinating diseases.

Mayo Clinic neurologists discovered the role of antibodies in promoting tissue repair and the mechanisms by which they do so in demyelinating diseases. Current projects in remyelination include the generation of human antibodies and their use in humans to promote repair and remyelination of nerves. Such research will yield to a clinical trial of a monoclonal antibody to promote endogenous remyelination, the first effort of its kind.

Related work addresses the transplantation of stem cells from a patient's own bone marrow into the spinal cord to synthesize myelin. Future research includes testing a combination of cell transplantation and human antibodies to induce repair of CNS lesions. The implications of this research hold promise for nerve repair in a wide variety of degenerative diseases of the CNS as well as for repair of spinal cord injury.

Patterns of Demyelination in Multiple Sclerosis Lesions

Multiple sclerosis researchers at Mayo Clinic have determined that the pattern of demyelination and tissue injury in early MS lesions differs between MS patients. They described four distinct patterns of tissue injury in MS. Since a pattern of tissue injury remains identical among all early lesions in a given patient, they have suggested that the mechanisms of tissue injury in MS may be heterogeneous and may vary among patient subgroups. This may have important therapeutic relevance and may help explain the variability seen among MS patients with respect to clinical course, prognosis, and response to treatments. A central focus of Mayo Clinic MS researchers is to identify clinical, genetic, serologic, and imaging correlates of these distinct patterns of tissue injury in order to better tailor MS therapies for a specific patient.

Imaging to Better See Demyelination

Determining lesion subtype in MS usually requires tissue biopsy. However, Mayo Clinic researchers are generating new MRI imaging techniques and laboratory tests to identify MS subtype without invasive surgery. In addition, Mayo researchers are conducting the first approach at MRI imaging of individual cells in vivo, enabling scientists to determine how antibodies enter demyelinating lesions. This research will have widespread implications not only for inflammatory disorders of the CNS such as MS but for inflammatory disorders anywhere in the body. State-of-the-art imaging techniques are also being applied at the cellular level to enable scientists to visualize nerve axon function in an effort to identify the mechanisms of axonal injury and the effects of demyelination on axonal signaling.

Treatment for Specific Subtypes of Multiple Sclerosis

Mayo Clinic pioneered plasmapheresis (exchange of the patient's blood plasma) as a treatment for severe and acute MS relapse. It can result in dramatic improvement in some patients. Currently Mayo researchers are investigating factors that will predict which patients will benefit the most from this therapy.

Fatigue

In an effort to determine the underlying cause and the prevalence of chronic neurologic-based fatigue in MS, Mayo Clinic researchers are investigating the use of aspirin for chronic fatigue in a placebo-controlled study following promising results from an earlier Mayo study. These preliminary results added weight to the possibility that MS fatigue may be caused by immune system alterations.

Proteomics

Many diseases are caused by abnormal protein function, but knowledge of protein abnormalities in MS is extremely limited. New proteomic techniques, uniquely available at Mayo Clinic, have allowed rapid and complete analysis of a number of relevant proteins. The goal of MS proteomics research at Mayo is to determine when progressive MS begins so as to distinguish patients at risk for aggressive forms of the disease who need early intervention from patients with more benign forms of the disease.

Researchers at Mayo are also looking into a newly identified family of enzymes, called kallikreins, which aid in breaking down proteins in the body, and the role they play in the pathogenesis of CNS inflammatory diseases, including MS. The goals are to find protein patterns that will help determine prognosis early on so as to determine which patients need aggressive intervention and which ones may not need them at all (benign MS).

Genetics

The risk of developing MS is increased twenty-fold in immediate relatives of patients with MS. In addition, women are twice as susceptible to MS as men. Genetic research into MS at Mayo Clinic has a long legacy. For twenty-five years, every patient with MS in Olmsted County, Minnesota, has been followed, generating a unique resource of clinical and DNA data. Mayo Clinic also participates in multi-institutional genetic research as part of a U.S. consortium on the genetics of MS.

The goal of Mayo's MS genetic research is to understand genetic influences on susceptibility to MS, on the course and severity of the disease, and to identify genes that might predict response to treatment. Current projects include investigation of the interferon gamma gene, the genetic markers that control apoptosis or programmed death in lymphocyte cells, and the Carter effect, research that has recently suggested that men are more likely than women to transmit MS. In addition, studies analyzing the potential effect of genes on MS lesions are underway.

Epidemiology

The twenty-five–year investigation of individuals with MS in Olmsted County has produced important data on the natural history of the disease. It has also identified a cohort of patients that have what is called "benign MS." These patients have been followed for over twenty-five years and have not developed significant symptoms, despite the fact that some show large MRI lesions. By comparing their DNA to those with symptomatic forms of MS, Mayo's researchers are uncovering genetic factors that play a role in protecting patients from severe forms of MS. Mayo is uniquely positioned to study the natural history and prevalence of MS in several populations. In Minnesota, the population is primarily white and of northern European extraction. Mayo's Jacksonville, Florida, campus provides access to a patient population of black Americans, and its Scottsdale, Arizona, campus provides access to indigenous Native American populations and to Hispanic populations. Mayo's standardized patient histories ensure that data collected at these sites can be rigorously controlled in both epidemiologic and clinical trials research.

Devic's Disease

Devic's disease, also known as neuromyelitis optica, is a relatively uncommon disorder of the central nervous system, which results in demyelinating lesions in the optic nerves in the eyes and nerves in the spinal cord. It is commonly characterized as a variant of MS and can leave patients blind and wheelchair-bound within five years of diagnosis. Mayo researchers have defined the signs and symptoms required for diagnosis of the disorder and have identified a unique serum diagnostic antibody marker (NMO-IgG) that has greatly improved diagnosis. This simple blood test allows early distinction of Devic's disease from MS so that appropriate treatment can be initiated immediately. They have also identified the target antigen of NMO-IgG, the water channel aquaporin-4. Now they are defining the genetics and epidemiology and natural history of this disease as well as developing models to allow development of specific immunotherapies.