Understanding the Genetic Determinants of a Benign Versus Severe Course of MS

Epidemiology of Multiple Sclerosis in Olmsted County, MN

Drs. Pittock and Rodriguez recently published a series of high impact papers describing the natural history of MS in Olmsted County over a 25-year period. Dr. Rodriguez and colleagues tracked the incidence and prevalence of MS in this population-based cohort of patients since 1905.

The prevalence of MS in Olmsted County, Minnesota, is one of the highest reported in the United States. Incidence of the disease has increased over the decades but, apparently, has reached a plateau in the past five to ten years. Epidemiologic investigation of this population has been critical to understanding the natural history of MS. An important subset of these patients has been designated as having "benign MS." In 25 years of follow-up, these patients have not developed significant neurological deficits, despite accrual of a large MRI lesion burden in some. The underappreciated benign cohort represents about 15 percent of all MS patients.

The findings of this study provide insight into the genetic basis of susceptibility to MS and genetic influences on the course and severity of the disease. The basic strategy is to analyze DNA sequencing from individual patients to identify genetic variations, to determine their frequency in MS patients as well as appropriately matched control patients and thereby to determine whether those variants correlate with MS or certain subtypes of MS (mild "benign" MS or severe MS).

Ultimately, correlation between the presence of genetic variations in the DNA sequence, alteration in protein function, and MS susceptibility will determine the significance of the observed statistical associations. Dr. Brian Weinshenker leads the genetic studies related to human inflammatory CNS demyelinating disorders. Dr. Orhun Kantarci (Assistant Professor in Neurology) recently received a grant from the National MS Society to study the correlation of MRI parameters and "benign" phenotype (NMSS PP1298). Dr. Marcelo Matiello has received a 3-year Postdoctoral Fellowship from the NMSS (started July 1, 2008) to investigate genetic aspects of CNS aquaporin-4 autoimmunity and factors predisposing to benign versus severe clinical course in that disorder.

The standardization of MRI studies is directed by Drs. Erickson (Radiology) and Lucchinetti. Neuroimaging, and particularly MRI, has proven to be a valuable diagnostic tool and surrogate biomarker for MS. More recent advances in MRI technology, such as magnetization transfer sequences and diffusion tensor imaging, may further elucidate the pathological and functional changes associated with MS. MRI data may also be used in a more quantitative manner such as volumetric tissue classification based upon signal characteristics in multiple pulse sequences. Use of volumetric analyses in routine clinical practice has not been the standard of care, but clinical trials are referenced to this outcome increasingly and it has potential importance for monitoring patients' responses to different treatment. In order to explore these, as well as future advances in MRI technology, we have developed a standardized imaging protocol for MS. In addition to standard MRI imaging including T1, T2, proton density, T1 with gadolinium and FLAIR sequences, this protocol includes standard pulse sequences and allows for the addition of newly developed techniques. The slice volumes have been designed and standardized with thin cuts to allow volumetric measurements. As neuroimaging techniques evolve, a repository of quality data will allow longitudinal and retrospective investigations to validate newly developed techniques.

In addition, we have developed the tools to do MRI and spectroscopy in animals with demyelinating disorders. The work is led by Dr. Slobodan Macura and Dr. Aleksandar Denic, a graduate student in Dr. Rodriguez's laboratory. We have recently determined a novel approach using spectroscopy of the brainstem to determine the state of axonal injury versus preservation in the spinal cord. This work is supported by the Collaborative Research Center grant from the National MS Society (CA1011).

Aptamers

Dr. Maher has developed the methodology to screen large panels of small RNA or DNA molecules called aptamers. In collaboration with Dr. Rodriguez, Dr. Maher has recently identified an RNA aptamer that specifically binds myelin. This aptamer, tagged with biotin, is currently under investigation as a tool to label demyelinating lesions in animals. In collaboration with Dr. Macura, Dr. Maher uses the aptamer to label lesions on MRI. Finally, we are testing the aptamer in experimental models to determine its efficacy in alleviating demyelination or enhancing remyelination. This work is supported by the Collaborative MS Center grant from the National MS Society (NMSS CA1011).

Genetic Analysis of Spontaneous Central Nervous System Repair

Dr. Bieber is studying a viral disease of the mouse central nervous system that causes a pathologic and neurologic condition that is similar to MS. This mouse model of MS has been a useful tool to study the development of MS and examine possible treatments.

Recent study has focused on two different strains of mice. In one strain, B10.Q mice, viral infection results in chronic demyelination with progressive loss of neurologic ability, and eventual paralysis and death. In FVB mice, however, infection results in demyelination similar to that observed in B10.Q mice. However, midway through the development of the disease, these mice undergo almost complete remyelination and repair of MS-induced damage. Neurologic disability ceases and the animals regain full neurologic function. This "reparative phenotype" is highly penetrable and is inherited as a dominant genetic trait.

Why does CNS repair and remyelination differ in the two strains? Using various techniques, including bone marrow transplant and genetic mapping, Dr. Bieber and colleagues seek to identify genes whose pattern of activity and inheritance might help explain the differences in remyelination potential that are observed between these two types of mice. Such genes might suggest themselves as potential targets for therapeutic intervention in MS. Thus far, two genes have been identified; one affects the immune function and the other affects oligodendrocyte function. These genes are being sequenced in the two strains. If differences are found, then we will examine these genes in the Olmsted County Prevalence MS Cohort (funded by the MS Society of Canada CMS 01-04-6).