Disease biomarkers in multiple sclerosis: potential for use in therapeutic decision making

Multiple sclerosis (MS) is an autoimmune disorder of the brain and spinal cord that predominantly affects white matter. MS has a variable clinical presentation and has no 'diagnostic' laboratory test; this often results in delays to definite diagnosis. In confronting the disease, early diagnosis and appropriate, timely therapeutic intervention are critical factors in ensuring favorable long-term outcomes. The availability of reliable biomarkers could radically alter our management of MS at critical phases of the disease spectrum. Identification of markers that could predict the development of MS in high-risk populations would allow for intervention strategies that may prevent evolution to definite disease. Work with anti-myelin antibodies and the ongoing analysis of microarray gene expression have thus far not yielded biomarkers that predict future disease development. Similarly, extensive studies with serum and cerebrospinal fluid (CSF) have not yielded a disease-specific and sensitive diagnostic biomarker for MS. Establishment of disease diagnosis always leads to questions about long-term prognosis because in an individual patient the natural history of the disease is clinically unpredictable. Biomarkers that correlate with myelin loss, spinal cord disease, grey matter and subcortical demyelination need to be developed in order to accurately predict the disease course. The bulk of effort in biomarker development in MS has been concentrated in the area of monitoring disease activity. At present, a disease 'activation' panel of CSF biomarkers would include the following: interleukin-6 or its soluble receptor, nitric oxide and nitric oxide synthase, osteopontin, and fetuin-A. Although disease activity in MS is predominantly inflammatory, disease progression is likely to be the result of neurodegeneration. Therefore, the roles of proteins indicative of neuronal, axonal, and glial loss such as neurofilaments, tau, 14-3-3 proteins, and N-acetylaspartate are all under investigation, as are proteins affecting remyelination and regeneration, such as Nogo-A. With the increasing awareness of cognition dysfunction in MS, molecules such as apolipoprotein and proteins in the amyloid precursor protein pathway implicated in dementia are also being examined. Serum biomarkers that help monitor therapeutic efficacy such as the titer of antibody to beta-interferon, a first-line medication in MS, are established in clinical practice. Ongoing work with biomarkers that reflect drug bioavailability and factors that distinguish between medication responders and nonresponders are also under investigation. The discovery of new biomarkers relies on applying advances in proteomics along with microarray gene and antigen analysis and will hopefully result in the establishment of specific biomarkers for MS.