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described below summarize the committee's conclusions about which directions appear most likely to provide the fundamental knowledge that can lead to the development of effective therapies (see Box 1 for summary).

RECOMMENDATION 1: Research on the pathological changes underlying the natural course of MS should be emphasized, because it provides the key to predicting disease course in individual patients, understanding the physiological basis of MS, and a basis for developing improved therapeutic approaches.

Unpredictability imposes a particularly acute burden on people with MS. They have no way of knowing when a relapse will occur, how impaired they will be, or whether they will recover from the relapse. Yet it is now clear that disease activity precedes relapses. Understanding these pathological changes is the first step toward predicting—at least in the short term—disease progression in individual patients.

Research on the natural course of MS would include defining the relationship between cellular and molecular changes and the progression of disability, as well as determining the physiological basis for different clinical manifestations of MS. Changes in gene expression should be analyzed in individual cell types, particularly those in and at the borders of lesions. Such information will also improve the ability to develop more refined diagnostic tools, provide benchmarks against which to measure the effect of therapeutic interventions, and provide the scientific basis to identify new therapeutic approaches.

Research on pathological changes occurring early in the disease should be particularly emphasized. This should also include the development of improved diagnostic criteria (most likely, criteria based on neuroimaging) that allow early and more accurate diagnoses of MS. If aggressive treatment is to be instituted at the onset of disease, early and accurate diagnosis is especially important.

RECOMMENDATION 2: Research should be pursued to identify how neurons are damaged in MS, how this damage can be prevented, and how oligodendrocytes and astrocytes are involved in damage and repair processes.

Oligodendrocytes, astrocytes, and neurons can, in a sense, all be regarded as the cellular “victims” in multiple sclerosis. It is clear that oligodendrocytes and the myelin sheaths they form are damaged, astrocytes respond by forming a glial scar, and in some cases, axons (outgrowths of neurons) degenerate in MS. However, a better understanding of the neuronal response to injury and capacity for repair, the capacity of myelin-forming cells to remyelinate neurons and restore function, and the contribution of astrocytes is essential to deciphering the neuropathology of MS. Although much is known, many questions remain, and their answers have important implications for therapy.

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