The long-term objective of this research is to advance our understanding of brain inflammatory and demyelination processes involved in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis. Demyelination is a process where the myelin sheath undergoes physical and chemical degradation of lipid and protein components and is an integral part of CNS diseases such as multiple sclerosis, encephalomyelitis, and radiation necrosis. This project will be accomplished by sequentially and noninvasively evaluating anatomical and chemical properties of central nervous system tissue using proton MR imaging, proton MR spectroscopy, and diffusion imaging. This project will noninvasively measure lipid, lipid precursor (phosphocholine), and N-acetyl aspartate (NAA) changes involved in EAE using recently optimized pulse sequences for volume localization and for chemical shift imaging. At specific time intervals after the induction of EAE, we will define the biologic significance of MR signal changes in proton metabolites of the brain (NAA, choline, creatine, and mobile lipids) by correlating MR changes with histologic changes. We expect that neuronal damage will be associated with a decrease in N-acetyl aspartate and myelin sheath damage will be associated with changes in lipids and lipid-precursors (phosphocholine). Diffusion imaging will be used to measure changes in restricted water diffusion properties associated with edema, membrane damage, and necrosis during demyelination. A novel application of diffusion-weighted spectroscopy is proposed to separate the MR signal of small molecular weight compounds containing choline from large molecular weight compounds. Since the rate of incorporation of choline into the brain phosphatidyl choline is important in the synthesis of new myelin membrane, this rate will be assessed using a phosphonium analogue of choline. This project will provide new information about the initial stages of demyelination before the onset of MRI-detectable lesions and win help define the relationship between myelin-membrane damage and neuronal damage. Once the association between cellular activity (neurons, glial cells, and lymphocytes) and these MR techniques is better understood, these techniques will assist in staging demyelination and will have important clinical application in monitoring disease progression and in determining the effectiveness of new therapeutic drugs.
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