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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030722-03
Application #
2268693
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1992-04-01
Project End
1995-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Richards, T L; Dager, S R; Posse, S (1998) Functional MR spectroscopy of the brain. Neuroimaging Clin N Am 8:823-34
Gardner, J C; Yazdani, F (1998) Correlating MR lesions and functional deficits in multiple sclerosis patients. Anatomical atlas registration. Phys Med Rehabil Clin N Am 9:569-86, vi
Richards, T L; Lappin, M S; Lawrie, F W et al. (1998) Bioelectromagnetic applications for multiple sclerosis. Phys Med Rehabil Clin N Am 9:659-74
Heide, A C; Kraft, G H; Slimp, J C et al. (1998) Cerebral N-acetylaspartate is low in patients with multiple sclerosis and abnormal visual evoked potentials. AJNR Am J Neuroradiol 19:1047-54
Rose, L M; Richards, T L; Peterson, J et al. (1997) Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin. Mult Scler 2:259-66
Posse, S; Dager, S R; Richards, T L et al. (1997) In vivo measurement of regional brain metabolic response to hyperventilation using magnetic resonance: proton echo planar spectroscopic imaging (PEPSI). Magn Reson Med 37:858-65
Korenberg, M J; Sakai, H M; Naka, K I (1997) Complexity and frequency hierarchies in the catfish retina. Front Med Biol Eng 8:87-107
Richards, T L; Lappin, M S; Acosta-Urquidi, J et al. (1997) Double-blind study of pulsing magnetic field effects on multiple sclerosis. J Altern Complement Med 3:21-9
Richards, T L; Alvord Jr, E C; Peterson, J et al. (1995) Experimental allergic encephalomyelitis in non-human primates: MRI and MRS may predict the type of brain damage. NMR Biomed 8:49-58
Jimenez, J V; Richards, T L; Heide, A C et al. (1995) Incorporation of a phosphonium analogue of choline into the rat brain as measured by magnetic resonance spectroscopy. Magn Reson Med 33:285-92

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