The general goals of this proposal are to improve the capabilities of in vivo MRS, and to combine these techniques with histopathological and immunohistochemical analyses to provide a better understanding of the pathophysiological alterations observed in Proton MRS of brain tumors. The technique improvements which are proposed are: 1) develop frequency selective adiabatic pulses which uniformly suppress (dephase) magnetization outside tissue regions of interest, despite variations in the radiofrequency field produced by the transmitter coil; and 2) develop adiabatic pulses which will provide uniform excitation in multi slice chemical shift imaging (CSI) implemented with surface coil transmitters. Correlative studies using in vivo MRS and histopathological and immunohistochemical analyses will test the following hypotheses: 1) Brain tumor lactate observed with Proton MRS is compartmentalized into metabolically active and inactive pools. The active pool is produced in viable cells, whereas the inactive lactate is present in necrotic, hemorrhagic, or edematous regions. 2) Glycolytic activity is high in tumor regions densely packed with viable neoplastic cells. During an infusion of C 13 glucose, the C 13 enrichment of lactate in a volume of tumor, as measured with Proton CSI, will be proportional to the fraction of proliferating cells in that volume. 3) The concentrations of choline compounds in brain tumors are indicative of membrane turnover, and therefore, should also correlate with quantitative immunohistochemical measures of cell proliferation. These hypotheses will be tested on intracerebral gliomas induced in rats by three different cell strains: C6, F98, and T24. Concentrations of choline and lactate will be measured with in vivo Proton CSI using high spatial resolution (<1 mm) on a 9.4 Tesla 31 cm horizontal bore magnet. The concentration of metabolically active tumor lactate will be measured following i.v. C 13 glucose infusion using short TE heteronuclear spectral editing. The MRS measurements will be correlated with qualitative and quantitative histology including immunohistochemical measures of proliferation state using monoclonal antibodies against bromodeoxyuridine (BrDU).
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