TESTING INOSITOL HYPOTHESIS IN PATIENTS W/ PROBABLE ALZHEIMER DISEASE

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The aim of this project is to further define the significance of the recently discovered increase in cerebral myo-inositol (ml), suggesting that INOSITOL metabolism is disordered. Increased inositol signal may thus be a newly identified diagnostic marker for Alzheimer disease (AD) that can be measured using magnetic resonance spectroscopy. One of the goals of this collaboration is to further define the enzymatic locus of defective inositol metabolism in AD using natural abundance 13C MRS at 4 Tesla to directly assay total-free inositol content of the brain in AD subjects, to exclude contributions from glycine to the diagnostic peak of mI in the 1H MR spectrum. Clinical spectra have been acquired at 1.5 Tesla using 1H MRS, where myo-inositol is essentially one prominent peak at 3.56 ppm. However, the signal change is small and could equally well be caused by increased glycerol, glycine or myo-inositol phosphate resonances, all of which resonate at the same chemical shift at 1.5 Tesla. 13C MRS can be used to distinguish these signals, since glycine resonates for example at a distinct chemical shift. Sensitivity at 1.5 Tesla does not permit observation of changes in the glycine concentration, which is typically 1?mol/g. The recent establishment of 13C MRS at 4 Tesla suggested that the sensitivity should be sufficient to define whether glycine, glycerol or phosphorylated inositol account for the signal change seen at 1.5 Tesla. We have already performed 13C studies on three patients who were flown over from California. The results demonstrated unequivocally that myo-inositol was elevated in these patients.