Recent 31P NMR studies from this laboratory have demonstrated alterations of membrane phospholipid metabolism in AD brain obtained at autopsy and biopsy (Pettegrew et al. 1984, 1985, 1987ab, 1988a; Withers et al. 1987). The alterations do not correlate with the duration of the postmortem interval and are thought to reflect antemortem metabolic changes. AD brains contain significantly elevated levels of PME, which are precursors to membrane phospholipids, without significant elevations of PDE, which are breakdown products of membrane phospholipids. In contrast non-AD diseased control brains contain significant elevations of PDE. The areas of AD brain with PME elevations are the superior and middle frontal gyri and the inferior parietal cortex. These same cortical areas of AD brain have decreased glucose utilization and abnormal electrophysiological responses to event-related evoked potentials (Cutler et al. 1985, Duara et al. 1986, Horwitz et al. 1987, Rapoport et al. 1986, Fletcher and Sharpe 1986, 1988). Correlative 31P NMR and morphological studies suggest that the PME elevations precede the appearance of SP, but that the PDE elevations coincide with the appearance of SP; no correlations were observed between NFT and PME or PDE (Pettegrew et al. submitted). The purpose of this study is to determine what metabolic changes are present early in the course of AD compared to MSID and matched normal controls, and if these metabolic changes progress as the clinical manifestations progress. In order to address this problem, in vivo 31P NMR spectroscopy studies will be conducted on 25 patients with probable AD and mild to moderate dementia, 25 patients with MSID and 25 matched normal controls. The diagnosis of probable AD will be based on NINCDS-ADRDA criteria (McKhann et al. 1984). All subjects will be evaluated at entry into the study and at 6 month intervals over a 5 year followup for a total of 11 assessments in each subject. High-energy phosphate and membrane phospholipid metabolism will be assessed as well as intracellular pH in the dorsal prefrontal cortex of all subjects under resting conditions. The 31P NMR results will be compared with the clinical assessment of dementia and neuropsychological assessment of prefrontal cortical function.