Phosphorus magnetic resonance spectroscopy (31P MRS) studies have shown alterations in phosphorus metabolites in the brains of schizophrenics suggesting abnormalities in membrane phospholipid metabolism. Structural MRI studies have shown pervasive deficits of cortical gray but not white matter in the brains of schizophrenics. Because the low signal to noise ratios (S/N) of phosphorus metabolite in the brain necessitate analysis of large voxels containing mixtures of gray and white matter, none of the studies done to date have been able to determine whether or not these metabolic abnormalities are confined to gray matter. The primary aim of this project is to determine if the reported abnormalities in phospholipid metabolism observed in schizophrenia using 31 P MRS persists after controlling for voxel composition. To this end, 31 P MRS imaging techniques with nuclear Overhauser effect (nOe) and proton decoupling techniques will be applied to enhance the S/N and spectral resolution of the 31P metabolites, particularly the phosphomonoester (PME) and phosphodiester (PDE) peaks. Concurrently obtained structural images, segmented into CSF, gray, and white matter, will be used to assess the composition of spectroscopic voxels in anterior and posterior brain regions. 31p MRS brain scans will be obtained from 25 clinically stable, medicated patients meeting DSM-IV criteria for schizophrenia, aged 30-40 years old, with less that 10 years of illness, and 35 controls aged 20-50. Control data will first be used to model normal changes occurring over this age range. If necessary, analysis of patient data will take these changes into account. Data will be analyzed to test the following hypotheses; 1. There is altered membrane phospholipid metabolism in the brains of chronically treated schizophrenic patients which is reflected in reduced PME values even after the CSF, white and gray matter composition of spectroscopic vosels is taken into account. 2. These effects will be stronger in anterior than posterior brain regions, reflecting the greater vulnerability of the frontal lobes to untoward neurodevelopmental events. 3. Patients who return for treatment after self withdrawal of medications will show enhanced PDE and reduced PME. After treatment, PDE will normalize, but PME will remain reduced. Additional exploratory analysis will include (1) an investigation of association between 31P metabolite values and age, length of illness, severity of negative and positive symptom, and medication level; (1) a description of any differences between schizophrenics and controls in intensity and regional distribution of the high energy phosphorous metabolites, phosphocreatine (PCr), and adenosine triphosphate (ATP); (3) an investigation of the contribution of white and gray matter voxel composition to spectroscopic values for these high energy metabolites.
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