In this study, we propose to expand our ongoing, longitudinal in vivo MRS and MRI studies of drug-naive, first-episode schizophrenics and matched controls. Our previous studies focused on 31P MRS of the prefrontal cortex (PFC) and also included non-schizophrenic psychotics and matched high- functioning adult autistic subjects. Our studies to date demonstrate decreased membrane synthesis [phosphomonoesters (PME)] and decreased energy consumption [phosphocreatine (PCr) and ATP] in the drug-naive, first-episode schizophrenics as contrasted with increased PME in autistics. In the drug-naive, first-episode schizophrenics, highly significant correlations are found between neurophysiologic (eye movement), neuropsychologic, and clinical measures and the levels of PCr and ATP (highest in the most severely affected) and PME and phosphodiesters (PDE) (both lowest in the most severely affected); correlations in the opposite sense (increased PMB and decreased ATP in the most severely affected) are observed in the autistics. The metabolic abnormalities are most pronounced in schizophrenics with a positive family history of schizophrenia, suggesting this may be a genetically inherited trait phenomenon. The findings suggest exaggerated synaptic pruning in schizophrenics with secondarily reduced consumption of high-energy phosphates. These findings support a neurodevelopmental hypothesis of schizophrenia. This study extend these observations by using combined 31P- 1H chemical shift imaging (CSI) to examine five specific brain areas (right and left) believed to represent a gradation of involvement in the pathophysiology of schizophrenia: PFC, superior temporal cortex, inferior parietal lobule, caudate, and occipital cortex. Longitudinal (24 month) studies will be conducted in 50 drug-naive, first-episode schizophrenics and 50 matched controls. In addition to studying more brain areas, the addition of 1H MRS will permit assessment of N-acetyl-L-aspartate (NAA) which is thought to be a measure of neuronal viability. We will continue to perform neuromorphometric, neurophysiologic (eye movement), neuropsychologic, and clinical assessment on these patients and correlate the neurochemical (MRS) findings with these important functional and neuromorphometric parameters. Our studies point to specific neurodevelopmental events which, with further study, could lead to strategies to prevent the proposed exaggerated synaptic pruning of schizophrenia and even earlier, could aid in the pre-symptomatic diagnosis of this challenging mental disorder.
