The study seeks evidence of age-related decreases in MRI volumetric measurements of hippocampus over a two year interval in older schizophrenic patients (50 years of age or more), in comparison to younger patients (18- 30 years old) and both older (50 years of age or more) and younger (18-30 years old) matched normal controls. Decreasing hippocampal volume over time is hypothesized in the older patients, vulnerable to an acceleration of hippocampal aging because of early, disease-related hippocampal insult, and repeated episodes of physiologic stress. Declarative memory performance and hippocampal-hypothalamic-pituitary-adrenal (HPA) axis activity, hypothesized to reflect the integrity of hippocampal formation, will also be measured in patients and controls over the two year interval. If validated by MRI data, these indirect measures will provide a cost- effective means of addressing supportive secondary hypotheses in larger samples in this and future investigations. The hypothesized progression in MRI, memory, and HPA axis measures is predicated on work in animal models demonstrating acute (transient) and chronic (neurotoxicity-related) site- specific effects of glucocorticoids (GCs) in hippocampus. The latter appear to be responsible for neuropathology in hippocampal aging and capable of accelerating that process in the face of both preexisting hippocampal damage and exposure to excess stress (i.e., GCs). Both conditions can occur in schizophrenia, offering an important test of the clinical significance of this work. In a pilot investigation, the candidate has prepared a novel protocol for measuring GC-mediated declarative memory changes, offering reductions in acute, GC-mediated variance in memory and hippocampal-HPA axis measures. Baseline and monthly contact with patients and controls will permit retrospective and prospective data collection on medical/psychiatric status, early illness course, premorbid status, and stressful life events to address confounds to outcome. The monthly contacts will also assist in the maintenance of a high follow-up rate and permit standardization of treatment conditions for patients. A series of statistical models, including multiple regression and analysis of variance will be used to analyze data.
