Hippocampal Pathology in Clinical High-Risk Patients and the Onset of Schizophrenia. 
We examined neuroimaging-derived hippocampal biomarkers in subjects at clinical high risk (CHR) for psychosis to further characterize the pathophysiology of early psychosis.  We hypothesized that glutamate hyperactivity, reflected by increased metabolic activity derived from functional magnetic resonance imaging in the CA1 hippocampal subregion and from proton magnetic resonance spectroscopy-derived hippocampal levels of glutamate/glutamine, represents early hippocampal dysfunction in CHR subjects and is predictive of conversion to syndromal psychosis.  We enrolled 75 CHR individuals with attenuated positive symptom psychosis-risk syndrome as defined by the Structured Interview for Psychosis-risk Syndromes.  We used optimized magnetic resonance imaging techniques to measure 3 validated in vivo pathologies of hippocampal dysfunction-focal cerebral blood volume, focal atrophy, and evidence of elevated glutamate concentrations.  All patients were imaged at baseline and were followed for up to 2 years to assess for conversion to psychosis.  At baseline, compared with control subjects, CHR individuals had high glutamate/glutamine and elevated focal cerebral blood volume on functional magnetic resonance imaging, but only baseline focal hippocampal atrophy predicted progression to syndromal psychosis.  These findings provide evidence that CHR patients with attenuated psychotic symptoms have glutamatergic abnormalities, although only CHR patients who develop syndromal psychosis exhibit focal hippocampal atrophy.  Furthermore, these results support the growing evidence that hippocampal dysfunction is an early feature of schizophrenia and related psychotic disorders.