Glutamate as a Marker of Cognitive Function in Schizophrenia: A Proton Spectroscopic Imaging Study at 4 Tesla

Background: Cognitive deficits in schizophrenia may be related to glutamatergic dysfunction, but in vivo measurement of glutamate metabolism has been challenging. We examined the relationship between glutamate metabolism and cognitive function in schizophrenia. Methods: Thirty subjects with DSM-IV schizophrenia and 28 healthy volunteers were studied using 4 Tesla proton echo planar spectroscopic imaging. Glutamate plus glutamine (Glx), N-acetylaspartate compounds, and Inositol concentrations in gray and white matter and broad neuropsychological function were assessed in all subjects. Results: Glutamate plus glutamine was positively correlated with overall cognitive performance in the schizophrenia group (p = .0006), accounting for about 36% of the variance. No correlation was found in control subjects. Group-averaged Glx levels were similar in schizophrenia and control subjects. N-acetylaspartate compounds were reduced in cortical gray matter in the younger schizophrenia subjects (age < 30; p = .04) compared with age-matched control subjects. Inositol was increased in cortical gray (p = .002) and white matter (p = .02) in the older schizophrenia subjects (age > 30) compared with age-matched control subjects. Conclusions: Although not reduced in schizophrenia as a group, lower Glx levels correlates with impaired cognition in the illness. This suggests heterogeneity in mechanisms that regulate glutamate function in schizophrenia. Patients with reduced glutamatergic reserves may be rendered into a more severe hypoglutamatergic state with cognitive consequences. Reduced cortical gray matter N-acetylaspartate compound concentration early in the illness with normalization in older subjects is consistent with a process of early dendritic retraction with subsequent increased neuronal packing. Later in the illness, Inositol elevation suggests glial involvement.