176.3 Elevated Brain Lactate and Glutamine/glutamate in Schizophrenia: A 7T MRS Study

Abstract

Background: Mitochondrial and bioenergetic alterations may play a role in the pathophysiology of schizophrenia, either directly or via alterations in underlying neurotransmitter systems. Postmortem, preclinical, cerebrospinal fluid, and 31P-magnetic resonance spectroscopy (MRS) studies provide some support. A recent 31P magnetization transfer MRS study found reduced creatine kinase reaction rate and pH in schizophrenia, consistent with dysfunctional glucose metabolism and the accumulation of lactate. This study tested the hypothesis that abnormal glycolysis leads to elevated lactate concentrations in subjects with schizophrenia. The high sensitivity of 7T MRS was used to measure brain lactate levels in vivo. The glutamatergic metabolites were also examined with the prediction that glutamine to glutamate (Gln/Glu) ratio would be higher in schizophrenia. Methods: Thirty-one controls and 29 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips “Achieva” 7T scanner, and spectra were acquired from a voxel in the anterior cingulate cortex using STEAM (TE/TM/TR=14/33/3000 ms, 128 NEX, and 16 NEX water). Patients were assessed for psychiatric symptom severity, and all participants completed the MATRICS Consensus Cognitive Battery (MCCB) for general cognitive function and UCSD Performance-Based Skills Assessment (UPSA) for functional capacity. The relationship between lactate, psychiatric symptom severity, MCCB, and UPSA were examined. Results: Lactate was significantly higher in patients compared to controls (P = .045). Higher lactate was associated with lower general cognitive function (r = −.36, P = .01) and functional capacity (r = −.43, P = .001). The glutamine to glutamate ratio (Gln/Glu) was higher in patients compared to controls (P = .021). Similar to lactate, higher Gln/Glu was significantly related to lower general cognitive function (r = −.4, P = .004) and functional capacity (r = −.45, P = .001). Conclusion: This is the first study to report elevated in vivo anterior cingulate lactate levels in schizophrenia. Anterior cingulate Gln–Glu ratio was also higher in schizophrenia, which is consistent with previous reports. The results support the hypothesis that brain bioenergetics are altered in schizophrenia reflecting inefficient or diminished aerobic metabolism and a shift towards anaerobic metabolism. Elevated lactate may prove to be a useful biomarker of cognitive and functional capacity in schizophrenia. Interventions to promote more efficient mitochondrial energy metabolism may prove useful for enhancing cognition and alleviating functional impairments in schizophrenia.