The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 Tesla, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, myo-inositol, GABA, glutathione or other metabolites. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia.

Metabolic dysfunction and microvascular abnormality may contribute to the pathogenesis of schizophrenia. Most previous studies of cerebral perfusion in schizophrenia measured total cerebral blood volume (CBV) and cerebral blood flow (CBF) in the brain, which reflect the ensemble signal from the arteriolar, capillary, and venular compartments of the microvasculature. As the arterioles are the most actively regulated blood vessels among these compartments, they may be the most sensitive component of the microvasculature to metabolic disturbances. In this study, we adopted the inflow-based vascular-space-occupancy (iVASO) MRI approach to investigate alterations in the volume of small arterial (pial) and arteriolar vessels (arteriolar cerebral blood volume [CBVa]) in the brain of schizophrenia patients. The iVASO approach was extended to 3-dimensional (3D) whole brain coverage, and CBVa was measured in the brains of 12 schizophrenia patients and 12 matched controls at ultra-high magnetic field (7T). Significant reduction in grey matter (GM) CBVa was found in multiple areas across the whole brain in patients (relative changes of 14%-51% and effect sizes of 0.7-2.3). GM CBVa values in several regions in the temporal cortex showed significant negative correlations with disease duration in patients. GM CBVa increase was also found in a few brain regions. Our results imply that microvascular abnormality may play a role in schizophrenia, and suggest GM CBVa as a potential marker for the disease. Further investigation is needed to elucidate whether such effects are due to primary vascular impairment or secondary to other causes, such as metabolic dysfunction.

Contributors Jun Hua conducted data collection, data analysis and interpretation, drafting of the article, revision of the article, and final approval. Nicholas I.S. Blair conducted the functional MRI data analysis. Adrian Paez contributed to data analysis and revision of the article. Ann Choe contributed to data interpretation and revision of the article. Anita D. Barber contributed to data interpretation and revision of the article. Allison Brandt contributed to the collection and analysis of the clinical data, and revision of the article. Issel Anne L. Lim contributed to data collection. Feng Xu contributed to data interpretation and revision of the article. Vidyulata Kamath contributed to data interpretation and revision of the article. James J. Pekar contributed to study design, data interpretation and revision of the article. Peter C.M. van Zijl contributed to study design, data interpretation, and revision of the article. Christopher A. Ross contributed to study design, data interpretation, and revision of the article. Russell L. Margolis contributed to study design, data analysis and interpretation, drafting of the article, revision of the article, and final approval. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest Equipment used in the study was manufactured by Philips. Peter C.M. van Zijl receives grant support from Philips, is a paid lecturer for Philips, and is the inventor of technology that is licensed to Philips. This arrangement has been approved by Johns Hopkins in accordance with its conflict of interest policies.