Using Neuroimaging to Investigate Mechanism-based Biomarkers of Schizophrenia

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

Project Summary/Abstract Neuroimaging research has revolutionized our understanding of the biological factors that are contributing to psychiatric illness, particularly schizophrenia (SZ). One of the most intriguing recent imaging findings in SZ is an increased extracellular water volume (Free Water - FW), particularly in early phases of this disease. The extracellular nature of FW increase suggests that it could be associated with extracellular matrix and/or blood brain barrier (BBB) permeability. FW relationship with peripheral inflammation points to immunological brain response. The biological nature of the FW increase in SZ, however, is still not clear. In this application, we propose to investigate the neurobiological correlates of this phenomenon. Specifically, we will utilize a novel, thoroughly validated animal model (Gclm knockout) in which oxidative stress and neuroinflammation are mediated by a feedforward loop induced by matrix metalloproteinase 9 (MMP-9), and test whether the phenotype associated with this model correlates with FW increase. We will characterize this relationship in two ways - first, we will use large, already collected, multi-site and multi-modal patient data to test for the relationship between neuroimaging, blood biomarkers, and cognition. Then, we will test this relationship in a transgenic animal model using Gclm knockout mice and oxidative stress and MMP-9 modifiers. We expect that upon successful completion of this project, we will have developed a clinically-feasible analytic paradigm that will propose and validate novel noninvasive biomarkers to mechanistically link oxidative stress and neuroinflammation to cognitive deficits observed in SZ. If successful, our proposal would potentially add a new biological target for the treatment of cognitive deficits prevalent in SZ and provide a noninvasive tool to monitor such treatment.