This Veterans Affairs Career Development Award (CDA-2) proposes to examine levels of neuroinflammation and oxidative stress in the brains of Veterans with schizophrenia, and to relate these processes to each other and to important functional outcomes. Neuroinflammation, which refers to the recruitment of immune cells in response to injury, and the antioxidant defense system (AODS), which refers to the molecules and enzymes that neutralize an excess of free radicals (oxidative stress), are important protective responses to injury in the brain. Both have been shown to be altered in schizophrenia compared to healthy controls, and may be related to the pathogenesis of schizophrenia. Furthermore, their relationship to disrupted functional outcomes in schizophrenia including occupational status, housing status, and social relationships, remains relatively unstudied. Until recently, markers for neuroinflammation and the AODS have only been examined in postmortem tissue, peripheral blood, or cerebrospinal fluid (CSF) of patients. This CDA-2 proposes to examine both neuroinflammation and the AODS directly in brain of Veterans with schizophrenia and control subjects with two relatively novel techniques: 1) neuroinflammation will be measured with second-generation radioligand binding to the molecule translocator protein (TSPO), using positron emission tomography (PET); subjects will be genotyped in order to exclude the low affinity binding phenotype prior to entering the study, and 2) the AODS will be measured with levels of glutathione, the most important antioxidant molecule in the brain, using magnetic resonance spectroscopy (MRS). The specific area of focus will be dorsolateral prefrontal cortex in light of this area?s importance for cognitive function in schizophrenia. The project has three scientific goals: a) Brain levels of neuroinflammation and the AODS will be compared between patients with schizophrenia and healthy controls. b) The relationship of neuroinflammation and oxidative stress to each other in patients will be examined, along with their relationship to cognitive performance and community function via clinical assessments and interviews. c) The peripheral inflammatory markers TNF-a, IL-6, IL-10, INF-g and CRP will be measured, and their relationship to the above central markers will be examined. This information will shed light on the roles of two key processes in the brain in schizophrenia, and their influence on quality of life for Veterans with schizophrenia. In addition to these scientific aims, this proposal will provide the applicant, Dr. Yvonne Yang, with expertise in PET neuroimaging and MRS neuroimaging, and expertise in the field of neuroinflammation in schizophrenia. Dr. Yang?s training plan includes regular meetings with her mentors: expert in PET neuroimaging Dr. Mark Mandelkern, MRS physicist Dr. Albert Thomas, psychiatrist and expert in MRS of glutathione Dr. Richard Maddock, expert in psychoneuroimmunology Dr. Michael Irwin, and her primary mentor Dr. Michael Green. It also includes workshops, conferences, formal didactics, and training in the responsible conduct of research. The scientific project, training plan, and mentoring plan described above will provide Dr. Yang with the skills and expertise to independently lead further studies investigating the role of neuroinflammation in schizophrenia, and lay the groundwork for a personalized medicine treatment paradigm using anti-inflammatory and antioxidant agents, through a VA Merit Award proposal.
Schizophrenia and related psychotic disorders are a major cause of disability worldwide. Current treatments can improve schizophrenia symptoms such as hallucinations and delusions, but do not affect the symptoms most closely correlated with real-world functioning (cognitive and negative symptoms). An improved understanding of how neuroinflammation contributes to the pathophysiology of schizophrenia could lead to a) novel treatments for cognitive and negative symptoms, b) identification of biomarkers that could help guide future treatment, and c) foundation for a personalized medicine approach to the treatment of schizophrenia, including utilization of anti-inflammatory and antioxidant treatment. These developments may, in turn, improve the vocational, housing, and social situation of Veterans and others with schizophrenia. !
