The current proposal in response to PAR 11-031, Brain Disorders in the Developing World: Research Across the Lifespan (R21) will build on an existing collaboration between University of California San Diego (UCSD) and the Instituto Nacional de Neurolog?a y Neurocirug?a (INNN), Mexico City. Further collaboration, with an emphasis on understanding and treating the neuropathological changes in early psychosis could have a significant impact on early psychosis research in Mexico since INNN is a central training site in this city of over 20 million people. The proposed R21 will 1) provide resources to develop the recruitment infrastructure for potentially very large numbers of antipsychotic na?ve first episode psychosis patients in Mexico City. In addition, the Mexican site will enhance their neuroimaging program at the INNN by obtain training from UCSD in Magnetic resonance imaging (MRI) analysis techniques including segmentation analysis of cortical thickness and free water analysis of Diffusion Tensor Imaging (DTI) data. To assure between site reliability of neuroimaging biomarkers, we will perform a traveling subjects study during the first three months of the project. Finally, 2) we will also obtain pilot neuroimaging and inflammatory biomarker data in antipsychotic naive first episode patients and normal controls at both sites in preparation for a longitudinal study that investigates neuroinflammation and anti-inflammatory treatment in the same population. Ultimately we plan to submit a translational R01 that will investigate neuroinflammatory mechanisms in human and animal models of early psychosis. It has been postulated that early-life exposure to infection and/or inflammation has the potential to induce latent neuroinflammatory abnormalities that can be unmasked by exposure to stressful stimuli, activating microglia and enhancing the production of pro-inflammatory cytokines in the CNS. Animal models have demonstrated that the neurodevelopment effects of prenatal infection/inflammation can be attenuated by interventions targeting activated inflammatory response systems or associated physiologically processes. Consistent with the basic science research, recent studies in early psychosis patients suggest that anti-inflammatory interventions may attenuate negative and cognitive symptoms. In contrast, anti-inflammatory strategies are not effective in chronic schizophrenia, suggesting that neuroinflammatory processes are active during the early phase of disease and an important target for intervention. The use of multimodal neurobiological techniques as proposed in this application can provide further insight into the mechanism by which psychosis emerges. With increasing knowledge of the aberrant neurodevelopmental processes at the onset of psychosis, it may become possible to develop better treatment interventions to modify the disease outcome, morbidity and mortality.
This proposal will help to develop recruitment and neuroimaging infrastructure for antipsychotic na ve first episode psychosis patients in Mexico City while generating pilot data for a collaborative project with San Diego to study neuroinflammation in early psychosis.