Background: Evidence has been accumulating for an immune-based component of psychiatric disorder etiology, particularly schizophrenia. One of the first indications of such a link comes from early epidemiological studies, which found an increased incidence of schizophrenia in offspring of mothers who had an infection (e.g., influenza) during pregnancy. Recent work has identified genetic links to the major histocompatibility complex, pro-inflammatory cytokine elevations in cerebrospinal fluid and plasma, as well as mixed evidence of microglial activation. While these findings provide strong evidence of an immune component, human studies are inherently limited by the heterogeneity of the sample and inability to make strong inferences about causality. Consequently, we have developed a non-human primate (NHP) model of maternal immune activation (MIA) using a modified form of the viral mimic polyIC (polyICLC) to test the hypothesis that maternal immune response contributes to changes in the developing brain and behavior of NHP offspring. In a previous cohort of MIA-exposed offspring, our group observed increased pre-synaptic dopamine levels in the striatum using 6-[18 F]fluoro-L-mtyrosine (FMT) positron emission tomography, in addition to pubertal-onset behavioral abnormalities, which may model part of the neurodevelopmental pathway towards psychosis. The current study builds on this model and examines the effect of maternal immune activation on a promising biomarker of neuroinflammation in vivo-extracellular free water-a diffusion magnetic resonance imaging measure obtained with a multi-shell acquisition (i.e., Pasternak, Shenton, and Westin, 2012). We sought to test the hypothesis that offspring of pregnant monkeys who received polyICLC injections at the end of the first trimester would show increased extracellular free water compared to control offspring. Method(s): Fourteen pregnant rhesus monkeys (Macaca mulatta) received polyICLC and 10 pregnant monkeys received saline injections at the end of the first trimester. An additional four offspring were added to reach target enrollment of 14 control animals. The offspring from both groups (all of whom were male) underwent a diffusion MRI scan on a 3 Tesla Siemens Skyra scanner in which multiple b-value shells were acquired to improve estimation of extracellular free water. Diffusion data was collected when the offspring were one month, 6 months, and 12 months of age, although only 6-month preliminary findings are currently presented. Diffusion images were aligned to individual subject MPRAGE scans, and existing segmented MPRAGE masks were used to define whole-brain gray- and white-matter free water estimates. Individual subject structural scans were then nonlinearly aligned to generate a common group average template and the group average template was subsequently nonlinearly aligned to a neurodevelopmental rhesus atlas. Finally, regional parcellations from the rhesus atlas were brought back into individual subject space via inverse transformations in order to generate subject-specific regions of interest. For this preliminary analysis, the frontal cortex was selected as an a priori region of interest in addition to the more global whole-brain gray and white matter masks. Group differences were assessed using repeated measures ANOVA and independent samples t-tests implemented in SAS. Result(s): Six-month-old MIA-exposed rhesus offspring showed a trend for increased whole-brain white matter extracellular free water (p= .09) with no significant difference in whole-brain gray matter free water (p =.27) compared to control offspring. However, analysis of the frontal region of interest revealed significantly increased gray matter free water in the left hemisphere (p= .013) with a trend towards increased gray matter free water in the right hemisphere (p =.081). There were no significant differences between MIA-exposed and control offspring in basic motor and reflex development or growth trajectories. Conclusion(s): These data suggest that despite the lack of behavioral abnormalities at this early age, extracellular free water values are increased in MIA-exposed offspring, particularly in frontal gray matter. More global whole-brain free water group differences, however, did not reach statistical significance, which may indicate some regional specificity to these changes early in development. The addition of the 12-month imaging timepoint, due to be completed in two months, will provide important context and give a better indication of the trajectory of free water changes both at global and local levels. Nonetheless, the NHP MIA model complements the human schizophrenia literature in which extracellular free water increases have been repeatedly identified. Further support for the NHP MIA model is provided by findings from our previous cohort of MIA-treated NHP offspring, which showed significantly higher striatal [18 F]FMT binding potential, along with abnormal behaviors. Ultimately, these data provide validation of the clinical relevance of the NHP MIA model and improve our understanding of neuroimmune mechanisms in the development of psychiatric disorders, particularly schizophrenia.
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Carter, C., Lesh, T., Tanase, C., Bennett, J., Iosif, A.-M., Van Der Water, J., … Baumann, M. (2018). T35. DIFFUSION MEASURES OF EXTRACELLULAR FREE WATER IN A NON-HUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION: EXPLORING NEUROIMMUNE MECHANISMS OF PSYCHIATRIC DISORDERS. Schizophrenia Bulletin, 44(suppl_1), S126–S126. https://doi.org/10.1093/schbul/sby016.311