Project Description:
Despite advances in understanding how neuroinflammation contributes to the etiology of psychiatric disorders, the field of autism spectrum disorder (ASD) research has lagged, with no published studies that have directly evaluated neuroinflammation in ASD. This is despite the fact that there are multiple lines of evidence that ASD is characterized by neuroinflammation. This evidence derives from: higher concentrations of cytokines (proteins that regulate the bodys immune response) in the blood of children with ASD, preclinical findings of neuroinflammation in animal models of ASD, and increased ASD risk following maternal viral infection in the first trimester of pregnancy or bacterial infection in the second trimester of pregnancy, both of which expose children who develop ASD in utero to maternal inflammatory antibodies; post-mortem data that indicate altered microglia activation in ASD, and transcriptome findings that reveal dysregulated genes that regulate microglial responses in ASD brains.
The only way to assess neuroinflammation in vivo is by positron emission tomography (PET) imaging using a tracer that is specifically sensitive to neuroinflammatory processes. In 2016, UNC became only the fourth institution in the country to obtain a brain imaging scanner capable of collecting PET and magnetic resonance imaging (MRI) brain imaging data simultaneously (simultaneous PET/MR). This breakthrough technology allows for the acquisition of PET data with a tracer that is specifically sensitive to neuroinflammation, while simultaneously collecting both structural and functional MRI data to evaluate brain anatomy and brain functioning (see figure to the right).
In December, 2019, we were one of only four winners of the first annual UNC Neuroscience Center NeuroSpark pilot award competition that funded us to investigate neuroinflammation in males with ASD using simultaneous PET/MR. In this Foundation of Hope application, we are proposing to collect neuroinflammation PET scans from females with ASD to investigate sex differences in neuroinflammation in ASD. This represents a critical extension of this line of research. Males are four times more likely than females to have ASD, and microglia (the major brain immune cell) plays a central role in sexual differentiation of the brain. There are widespread sex differences in the neurobiology of ASD: maternal and early postnatal immune activation produce sex-specific effects in preclinical ASD model organisms and perinatal inflammation has sex-dependent effects on brain development. In animal models, males have a higher concentration than females of microglia in brain regions implicated in the pathogenesis of ASD, suggesting that sex differences in ASD prevalence may be linked to sex differences in neuroinflammation during early brain development. For these reasons, we believe that studying sex differences in neuroinflammation in ASD has the potential to reveal important insights about ASD biology, mechanisms underlying sex differences in ASD prevalence, and ultimately, sex-specific ASD treatments that target neuroinflammation.
We are proposing here to collect neuroinflammation PET data from females with ASD (n=10) to combine with (1) PET data we are collecting from males with ASD (n=10, supported by our NeuroSpark pilot award) and (2) PET data we are collecting from controls (n=20) funded by K23 MH113733 to Co-I Walsh. By leveraging these other sources of funding to our team, we will maximize the full impact of this FoH funding.
