Reuter-Rice and Colleague Submit NIH R01 Application

Kudos to Karin Reuter-Rice, associate professor; and Allison Ashley-Koch of Duke University School of Medicine for the submission of their NIH R01 application entitled "Immunogenetic Signatures in Children Recovering from Mild TBI." This proposal requests funding for a five-year period with a start date of April 1, 2020.

Concussion is a mild traumatic brain injury (mTBI) and in children it is a “silent epidemic”. It accounts for 75% of the more than 1 million annual pediatric emergency department (ED) visits, making it a serious public health concern in the United States. Concussion is a direct or indirect blow to the head which can lead to a transient loss of consciousness, amnesia, and/or mental status changes. As many as 60% of children with mTBI remain affected by post-concussion symptoms (PCS) at 1 month post-injury and 33% of children can have prolonged PCS at 3 months post-injury. PCS is associated with headache, cognitive deficits, sleep disturbance, and emotional dysregulation, which impacts a child’s return to learn and play. Children also take longer to recover from concussion than adults. Therefore, early identification of the child who is at risk for PCS would radically impact the timing, evaluation and effectiveness of treatment strategies and lead to improved health outcomes. PCS results from biological, physiological, psychological, and social factors, which all play a role in prolonged PCS. Therefore, it is critical to understand the underlying mechanisms that influence PCS development. PCS has been linked to traumatic/diffuse axonal injury and neuroinflammation, which activate immune cells, non- immune cells, and increase inflammatory mediators. Thus, individual genetic and genomic differences in these processes are likely to contribute to the development of PCS, although they remain to be thoroughly explored. Our preliminary data suggests that immunologic genetic variants are associated with underlying risk for poor cognitive and functional outcomes and PCS in children with mTBI. We hypothesize that genetic and transcriptomic data will give rise to immune signatures that will (largely) distinguish children with mTBI who develop PCS, from those who do not. This proposal plans to extend our preliminary findings in a comprehensively phenotyped cohort (N=500) of children (11-17 years) with mTBI, some of whom will exhibit PCS. We will prospectively evaluate PCS in a well-powered ED cohort of children with mTBI. We will interrogate genetic variation in neuroinflammatory and immune candidate genes and define whole transcriptome expression patterns over three key inflammatory time-points (acute t1= <72 hours post-injury; subacute t2 = 1 month post- injury; chronic t3 = 3 months post-injury) to establish whether there are immunogenetic and immunogenomic signatures that differ among children with mTBI who do and do not develop PCS. Our project will fill a gap in knowledge by interrogating genetic and genomic variation and transcriptional patterns in a large, well-powered and deeply-phenotyped pediatric cohort over three time-points, including the crucial 1 and 3 month post-injury periods where PCS becomes evident. The potential impact of identifying genetic and genomic markers that reliably predict PCS following mTBI would be enormous. It could fundamentally shift our current understanding of mechanisms leading to PCS, and lead to improved clinical and therapeutic strategies following mTBI.