The Impact of Diffuse Mild Brain Injury on Clinical Outcomes in Children

Lovelace Biomedical Research Institute, Albuquerque NM

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Abstract

Abstract. Pediatric mild traumatic brain injury (pmTBI) remains a large public health concern due to the number of youths affected each year and the risk for permanently altered neurodevelopmental trajectories. Emerging evidence from our ongoing R01 project and other independent studies suggests a potential mismatch between symptomatic (self-reported post-concussive symptom load; PCS) and physiological recovery as indexed by advanced imaging biomarkers. This exponentially increases the risk for a cumulative and potentially super- additive second injury if premature decisions are made about return to activity. The proposed renewal application builds upon a very successful R01 program (29 publications, over-recruitment [N=566 unique participants] during COVID-19 pandemic, high [>80%] retention rates) that demonstrated diffuse microstructural and vascular injuries that persisted up to 4 months post-injury. The proposed renewal further elucidates the mechanisms underlying these diffuse axonal and vascular injuries, including altered myelin volume fractions, neuroinflammation (quantified through myo-inositol and the anti-oxidant glutathione in cerebro), arterial transit times, as well as the balance between excitatory (glutamate and glutamine) and inhibitory (γ-Aminobutyric acid; GABA) neurotransmission that is critical for the maintenance of neuronal homeostasis. These imaging markers will be complimented by traditional (e.g., neurofilament light [NFL], glial fibrillary acid protein [GFAP]) and novel blood- based biomarkers of blood-brain barrier breach and endothelial damage. Our new preliminary data provides evidence that NFL remains elevated up to 4 months post-injury and is associated with white and grey matter abnormalities on advanced imaging, with initial feasibility studies established for all other novel imaging and blood-based biomarkers. To achieve our renewal objectives, 178 pmTBI (ages 13-18) and 132 matched (age, sex and social economic status) healthy controls (HC) will be enrolled across acute (1-48 hours post-injury; blood and minimal clinical assessments); sub-acute (SA: 3-10 days; full clinical, imaging and blood collection assessments) and early chronic (EC: ~4 months; full clinical, imaging and blood collection assessments) visits. Patients and HC, as well as their primary caregivers, are assessed with a comprehensive Common Data Elements clinical battery to characterize cognitive, physical and emotional sequelae of concussion. Our published data demonstrate that equivalent assessments of clinical and biomarker data in HC are necessary to disambiguate trauma effects from sex and age-related typical neurodevelopment, which occurs even within a 4- month assessment window and is unique to pediatric populations (i.e., cannot be inferred from adults).