Sex-Specific Hormonal and Head Kinematic Effects on Blood Biomarker Responses to Repeated Head Impacts - PROJECT SUMMARY Brain trauma, ranging from low-severity repeated head impacts (RHI) to mild-to-severe traumatic brain injury (TBI), affects millions annually in the United States and can result in cognitive, physical, and psychosocial impairments. Sex differences in TBI outcomes have been consistently reported, with females typically showing higher incidence and more prolonged symptoms than males in similar sports. Sex hormones—progesterone, estradiol, and testosterone—can play a critical role in modulating these differences, as they have exhibited neuroprotective effects in both animal research and human TBI treatments. Cortisol, a major stress hormone, may also influence brain injury outcomes, but the impact of natural hormone levels and the variations in post- trauma outcomes remain unclear. Clinical TBI studies are limited by variability in injury mechanisms and severity and often lack pre-injury data and precise measurement of head impact kinematics. Translating animal model findings to human populations is also challenging. Controlled RHI protocols, like soccer heading practice, now offer opportunities to collect pre-impact data and control head impact energy, addressing injury variability. Advances in blood biomarker detection technologies allow sensitive assessment of brain injury due to TBI and RHI—even when impacts are seemingly insignificant. Well-studied biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light (NF-L), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and tau provide insights into brain changes after mild head impacts. This study hypothesizes that pre-injury hormone levels, impact kinematics, and post-injury hormone changes collectively influence brain trauma outcomes and TBI biomarker elevations after RHI, potentially explaining the observed sex differences. Specifically, we aim to 1) assess the effect of pre-exposure hormone levels (progesterone, estradiol, testosterone, cortisol) and kinematic severity on TBI biomarkers (GFAP, tau, NF-L, UCH-L1) after RHI in males and females, and 2) characterize how changes in hormone levels are associated with biomarker trajectories after RHI. We will analyze head kinematics and blood from 40 athletes (20 males, 20 females) who performed controlled soccer headings, with samples before and at multiple intervals post-RHI with menstruation cycle phase considered in females. This research advances personalized, sex-specific TBI management through investigation of how sex and stress hormones and biomechanics shape brain injury biomarkers and outcomes. The findings from this project can enhance risk assessment and prognostication, inform the timing of interventions, guide protective equipment design, and support development of tailored therapies. This pilot leverages available samples and new measurements and analysis, fitting the NIH R03 mechanism's scope, timeframe, and budget.
