A mechanistic clinical trial of omega-3 fatty acids to prevent subconcussive neural injury

PROJECT SUMMARY/ABSTRACT Subconcussive head impacts (SHI), defined as a head impact without overt symptoms of concussion, are incredibly common among soccer players as a result of soccer heading. SHI from repetitive soccer headings may pose a risk of triggering neurodegenerative disorders later in life. However, despite the popularity of soccer with nearly 24 million people in the U.S. across all ages and sexes playing soccer, there is currently no prophylactic intervention to mitigate or ameliorate neurologic stress from soccer heading. Our data suggest at least 4 neurologic features related to subconcussive brain injury. For example, acute SHI from soccer headings and football tackles lead to elevation of neural injury blood biomarkers (NF-L, GFAP, tau, UCH-L1, S100B), changes in axonal microstructural integrity, and sympathetic hyperreactivity, triggering hypertensive characteristic, and neuro-ophthalmologic impairments, such as convergence and saccades. Growing data from many preclinical and clinical studies suggest that these cellular and physiologic alterations may be preventable by pretreatment with omega-3 fatty acids (FA), especially with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which has shown to alleviate neuronal and glial oxidation and calcium triggered excitotoxicity, mitigate elevations of plasma NF-L levels (axonal injury marker), and maintain cognitive function after various severities of traumatic brain injury (TBI). We propose a randomized controlled trial to obtain mechanistic insights into the biophysiologic interaction between DHA+EPA pretreatment and acute SHI and determine whether, and to what extent, pretreatment with DHA and EPA combined is neuroprotective against repetitive SHI. Our central hypothesis is that DHA+EPA pretreatment will be neuroprotective against SHI. We hypothesize that 20 controlled acute soccer headings will result in microdamage to neuronal structures and sympathetic hyperreactivity, but that 8 weeks of pretreatment with 3.4 g/d DHA+EPA will significantly prevent such alterations. There are three synergistic aims. We hypothesize that (1) DHA+EPA will prevent neuronal and astrocyte damage after acute and cumulative SHI, as assessed by the panel of blood biomarkers (NF-L, tau, GFAP, UCH-L1, S100B); (2) DHA+EPA pretreatment will attenuate disruption in axonal microstructure and altered functional connectivity after acute and cumulative soccer headings; and (3) DHA+EPA pretreatment will prevent the triggering of sympathetic hyperreactivity after soccer headings, as reflected by a typical cardiovascular response to the cold pressor test. If our hypotheses are confirmed, our findings will provide a means to intervene in the SHI-induced neurological damage that can be monitored through multimodal neurologic assessments. Clinical implications of the study translate beyond soccer to the public at large.