Research now suggests that head impacts commonly occur during contact sports in which visible signs or symptoms of neurological dysfunction may not develop despite those impacts having the potential for neurological injury. Recent biophysics studies utilizing helmet accelerometers have indicated that athletes at the collegiate and high school levels sustain a surprisingly high number of head impacts ranging from several hundred to well over 1000 during the course of a season. The associated cumulative impact burdens over the course of a career are equally important. Clinical studies have also identified athletes with no readily observable symptoms but who exhibit functional impairment as measured by neuropsychological testing and functional MRI. Such findings have been corroborated by diffusion tensor imaging studies demonstrating axonal injury in asymptomatic athletes at the end of a season. Recent autopsy data have shown that there are subsets of athletes in contact sports who do not have a history of known or identified concussions but nonetheless have neurodegenerative pathology consistent with chronic traumatic encephalopathy. Finally, emerging laboratory data have demonstrated significant axonal injury, blood-brain barrier permeability, and evidence of neuroinflammation, all in the absence of behavioral changes. Such data suggest that subconcussive level impacts can lead to significant neurological alterations, especially if the blows are repetitive. The authors propose “subconcussion” as a significant emerging concept requiring thorough consideration of the potential role it plays in accruing sufficient anatomical and/or physiological damage in athletes and military personnel, such that the effects of these injuries are clinically expressed either contemporaneously or later in life.
Julian E. Bailes, Anthony L. Petraglia, Bennet I. Omalu, Eric Nauman and Thomas Talavage
Brandon P. Lucke-Wold, Ryan C. Turner, Aric F. Logsdon, Linda Nguyen, Julian E. Bailes, John M. Lee, Matthew J. Robson, Bennet I. Omalu, Jason D. Huber and Charles L. Rosen
Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration.
The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors’ clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler.
The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase–3β. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy.
Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.