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
Bennet Omalu, Jennifer L. Hammers, Julian Bailes, Ronald L. Hamilton, M. Ilyas Kamboh, Garrett Webster and Robert P. Fitzsimmons
Following his discovery of chronic traumatic encephalopathy (CTE) in football players in 2002, Dr. Bennet Omalu hypothesized that posttraumatic stress disorder (PTSD) in military veterans may belong to the CTE spectrum of diseases. The CTE surveillance at the Brain Injury Research Institute was therefore expanded to include deceased military veterans diagnosed with PTSD. The authors report the case of a 27-year-old United States Marine Corps (USMC) Iraqi war veteran, an amphibious assault vehicle crewman, who committed suicide by hanging after two deployments to Fallujah and Ramadi. He experienced combat and was exposed to mortar blasts and improvised explosive device blasts less than 50 m away. Following his second deployment he developed a progressive history of cognitive impairment, impaired memory, behavioral and mood disorders, and alcohol abuse. Neuropsychiatric assessment revealed a diagnosis of PTSD with hyperarousal (irritability and insomnia) and numbing. He committed suicide approximately 8 months after his honorable discharge from the USMC. His brain at autopsy appeared grossly unremarkable except for congestive brain swelling. There was no atrophy or remote focal traumatic brain injury such as contusional necrosis or hemorrhage. Histochemical and immunohistochemical brain tissue analysis revealed CTE changes comprising multifocal, neocortical, and subcortical neurofibrillary tangles and neuritic threads (ranging from none, to sparse, to frequent) with the skip phenomenon, accentuated in the depths of sulci and in the frontal cortex. The subcortical white matter showed mild rarefaction, sparse perivascular and neuropil infiltration by histiocytes, and mild fibrillary astrogliosis. Apolipoprotein E genotype was 3/4. The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.
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.