Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model

Lee E. Goldstein, Andrew M. Fisher, Chad A. Tagge, Xiao Lei Zhang, Libor Velisek, John A. Sullivan, Chirag Upreti, Jonathan M. Kracht, Maria Ericsson, Mark W. Wojnarowicz, Cezar J. Goletiani, Giorgi M. Maglakelidze, Noel Casey, Juliet A. Moncaster, Olga Minaeva, Robert D. Moir, Christopher J. Nowinski, Robert A. Stern, Robert C. Cantu, James GeilingJan K. Blusztajn, Benjamin L. Wolozin, Tsuneya Ikezu, Thor D. Stein, Andrew E. Budson, Neil W. Kowall, David Chargin, Andre Sharon, Sudad Saman, Garth F. Hall, William C. Moss, Robin O. Cleveland, Rudolph E. Tanzi, Patric K. Stanton, Ann C. McKee

Research output: Contribution to journalArticlepeer-review

Abstract

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shockwaves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning andmemory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.

ASJC Scopus subject areas

  • Medicine(all)

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