[p3–127]: Concussion, Microvascular Injury, and Early Tauopathy in Young Athletes After Impact Head Injury and an Impact Concussion Mouse Mode
Year: 2017
Type: article
Abstract: The mechanisms underpinning concussion, traumatic brain injury (TBI), and chronic traumatic encephalopathy (CTE) are poorly understood. Postmortem brains from teenage athletes in the acute-subacute period after impact head injury exhibited astrocytosis, axonopathy, microvascular injury, perivascular neuroinflammation and phosphorylated tau (p-tau) proteinopathy. We developed an impact concussion mouse model that uses momentum transfer to produce traumatic head acceleration (1, 2). To investigate the connection between impact TBI and CTE, we have developed a mouse model to mimic impact-induced TBI. The post-mortem techniques used to characterize focal tauopathy and neuroinflammation consist of comprehensive neuropathological analysis and immunophenotyping along with metallomic imaging to assess alternation in microvascular integrity. Unanesthetized C57BL/6 mice subjected to lateral impact exhibited transient contralateral hemiparesis, truncal ataxia, impaired balance, abnormal locomotion, decreased arousal, and memory deficits that recapitulated concussion in humans. Impact injury induced axonopathy, blood-brain barrier (BBB) disruption, TGFβ1/pSMAD2-associated astrocytosis, microgliosis, and peripheral monocyte infiltration in ipsilateral cortex. P-tau was detected in ipsilateral cortical axons by 24 hours, progressed bilaterally by 2 weeks, and persisted at least 5.5 months post-injury. Trauma pathologies colocalized with extravasated serum albumin that was detectable by dynamic neuroimaging in vivo. Impact also induced early, persistent, bilateral impairments in hippocampal axonal conduction and long-term potentiation (LTP) of synaptic transmission in medial prefrontal cortex. Concussive signs did not correlate with BBB disruption, microgliosis, monocyte infiltration, axon dysfunction, defective LTP, or tauopathy. Concussion was observed after head impact but not after blast exposure under conditions that produce comparable head kinematics. Computational modeling showed that blast generated distributed force loading on the head and diffuse shear stress in brain. Impact produced point loading with seven-fold greater peak shear stress in brain before onset of gross head motion. We conclude that fast-acting, high-amplitude cortical shear stresses trigger concussive signs, whereas longer duration, lower amplitude forces induce structural damage and sequelae. Closed-head impact can induce TBI and trigger antecedent CTE pathologies independent of concussion.
Source: Alzheimer s & Dementia
Authors: Andrew M. Fisher, Chad A. Tagge, Olga Minaeva, Amanda Gaudreau, Juliet A. Moncaster, Xiao‐Lei Zhang, Mark W. Wojnarowicz, Noel F. Casey, Haiyan Lu, Olga Kokiko‐Cochran, Sudad Saman, Maria Ericsson, Kristen Onos, Ronel Veksler, Vlad Senatorov, Asami Kondo, Xiao Zhou, Omid Miry, Linnea R. Vose, Katisha Gopaul, Chirag Upreti, Christopher Nowinski, Robert Cantu, Victor E. Alvarez, Ning Hua, Yorghos Tripodis, Andrew Anderson, Gareth Howell, Daniela Kaufer, Garth F. Hall, Kun Ping Lu, Richard Ransohoff, Robin O. Cleveland, Neil W. Kowall, Bertrand R. Huber, Thor D. Stein, Bruce T. Lamb, William C. Moss, Alon Friedman, Patric K. Stanton, Ann C. McKee, Lee E. Goldstein
Institutions: Boston University, New York Medical College, Cleveland Clinic, University of Massachusetts Lowell, Harvard University, Jackson Laboratory, Ben-Gurion University of the Negev, University of California, Berkeley, Beth Israel Deaconess Medical Center, Beth Israel Deaconess Hospital, VA Boston Healthcare System, Lawrence Livermore National Laboratory, University of Oxford, Indiana University Indianapolis, Indiana University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4239840838