TY - JOUR
T1 - Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model
AU - Tagge, Chad A.
AU - Fisher, Andrew M.
AU - Minaeva, Olga V.
AU - Gaudreau-Balderrama, Amanda
AU - Moncaster, Juliet A.
AU - Zhang, Xiao Lei
AU - Wojnarowicz, Mark W.
AU - Casey, Noel
AU - Lu, Haiyan
AU - Kokiko-Cochran, Olga N.
AU - Saman, Sudad
AU - Ericsson, Maria
AU - Onos, Kristen D.
AU - Veksler, Ronel
AU - Senatorov, Vladimir V.
AU - Kondo, Asami
AU - Zhou, Xiao Z.
AU - Miry, Omid
AU - Vose, Linnea R.
AU - Gopaul, Katisha R.
AU - Upreti, Chirag
AU - Nowinski, Christopher J.
AU - Cantu, Robert C.
AU - Alvarez, Victor E.
AU - Hildebrandt, Audrey M.
AU - Franz, Erich S.
AU - Konrad, Janusz
AU - Hamilton, James A.
AU - Hua, Ning
AU - Tripodis, Yorghos
AU - Anderson, Andrew T.
AU - Howell, Gareth R.
AU - Kaufer, Daniela
AU - Hall, Garth F.
AU - Lu, Kun P.
AU - Ransohoff, Richard M.
AU - Cleveland, Robin O.
AU - Kowall, Neil W.
AU - Stein, Thor D.
AU - Lamb, Bruce T.
AU - Huber, Bertrand R.
AU - Moss, William C.
AU - Friedman, Alon
AU - Stanton, Patric K.
AU - McKee, Ann C.
AU - Goldstein, Lee E.
N1 - Publisher Copyright:
© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-Term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.
AB - The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-Term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.
KW - TREM2
KW - chronic traumatic encephalopathy
KW - concussion
KW - tau protein
KW - traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=85041686722&partnerID=8YFLogxK
U2 - 10.1093/brain/awx350
DO - 10.1093/brain/awx350
M3 - Article
C2 - 29360998
AN - SCOPUS:85041686722
SN - 0006-8950
VL - 141
SP - 422
EP - 458
JO - Brain
JF - Brain
IS - 2
ER -