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Brain. 2018 Feb 1;141(2):422-458. doi: 10.1093/brain/awx350.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

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Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.
Boston University College of Engineering, Boston, MA 02215, USA.
Boston University Photonics Center, Boston University, Boston, MA 02215, USA.
Boston University School of Medicine, Boston, MA 02118, USA.
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
The Center for Biometals and Metallomics, Boston University School of Medicine, Boston, MA 02118, USA.
Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA.
Electron Microscope Facility, Harvard Medical School, Boston, MA 02115, USA.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Departments of Brain and Cognitive Sciences, Physiology and Cell Biology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Alzheimer's Disease Center, CTE Program, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Neurosurgery, Emerson Hospital, Concord, MA 01742, USA.
VA Boston Healthcare System, Boston, MA 02130, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Lawrence Livermore National Laboratory, Livermore, CA 94551, USA.
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK.
National Center for PTSD, VA Boston Healthcare System, Boston, MA 02130, USA.
Department of Medical Neuroscience, Brain Repair Center, Dalhousie University, Halifax, B3H 4R2, Canada.


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.awx350media15713427811001.


TREM2; chronic traumatic encephalopathy; concussion; tau protein; traumatic brain injury

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