期刊
BRAIN
卷 145, 期 6, 页码 2049-2063出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awab450
关键词
concussion; repetitive mild traumatic brain injury; blood-brain barrier; dynamic contrast-enhanced MRI; biomarker
资金
- Office of the Assistant Secretary of Defense for Health Affairs, through the Epilepsy Research Program [W81XWH-17-1-0684]
- Israel Science Foundation [717/15]
- Binational Israel-USA Foundation (BSF) [2015363]
- Canadian Institutes of Health Research (CIHR) [PJT 148896]
- European Research Area Network Neuron Award (CIHR Award) [NDD 168164]
- Dalhousie Medical Research Foundation Morris Kohler Studentship
Parker et al. demonstrate that susceptibility to concussion is associated with blood-brain barrier dysfunction and neuroinflammation. Pharmacological treatment targeting the inflammation induced by blood-brain barrier dysfunction can protect brain function and improve neurological outcomes in a rodent model of traumatic brain injury. These findings are important for a better understanding of the complications of mild traumatic brain injury and the development of diagnostic and treatment methods.
Parker et al. show that susceptibility to concussion is linked to blood-brain barrier dysfunction (BBBD) and neuroinflammation. Pharmacological treatment of BBBD-induced inflammation restores BBB integrity, protects brain function, and improves neurological outcomes in a rodent model of traumatic brain injury. The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor beta (TGF beta) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective TGF beta receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory TGF beta signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGF beta signalling may be a novel strategy in treating mild traumatic brain injury.
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