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Traumatic brain injury is the leading cause of death in children and young adults globally. malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RnA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE.

Traumatic brain injury (TBI) is a complex injury that is hard to predict and diagnose, with many studies focused on associating head kinematics to brain injury risk. Recently, there has been a push towards using computationally expensive finite element (FE) models of the brain to create tissue deformation metrics of brain injury. Here, we develop a new brain injury metric, the Brain Angle Metric (BAM), based on the dynamics of a 3 degree-of-freedom lumped parameter brain model. The brain model is built based on the measured natural frequencies of a FE brain model simulated with live human impact data. We show it can be used to rapidly estimate peak brain strains experienced during head rotational accelerations. On our dataset, the simplified model highly correlates with peak principal FE strain (R 2 =0.80). Further, coronal and axial model displacement correlated with fiber-oriented peak strain in the corpus callosum (R 2 =0.77). Our proposed injury metric BAM uses the maximum angle predicted by our brain model, and is compared against a number of existing rotational and translational kinematic injury metrics on a dataset of head kinematics from 27 clinically diagnosed injuries and 887 non-injuries. We found that BAM performed comparably to peak angular acceleration, linear acceleration, and angular velocity in classifying injury and non-injury events. Metrics which separated time traces into their directional components had improved model deviance to those which combined components into a single time trace magnitude. Our brain model can be used in future work both as a computationally efficient alternative to FE models and for classifying injuries over a wide range of loading conditions. Key words:Brain injury, injury criterion, injury prediction, concussion 159.32, 131.53, and 132.02 respectively. Further, metrics such as HIC and SI which analyze acceleration magnitudes performed with lower sensitivity to those which treated each direction separately. Similarly, the VTCP, which takes into account peak linear and angular acceleration magnitude, had lower model deviance and higher AUCPR and AUCROC than metrics which treated each anatomical direction separately. Peak linear acceleration ( ⃗) had lower deviance, AUCPR, and AUCROC to peak angular kinematics and BAM but still outperformed many other metrics. While many previous studies suggest rotation is a primary cause of brain injury 16,17,56 , the results shown here indicate that linear acceleration still has predictive value in classifying brain injuries. This could be because in our dataset, with the majority of injuries taken from laboratory reconstruction data, the linear and angular acceleration values may be coupled more so than in-vivo data.However, single variate injury criteria, based on linear acceleration, had extremely low sensitivity in our dataset. We see that both HIC15 and SI predict only a single event with >50% risk of injury on our dataset due to a few non-injury events with high HIC15 and SI values. Surprisingly, many existing metrics had hig...

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