Mild Traumatic Brain Injury Causes Lasting Blood-Brain Barrier Dysfunction

Post by Deborah Joye

What's the science?

Players of contact sports such as American football are at particularly high risk for traumatic brain injury, which occurs when a sudden impact damages the brain. Repeated traumatic brain injury can result in neurodegenerative diseases later in life such as chronic traumatic encephalopathy. The brain’s microvasculature (the many small vessels supplying blood to the brain) can be damaged as a result of a traumatic brain injury. Specifically, dysfunction of the blood-brain barrier, which regulates which molecules can enter the brain, is connected to complications after traumatic brain injury and is also a hallmark of other brain disorders including stroke and epilepsy. To visualize how well the blood-brain barrier is working, researchers can measure how fast a tracer accumulates in the brain. Most previous studies have focused on tracer accumulation that happens very quickly and have seen very few differences. This week in Brain, Veksler and colleagues investigate more subtle blood-brain barrier dysfunction and demonstrate that a specific increase in slow-paced blood-to-brain transport is a hallmark of microvascular pathology that persists long after the initial brain injury.

How did they do it?

First, to test whether blood-brain permeability (leakiness) was different between football players and other groups, the authors performed their modified magnetic resonance imaging (MRI) protocol on 42 football players, and control groups of 27 non-contact sport athletes and 26 non-athletes. After MRI all participants also had blood drawn to test for markers of inflammation, and neuronal or glial injury. To test for changes in blood-brain barrier function over time, football players were scanned both during and after the season. By comparing with healthy brain scans, the authors were able to define the upper limit of “normal” permeability and visualize voxels (like a 3D pixel) where permeability was abnormally high. To test whether blood-brain permeability was associated with abnormalities in white matter, the authors also performed diffusor tensor imaging, which allows visualization of neuronal tracts. To investigate differences between slow and fast blood-to-brain transport, the authors tracked how quickly tracer accumulated in regions of the brain. As an additional comparison group, the authors also performed MRI scans in 51 patients with brain disorders that are known to include blood-brain barrier dysfunction (e.g. tumour, stroke). Finally, to test that brain injury through trauma or vascular injury is causal in blood-brain barrier leakiness, the authors repeated their experiments using both rat and mouse models. The authors performed modified MRI scans on both rat and mouse models of repetitive mild traumatic brain injury, as well as rat models of vascular injury and stroke.

What did they find?

The authors found that compared to healthy controls, football players had a much higher percentage of brain volume with abnormally high blood-brain barrier permeability. Increased leakiness was consistent across scans both during and after the season (roughly 6 months later). Some players showed a gradual decrease in abnormal permeability over time, while the other players actually showed an increase in permeability. An increase in blood-brain barrier dysfunction was associated with age, but not with number of concussions, years playing football, or scores on a concussion assessment test. The authors also found that certain regions of the brain were particularly susceptible to blood-brain barrier dysfunction, including the left temporal and occipital lobes (involved in understanding auditory and visual signals, respectively), the thalamus (an important relay for sensory information), the basal ganglia (important for movement), and white matter tracts (neuron tracts that connect different brain regions).

The authors also found that white matter tracts amongst football players showed abnormalities compared to healthy controls. These abnormalities were localized to thalamic radiations (connect the thalamus to the cortex), the corpus callosum (connects the two hemispheres of the brain), and two other long-range tracts which connect multiple brain regions (the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus). Importantly, measures of blood-based biomarkers for inflammation or glial/neuronal injury were not different between healthy controls and players, suggesting that measures of blood-brain permeability may detect damage that other assessments do not. The authors repeated their experiments in both rat and mouse models of mild traumatic brain injury, vascular damage, and stroke, and found that brain tissue around the core injury site displayed persistent slow transport blood-brain barrier dysfunction.

What's the impact?

This work is the first to use human brain imaging to distinguish between fast and slow leakage through a dysfunctional blood-brain barrier. These data also provide evidence, for the first time, that some football players show evidence of blood-brain dysfunction that lasts for months after the initial injury. Given the place of contact sports such as American football in society and the prevalence of players in many different age groups, understanding the consequences of repetitive traumatic brain injury is critical to developing better treatments and health outcomes. 

Veksler et al., Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players, Brain (2020). Access the original scientific publication here.