Hitting a football repeatedly is increasingly being linked to permanent brain damage
Rene Nijhuis/MB Media
Repeated blows to the head cause long-term damage to the delicate blood-brain barrier and can potentially lead to chronic traumatic encephalopathy (CTE), a neurodegenerative condition that affects some former football players, rugby players and boxers. The discovery could lead to new ways to diagnose, prevent and treat the devastating condition, which is currently only identified after someone has died.
“There are many drugs in development that seek to restore the blood-brain barrier for the treatment of neurological disorders, so the future will be very bright if we can see the approval of some of these drugs,” says Matthew Campbell of Trinity College Dublin in Ireland.
Campbell and his colleagues scanned the brains of 47 former footballers, rugby players and boxers who had retired an average of 12 years earlier. They also scanned the brains of retired athletes who had competed in non-contact sports, such as rowing, and people with no sporting background.
The participants were injected with a magnetic resonance imaging (MRI) contrast agent that only entered their brain tissue if it was able to breach the blood-brain barrier – the protective membrane that normally stops foreign or harmful substances from moving out of the blood vessels into the brain. In 17 of the retired contact athletes, the contrast agent could be seen leaking into many parts of their brains in MRI scans, suggesting that their blood-brain barriers were severely damaged. Among the participants who had not played contact sports, the contrast agent barely appeared.
The retired athletes with more extensive blood-brain barrier damage also performed worse in cognitive tests and memory tests. This suggests that damage to this barrier may be an early driver of CTE, which is characterized by thinking and memory problems, as well as depression and emotional instability. “There have been other pieces of evidence in the past that blood-brain barrier disruption is associated with CTE, but this strengthens the idea,” says Michael Buckland of the University of Sydney in Australia.
Repeated collisions and whiplash movements of the head during sports damage the blood-brain barrier via mechanical forces, says team member Chris Greene of the Royal College of Surgeons in Ireland. “The blood-brain barrier is often described as a wall, but it is better to think of it as a living, dynamic system. It consists of densely packed cells along small blood vessels in the brain,” he says. Impact forces loosen the seals between neighboring cells in this barrier, making it more permeable, he says.
Once this happens, proteins, immune cells and inflammatory substances circulating in the blood can begin to enter the brain and cause inflammation and damage, says Greene. As part of the study, the team also examined the brains of people who died with CTE and found evidence of immune cell and blood protein infiltration in affected brain areas. CTE shares many features with Alzheimer’s disease, which some researchers believe is also driven by a natural weakening of the blood-brain barrier with age and the resulting penetration of immune cells and other substances into the brain.
Like Alzheimer’s disease, CTE is characterized by an abnormal build-up of a protein called tau in the brain. In healthy brains, tau is a normal structural protein in neurons, but blows to the head can cause it to become misfolded and disorganized.
When head injuries simultaneously damage the blood-brain barrier, blood proteins and inflammatory substances can begin to enter the brain and exacerbate the problem by driving further misfolding and aggregation of cords, Greene says. Ultimately, this causes the cognitive changes seen in CTE, he believes. Buckland and his colleagues previously found that the brains of people who died with CTE contained gene signatures associated with blood-brain barrier compromise, which supports the latest research.
Currently, CTE can only be diagnosed after death based on autopsies that show abnormal tau buildup in the brain. But Campbell and Greene say their MRI technique could potentially be used to support a probable diagnosis in living people showing other symptoms, such as cognitive changes and mood swings. In the future, the imaging technique could also be used to monitor CTE risk in non-retired athletes, but further research is needed to support this, they say.
If disruption of the blood-brain barrier is indeed an early driver of CTE, it may be possible to repurpose or develop drugs that strengthen or repair the barrier, thereby preventing or slowing the condition’s progression, Greene says. For example, a drug called bevacizumab that reduces blood vessel leakage may be worth investigating, he says. Other drugs that reduce brain inflammation, such as minocycline, are also attracting interest, and there are more in development, he says.
“Instead of waiting until the tau pathology is entrenched, we may be able to intervene earlier by protecting the vasculature, reducing harmful blood-derived signals and calming the inflammatory cascade before it becomes self-perpetuating,” says Greene.
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