Boosting the blood-brain barrier could avert brain damage in athletes
Repeatedly heading a soccer ball increasingly associated with lasting brain damage
René Nijhuis/MB Media
Repeated blows to the head cause long-term damage to the delicate blood-brain barrier, which can lead to chronic traumatic encephalopathy (CTE), a neurodegenerative disease that affects some former footballers, rugby players and boxers. This discovery could lead to new ways to diagnose, prevent and treat this devastating disease, which is currently only identified after a person dies.
“Many drugs in development aim to restore the blood-brain barrier for the treatment of neurological disorders, so the future will be very bright if we can see 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 participated in non-contact sports, such as rowing, and people with no sporting experience.
Participants were injected with a magnetic resonance imaging (MRI) contrast agent that only entered their brain tissue if it was able to cross the blood-brain barrier – the protective membrane that usually prevents foreign or harmful substances from exiting blood vessels into the brain. In 17 of the athletes retired from contact sports, the contrast agent could be seen seeping into many parts of their brains during MRI scans, suggesting their blood-brain barriers were severely damaged. Among participants who did not play contact sports, the contrast agent was barely present.
Retired athletes with more extensive damage to the blood-brain barrier also performed worse on cognitive and memory tests. This suggests that damage to this barrier may be an early driver of CTE, characterized by impaired thinking and memory problems, as well as depression and emotional instability. “There has been other evidence in the past that disruption of the blood-brain barrier is associated with CTE, but this reinforces the idea,” says Michael Buckland of the University of Sydney in Australia.
Repeated collisions and head whips during sport 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 is made up of tightly packed cells lining tiny blood vessels in the brain,” he explains. Impact forces break down the joints 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, Greene explains. As part of the study, the team also examined the brains of people who died with CTE and found signs of infiltration of immune cells and blood proteins into affected brain areas. CTE shares many characteristics with Alzheimer’s disease, which some researchers also believe are due to a natural weakening of the blood-brain barrier with age and the resulting entry of immune cells and other substances into the brain.
Like Alzheimer’s disease, CTE is characterized by an abnormal accumulation 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 misfold and disorganize.
When head injuries simultaneously damage the blood-brain barrier, blood proteins and inflammatory substances can begin to enter the brain and make the problem worse by causing more tau misfolding and aggregation, Greene says. Ultimately, this causes the cognitive changes seen in CTE, he believes. Buckland and colleagues previously found that the brains of people who died with CTE contained genetic signatures associated with damage to the blood-brain barrier, supporting the latest research.
Currently, CTE can only be diagnosed after death based on autopsies showing abnormal accumulation of tau in the brain. But Campbell and Greene say their MRI technique could potentially be used to support a likely diagnosis in living people with other symptoms, such as cognitive and mood changes. In the future, the imaging technique could also be used to monitor CTE risk in non-retired athletes, but more research is needed to support this hypothesis, they say.
If disruption of the blood-brain barrier is indeed an early driver of CTE, it might be possible to repurpose or develop drugs that strengthen or repair the barrier, thereby preventing or slowing disease progression, Greene says. For example, a drug called bevacizumab, which reduces blood vessel leakage, might be worth studying, he says. Other drugs that reduce brain inflammation, such as minocycline, are also attracting interest, and more are in development, he says.
“Instead of waiting until tau pathology is entrenched, we may be able to intervene earlier by protecting the vascular system, reducing harmful blood signals, and calming the inflammatory cascade before it becomes self-perpetuating,” says Greene.
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