Boosting the blood-brain barrier could avert brain damage in athletes

Repeated head knocks cause long-term damage to the delicate blood-brain barrier, potentially driving chronic traumatic encephalopathy (CTE), a neurodegenerative condition that affects some former footballers, rugby players and boxers. The finding may 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 are seeking 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 medications,” says Matthew Campbell at 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, like rowing, and people without any sporting backgrounds.

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 usually stops foreign or harmful substances from moving out of blood vessels into the brain. In 17 of the retired contact sport athletes, the contrast agent could be seen leaking into many parts of their brains in MRI scans, suggesting that their blood-brain barriers were badly damaged. Among the participants who hadn’t played contact sports, the contrast agent barely showed up.

The retired athletes with more extensive blood-brain barrier damage also performed worse in cognitive and memory tests. This suggests that damage to this barrier may be an early driver of CTE, which is characterised by trouble thinking and memory problems, as well as depression and emotional instability. “There have been other bits of evidence in the past that blood-brain barrier disruption is associated with CTE, but this strengthens the idea,” says Michael Buckland at the University of Sydney in Australia.

Repeated collisions and whiplash movements of the head during sport damage the blood-brain barrier via mechanical forces, says team member Chris Greene at the Royal College of Surgeons in Ireland. “The blood-brain barrier is often described as a wall, but it’s better thought of as a living, dynamic system. It’s made up of tightly-packed cells lining tiny blood vessels in the brain,” he says. Impact forces loosen the seals between neighbouring cells in this barrier, making it more permeable, he says.

Once this occurs, proteins, immune cells and inflammatory substances circulating in the blood can start to get into 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 signs of immune cell and blood protein infiltration in affected brain areas. CTE shares many features with Alzheimer’s disease, which some researchers think 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.

Similarly to Alzheimer’s disease, CTE is characterised 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 disorganised.

When head injuries simultaneously damage the blood-brain barrier, blood proteins and inflammatory substances can start to get into the brain and worsen the problem by driving further misfolding and aggregation of tau, says Greene. Eventually, 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, supporting the latest research.

Currently, CTE can only be diagnosed after death based on autopsies showing abnormal tau build-up in the brain. But Campbell and Greene say their MRI technique could potentially be used to support a likely diagnosis in living people who are exhibiting other symptoms, like cognitive and mood changes. In future, the imaging technique may also be used to monitor CTE risk in non-retired athletes, but further research is needed to support this, they say.

If disruption to the blood-brain barrier is indeed an early driver of CTE, it may be possible to repurpose or develop drugs that reinforce or repair the barrier, thereby preventing or slowing the condition’s progression, says Greene. For example, a drug called bevacizumab that reduces blood vessel leakiness might be worth investigating, he says. Other drugs that reduce brain inflammation, like minocycline, are also attracting interest, and there are more in development, he says.

“Instead of waiting until 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-sustaining,” says Greene.