Scientists have found an antibody treatment approach that could prevent the secondary effects of TBI, such as sleep disruption, epilepsy and inflammation.
They first identified a molecule in the thalamas part of the brain which plays a key role in these post-brain injury problems developing; and showed that an antibody could stop them from emerging.
“No therapies currently exist to prevent the disabilities that can develop after a brain trauma,” says Jeanne Paz (above, left), associate investigator at Gladstone Institutes.
“So, understanding how the traumatic brain injury affects the brain, especially in the long term, is a really important gap in research that could help develop new and better treatment options.”
The study was conducted in collaboration with scientists at Annexon Biosciences, a clinical-stage biopharmaceutical company.
Traumatic brain injury affects 69 million people around the world annually, and is the leading cause of death in children and a major source of disability in adults.
“These injuries are frequent and can happen to anyone,” says Paz, who is also an associate professor of neurology at UC San Francisco (UCSF) and a member of the Kavli Institute for Fundamental Neuroscience.
“The goal of our study was to understand how the brain changes after traumatic brain injuries and how those changes can lead to chronic problems, such as the development of epilepsy, sleep disruption, and difficulty with sensory processing.”
To do so, Paz and her team recorded the activity of different cells and circuits in the brain of mice after brain injury.
The researchers monitored the mice continually and wirelessly, meaning the mice could go about their normal activities without being disrupted.
“We collected so much data, from the time of injury and over the next several months, that it actually crashed our computers,” says Paz. “But it was important to capture all the different stages of sleep and wakefulness to get the whole picture.”
During a trauma to the head, the region of the brain called the cerebral cortex is often the primary site of injury, because it sits directly beneath the skull.
But at later time points, the researchers discovered that another region—the thalamus—was even more disrupted than the cortex.
In particular, they found that a molecule called C1q was present at abnormally high levels in the thalamus for months after the initial injury, and these high levels were associated with inflammation, dysfunctional brain circuits, and the death of neurons.
“The thalamus seems particularly vulnerable, even after a mild traumatic brain injury,” says Stephanie Holden (above, right), first author of the study.
“This doesn’t mean the cortex isn’t affected, but simply that it might have the necessary tools to recover over time. Our findings suggest that the higher levels of C1q in the thalamus could contribute to several long-term effects of brain injury.”
The Paz Lab collaborated with Eleonora Aronica, neuropathologist at the University of Amsterdam, to validate their findings in human brain tissues obtained from autopsies.
They found high levels of the C1q molecule in the thalamus eight days after people had sustained a traumatic brain injury.
In addition, they determined that C1q in the thalamus likely came from microglia, the immune cells in the brain.
“Our study answered some very big questions in the field about where and how changes are happening in the brain after a trauma, and which ones are actually important for causing deficits,” says Paz.
The C1q molecule, which is part of an immune pathway, has well-documented roles in brain development and normal brain functions.
For instance, it protects the central nervous system from infection and helps the brain forget memories—a process needed to store new memories.
The accumulation of C1q in the brain has also been studied in various neurological and psychiatric disorders and is associated, for example, with Alzheimer’s disease and schizophrenia.
“C1q can be both good and bad,” says Paz. “We wanted to find a way to prevent this molecule’s detrimental effect, but without impacting its beneficial role.
“This is an example of what makes neuroscience a really hard field these days, but it’s also what makes it exciting.”
She and her group decided to leverage the “latent phase” after a traumatic brain injury, during which changes are occurring in the brain but before long-term symptoms appear.
“My cousin, for example, was hit in the head when he was 10 years old, and the impact broke his skull and damaged his brain,” says Paz. “But it wasn’t until he was 20 that he developed epilepsy. This latent phase presents a window of opportunity for us to intervene in hopes of modifying the disease and preventing any complications.”
Paz worked with collaborators at Annexon Biosciences, which produces a clinical antibody that can block the activity of the C1q molecule.
Then, her team treated the mice who sustained brain injury with this antibody to see if it might have beneficial effects.
When the researchers studied mice genetically engineered to lack C1q at the time of the trauma, the brain injury appeared much worse.
However, when they selectively blocked C1q with the antibody during the latent phase, they prevented chronic inflammation and the loss of neurons in the thalamus.
“This indicates that the C1q molecule shouldn’t be blocked at the time of injury, because it’s likely very important at this stage for protecting the brain and helping prevent cell death,” says Holden.
“But at later time points, blocking C1q can actually reduce harmful inflammatory responses. It’s a way of telling the brain, ‘It’s okay, you’ve done the protective part and you can now turn off the inflammation.'”
In addition to chronic inflammation, Paz and her team also uncovered abnormal brain activity in the mice with traumatic brain injury.
First, the researchers noticed disruptions in sleep spindles, which are normal brain rhythms that occur during sleep.
These are important for memory consolidation, among other things. The scientists also found epileptic spikes, or abnormal fluctuations in brain activity. These spikes can be disruptive to cognition and normal behaviour, and are also indicative of a greater susceptibility to seizures.
The scientists observed that the anti-C1q antibody treatment not only helped restore the sleep spindles, but also prevented the development of epileptic activities.
“Overall, our study indicates that targeting the C1q molecule after injury could avoid some of the most devastating, long-term consequences of traumatic brain injury,” says Holden.
“We hope this could eventually lead to the development of treatments for traumatic brain injury.”
Annexon’s anti-C1q inhibitors are designed to treat multiple autoimmune and neurological disorders, and are already being examined in clinical trials, including for an autoimmune disorder known as Guillain-Barré syndrome, where the drug has been shown to be safe in humans.
For Holden, who previously worked with individuals who experienced brain injury and heard many of their personal stories, the impact of this study is particularly meaningful.
“Brain injury is a hidden disability for many of the people I met,” she says. “The side effects they experience can be difficult to diagnose and their physicians often can’t provide any medical treatment.
“Being able to contribute to finding ways to treat the detrimental consequences of the injury after it happens is really inspiring.”
Paz and her lab are continuing to expand their understanding of what happens in the brain after injury.
Next, they will focus on studying whether they can help prevent convulsive seizures, which are often reported by people with severe traumatic brain injuries.
“The holy grail would be to have a treatment that could be offered to a patient after a trauma and that would prevent chronic inflammation in the brain, sleep disruption, and seizures,” she adds.
“Wouldn’t it be wonderful if our study helped make that a reality?”
PFA leaders pledge to donate brain to Concussion Legacy Project
Two senior figures at the PFA have pledged to donate their brain to research as part of the pioneering Concussion Legacy Project to protect future generations of players.
PFA Chief Executive Maheta Molango and PFA Chair John Mousinho have both made the pledge through a partnership with the Concussion Legacy Foundation UK, following the lead of England Rugby World Cup winner Steve Thompson.
The Concussion Legacy Project, unveiled yesterday, will research Chronic Traumatic Encephalopathy (CTE) and other consequences of brain trauma in athletes and military veterans in the UK.
PFA Chief Executive Molango, a former striker at Brighton & Hove Albion, Lincoln City and Oldham Athletic, said: “While being very mindful of taking immediate steps to protect current players, in the long-term ongoing research is vital to enable us to be able to answer more questions and best support members.
“We have been listening and engaging with leading academic experts, and they tell us that brain donation is a key piece to the puzzle in understanding CTE. We are excited to join a global network of the most prominent researchers in this area.”
Yesterday, Steve Thompson became the first athlete to pledge to the Concussion Legacy Project’s Brain Bank, with the former Lion previously stating that he cannot remember playing in England’s 2003 World Cup final win over Australia.
Today, Oxford United’s captain Mousinho, who has amassed over 500 league appearances over a fifteen-year professional career, committed his support for the project.
PFA Chair Mousinho explained: “Brain donation is an intensely personal decision for former players and their families. However, I have been inspired by the team at the Concussion Legacy Foundation and The Jeff Astle Foundation, and I have decided to commit my brain to future research in the hope that it can help play a part in protecting future generations.
“The Concussion Legacy Foundation has a strong ethos of supporting families and everyone affected by brain injury, and they are values we share at the PFA.”
Dawn Astle, who has been campaigning for two decades for football’s authorities to publicly recognise a link between the repeated heading of a football and dementia in later life, has given her full support to the new concussion initiative.
Speaking on behalf of The Jeff Astle Foundation, she said: “Brain donation is the most valuable gift of all for future generations of footballers. It may be many years before this jigsaw is complete but adding each piece, one at a time is the only way we will understand the true picture and make a better future for others.
“The Jeff Astle Foundation encourages families of athletes and veterans to donate the brain of their loved one to the Concussion Legacy Project at PledgeMyBrain.org.”
‘We want to be part of the solution – for Bill and future generations’
Dr Judith Gates speaks to NR Times about this weekend’s football match organised by Head for Change, which will be the first ever to involve no heading of the ball
The first football match which involves no heading of the ball will help raise awareness and stimulate conversation about the impact of head injury in sport, its organisers have said.
The 11-a-side match, involving 25 former professional footballers, has been hailed as an experiment as researchers try to discover whether the game can function without heading, in light of ever-growing research which links football to neurodegenerative disease.
It is organised by Head for Change, the organisation helping to drive forward calls for changes to player safety, and will only allow headers in the penalty box for the first half and then restrict all heading during the second half.
It will be held at Spennymoor Town Football Club, in County Durham, on Sunday at 3pm.
The event forms part of the “legacy” for former Spennymoor Town and Middlesbrough defender Bill Gates, who has sports-related dementia, and whose wife Dr Judith Gates is co-founder and chair of Head for Change.
“When Bill received his diagnosis in 2017, we made two promises to him,” Dr Gates tells NR Times.
“One was to optimise his life and do all we could to make his life as good as we could as a dad, grandad and great grandad, and the second was for his legacy, to do everything we could to be part of the solution for future generations of footballers and their families not to have to face this.
“The purpose of this match is to raise awareness of the dangers of heading the ball and to provide alternative discussion with purpose. It’s an experiment to see what the game will look like.
“To be clear, Head for Change is not suggesting heading should be banned, that is a decision for football’s governing authorities, not for us.
“But we want people to realise the impact. Bill was a Titan to me in his 20s, fit and indestructible, so if this disease can do this to him, it can happen to anyone.”
The match has attracted widespread media attention and comes after an array of stark academic findings, including the research from Professor Willie Stewart that footballers are up to five times more likely to suffer from dementia than the general population.
“Part of why I co-founded Head for Change was to be part of the solution,” says Dr Gates.
“We’re extremely aware that there is a lot of bashing going on and everyone is saying it’s someone else’s fault, but lessons must be learnt from the past.
“For too long we have been assured that our brain was safe in our skull, but we are increasingly understanding how the brain works and how it can be damaged through contact sports. Education will continue to play a very important role in what happens going forward.”
The match itself – which will also be raising money for The Solan Connor Fawcett Cancer Trust – will be held at Spennymoor Town’s stadium, The Brewery Field.
The town is where Dr Gates grew up and met her husband, and in a quirk of fate, Spennymoor Town’s chief executive Brad Groves used to work for Bill as a warehouseman when Bill owned a chain of sports stores.
The club, alongside those playing in the match, have been hugely supportive of their ambitions, says Dr Gates.
“We’ve been amazed at the extent to which they have stepped up, Spennymoor have been phenomenal. Brad has been so kind in offering whatever he can do to help. We are hugely appreciative,” she says.
“The players taking part are excited to be part of it, they may not be able to use one of their many footballing skills but they can use the rest of them.
“Spennymoor is a small town with a big heart and we are so pleased to be able to hold this match, and particularly here, at Bill’s first club.”
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