In 2018, Doctor Bennet Omalu, the medical pioneer who famously discovered the first cases of chronic traumatic encephalopathy (CTE) in American Footballers, predicted that contact sports such as rugby will cease to exist within the space of a generation. He cited the health hazards associated with repeated concussions and advocated banning children from playing all contact sports until the age of 18.

The merits of a complete ban are still up for debate, but the danger of repeated traumatic brain injury (TBI) has now become a major public concern, leading to reduced sport participation in younger age groups as concerned parents withdraw their children from contact sports. It was also the signature injury of the recent military conflicts in Afghanistan and Iraq, and is the leading cause of death and disability under the age of 45 years.

Because it disproportionately affects people of working age, it comes with astonishingly high socio-economic costs. In the US alone, it is estimated to cost the economy over $60 billion annually. In developing countries, it is the leading cause of destitution.

“I do think attitudes towards concussion and mild traumatic brain injuries are changing,” says Dr Valentina Di Pietro. “The direction of travel in professional sports organisations like the Premier League or the NFL is positive, but it is essential that we understand the importance of correctly diagnosing brain injury beyond that sphere – for non-professional sports, the military, and indeed anyone at risk of repeat incidents. This is a worldwide problem.”

Dr Di Pietro outlines one of the key questions facing researchers into brain injury, “The effects of a mild TBI are difficult to assess objectively. How do you know if a ‘blow to the head’ is a mild TBI? You might ask questions to test cognition. But, and here is the problem, players want to be on the pitch. Children want to go back to play. They will tell you that they feel fine. For an area that carries such risk, a more scientific approach is essential and that is why we are looking to see if we can use biomarkers to give an objective reading that tells us, much more accurately, who has suffered a mild TBI.”

Early findings for mild TBI

Dr Valentina Di Pietro is a Molecular Neuroscientist at the Institute of Inflammation and Ageing at the University of Birmingham. She joined in 2012, but her introduction to TBI research goes back to her PhD at the Catholic University of Rome.

“I was studying biochemistry and neurodegenerative diseases, including TBI, specifically looking at possible biomarkers for the diagnosis of mild, moderate and severe TBI, with a key focus on the molecular mechanisms of trauma in in-vitro models,” explains Dr Di Pietro.

“We showed that the pathological mechanisms in mild and severe TBIs are very different and need to be considered as such. Clinically, it is easy to diagnose a severe TBI. There is not much need for a diagnostic biomarker when the signs are so obvious. But it is much less clear for a mild TBI and that is what made it so interesting to me, and why my focus shifted towards that.”

“Our research on mild TBIs showed that there is a metabolic depression in the brain after a mild injury that returns back to normal, by itself within two week period. When you experience another concussion in that same window there is a delay in that recovery and that is where the risk of more severe complications really starts to increase.”

The cumulative effect of frequent mild TBIs results in the same pathology as a severe TBI – an increased risk of developing early Alzheimer’s’, Parkinson’s, or other neuropathological problems. Patients also experience a high incidence of cognitive and behavioural dysfunction, post-traumatic stress disorder and social isolation. This underpins the key reason for the heightened concern in sports and military settings.

“There is no treatment for suffering a mild TBI other than rest and removing yourself from high-risk situations,” says Dr Di Pietro. “Having a biomarker is crucial to help prevent repetitive concussion and the significant issues that come with the cumulative effect in what we call the ‘window of vulnerability’. It would be of great help to clinicians to be able to track progress throughout that window too.”

That discovery led to Dr Di Pietro’s next move, joining the lab of Professor Tony Belli at the University of Southampton. In 2012 the Belli lab moved to the University of Birmingham to start an in-vivo study and take the research to the next level.

New collaborators, new opportunities

In 2017, Dr Di Pietro was awarded a BRIDGE fellowship, providing the basis for collaboration between the cutting edge research in cognition, neuroimaging and material sciences at the Beckman Institute for Advanced Science and Technology at Illinois with the translational neuro-trauma expertise at the University of Birmingham.

The quest to identify a biomarker that can help discriminate between those with and without a mild TBI includes a landmark project, the REpetitive COncussion in Sport (RECOS) study, designed to look at the effects of repetitive concussion in athletes.

The team have recruited non-professional rugby players who have suffered a concussion since 2015 and collected a range of data; biofluids (urine, blood, saliva), results from a battery of neurocognitive tests and neuroimaging files (fMRI, MRI, DTI).

The key biomarkers in those biofluids – microRNAs, proteins and metabolites – will be analysed alongside the neurocognitive test results and neuroimages at the Biomedical Imaging Center at the Beckman Institute.

According to Dr Di Pietro, the benefits of collaboration with the Beckman Institute have been significant, “They are world leaders in the field of neuroimaging. By integrating and comparing biomarkers, neuroimaging and neuropsychology we can refine their individual diagnostic, prognostic and clinical utility. We can then evaluate their effectiveness to detect neural and cognitive recovery. Being able to lean on expertise from both institutions is key.”

At the outset of 2019, a further key partnership was secured, when Premier League footballers signed up to the study. Saliva and urine samples are being taken from both players with head injuries and uninjured 'control' players by club doctors after matches.

Towards a suite of biomarkers

In February 2018, headlines were made as the FDA announced the first-ever approval for a biomarker for concussion, based on measurements of proteins released from the brain post-event. It has been welcomed by the research community as an important step, but does not solve the problem of diagnosing mild TBI.

“It is a really useful tool,” says Dr Di Pietro, “but it exists at the other end of the trauma scale, if you will. It will tell you if a CT scan is needed for incidents that are more severe than concussion. It can exclude the more severe types of TBI which is useful to clinicians. But it is that line between mild TBI and non-concussion events that might prove most useful for point of care and reducing the chance of putting someone back into an environment where they risk more lasting damage – and there is no approved biomarker for this.”

It does, however, provide a boost for the field who are looking to develop a suite of biomarkers that can accurately diagnose mild TBI.

“For biomarkers, the simplicity of a pregnancy test is something of a ‘holy grail’. You can say with 99% confidence whether someone is pregnant or not. But it is an outlier. If you look at biomarkers for any other pathology they are much more complex.”

It is likely, therefore, that the team look to develop a scoring system based on a combination of biomarkers that can provide a single clinically useful reading. At the point of care it could assess whether a mild TBI had been received, and over the ensuing weeks could be used to track recovery. Once such a suite is developed, it will be tailored over time to accommodate more specific groups – such as children.

The outlook is promising. The RECOS project has already led to the publication of a paper, jointly published with the Beckman Institute, that identified a potential biomarker for concussion in saliva samples.

The initial finding will be built upon as more data is brought into the fold through the RECOS study, which has been the subject of quite a significant amount of media attention as it expanded to collaborate with the Rugby Football Union in 2017. Over 2,000 saliva and urine samples are now being analysed.

For Dr Di Pietro, there is further work to be done via Mirna Diagnostics, an entrepreneurial spinout that compliments the efforts of the academic community.

“There are different ways of working and different types of conversation in a more commercial environment, but it is really fascinating,” she says. “During our preliminary study with the Beckman Institute it became clear that a point of care biomarker-based tool was both possible, and usable beyond the top levels of sport. It is important to make such a thing fit for purpose and accessible to everyone, and teaming up with entrepreneurial minds via Mirna Diagnostics allows us to make it ‘real’.”

Through the collaboration of experts and the drive to improve diagnosis and management of a severely damaging problem, there is a sense that researchers are on the cusp of a significant breakthrough.

For the academic group at Birmingham, the research continues apace to explore new questions.

“Now we’re almost going back to the start,” says Dr Di Pietro. “It is one thing knowing what the biomarkers are, but now we’re asking why the biomarkers are expressed in concussions. Getting to grips with ‘why’ will open up our understanding of possible therapeutic treatments.”


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