Medic assessing rugby player for concussion

The global economic burden of traumatic brain injuries (TBIs), including concussions, is $400 billion annually - and TBI is the leading cause of death and disability in those aged under 45.

Each year, 1.4 million patients attend UK hospitals following a head injury, approximately 85% of which are categorised as a concussion – also known as a mild TBI.

However, it is estimated that more than 80% of concussions are unreported and undiagnosed, and TBI is one of the most difficult diagnoses to make for a variety of reasons.

In major trauma, the presence of variables - such as alcohol, drugs or shock from blood loss - can mask the presence of a brain injury, which leads to precious time being wasted before the correct treatment is implemented.

The converse is also true, as the current triage systems in many Western countries are design to over-diagnose TBI - but still miss over a third - which results in the inappropriate transfer of trauma patients to neurosurgical units for about two thirds of patients.

The problem is significantly worse at the milder end of the spectrum, and in contact sports in particular, where concussion is missed in more than 50% of cases.

Current tools to diagnose concussion rely on subjective tests and lack specificity and sensitivity, hence the intense quest for new ways to support pitch-side clinical decision-making.

In early 2018, the US Food and Drug Administration approved the first biomarker test for TBI - the Brain Trauma Indicator - which is based on two protein biomarkers.

However, this test is only designed to differentiate between brain CT scans which show positive and negative results for TBI.  Therefore, it is not suitable for concussion because for concussions all scans are negative by definition.  The test also takes several hours and is falsely positive in 63% of cases.

In 2014, the University of Birmingham set out to investigate the potential value of specific molecules, known as microRNAs, in detecting injury following trauma.

MicroRNAs are a class of small genetic fragments that communicate signals between different cells and tissues and had previously received great attention in oncology research as signatures of various cancers.

Through our research, we discovered that a small number of blood microRNAs could pinpoint the presence of a TBI with 99.7% accuracy in severe traumatic brain injury, which had never been achieved by any other biomarker before.

Whilst a blood test may work well for major trauma, we also recognised that a non-invasive assay would be far more beneficial for addressing the problem in sport, especially at grassroots level and in children. 

After we determined that diagnostic TBI microRNAs were also present in saliva, we partnered with the Rugby Football Union and Premiership Rugby to launch the largest diagnostic study in sport concussion to date.

This study, published in March 2021 in the British Journal of Sports Medicine, has refined and validated the saliva diagnostic panel in over 1,000 professional players in the top two tiers of England’s rugby.

Meanwhile, we are conducting a parallel study, funded by the Drake Foundation, in English Premier League footballers, and sample collection is also on-going in cricket, boxing and mixed martial arts.

Our biomarker discovery is now in the process of being commercialised as a patented over-the-counter salivary concussion test for elite male athletes by diagnostics and therapeutics developer Marker Diagnostics. 

With further sampling and product development, the test could have wide-reaching use and potential to reduce the risk of missing concussions not only in sport – from grassroots to professional levels – but also in wider settings such as military and healthcare.

Given the emerging concerns regarding the long-term brain health of those exposed to repeated concussions, and the number of concussions that are often missed or misdiagnosed, this non-invasive and accurate diagnostic test using saliva is a real game changer and may provide an invaluable tool to help clinicians diagnose concussions more consistently and accurately.

Co-authored by Dr Valentina Di Pietro - Lecturer in Neurotrauma & Professor Antonio Belli - Professor of Trauma Neurosurgery.