Towards a better understanding of traumatic brain injuries

Towards a better understanding of traumatic brain injuries
2.5 million people are affected by a TBI every year in Europe

SciTech Europa Quarterly highlights recent research into the relationship between traumatic brain injuries and alcohol abuse and dementia, as well as exploring the use of biomarkers to improve diagnosis.

Traumatic brain injuries (TBIs) occur when a sudden impact to the head causes damage to the brain, leading to a range of short- and long-term behavioural, physical, emotional, and cognitive problems. The leading cause of death and disability in children and young adults around the world, traumatic brain injuries affect some 2.5 million people in Europe every year, hospitalise one million, and kill as many as 75,000.

Here, SciTech Europa Quarterly highlights recent research which is improving our understanding of the possible long-term effects of traumatic brain injuries, and also offering new hope in efforts to diagnose and manage this complex and costly condition.

Does traumatic brain injury increase dementia risk?

People with a traumatic brain injury are at an elevated risk of developing dementia, according to a nationwide Swedish cohort study undertaken by researchers at Umeå University.

The study, which was published in PLOS Medicine, examined data from close to 3.3 million people aged 50 or above as of December 2005. Researchers then compared this to a dataset of all diagnoses of TBI and dementia in Sweden between 1964 and 2012.

The data was broken down into three different groups. First, researchers matched close to 165,000 individuals who had been diagnosed with a TBI to control participants who hadn’t. This retrospective cohort found that 6.3% of those with TBI developed dementia during a 15-year follow-up period, compared to just 3.6% of those without.

In a case-control cohort, researchers then compared roughly 140,000 individuals with a dementia diagnosis at follow-up to control participants without one, before looking at almost 50,000 pairs of siblings – one of whom had a TBI and one who didn’t.

The results suggest that the risk of developing dementia increases four- to six-fold in the first year post-TBI, and by 80% in the first 15 years. This risk significantly decreases over time, but it remains high at 25% 30 years later. Patients with a severe TBI or multiple traumatic brain injuries have an even higher risk of developing dementia.

Although previous studies have established a link between brain injuries and later dementia, they have had mixed results. Few have investigated the association long term, and none have looked at the influence of familial factors.

The size and scope of the study is thus significant, but there are nonetheless caveats to the findings, namely that dementia can be a risk factor for accidents resulting in TBI, and as such onset of the disease likely preceded the brain injury in many cases.

More research will therefore be needed to determine if there is a causal relationship between TBI and dementia.

Does TBI lead to alcohol abuse?

Childhood TBI and alcohol dependency

It has long been known that alcohol is a significant risk factor for TBI, but scientists at Ohio State University in the US were keen to discover whether the opposite might also be true: are people with traumatic brain injuries more likely to abuse alcohol?

To find out, researcher Zachary Weil and his team examined past literature on the subject, focusing in particular on the effect of a TBI in childhood or adolescence.

Their results were published in the journal Frontiers in Behavioural Neuroscience.

The literature revealed a clear link between traumatic brain injury while young and alcohol abuse later in life. Particularly striking is that under-five-year-olds with traumatic brain injuries are close to four times more likely to fall victim to substance abuse as teenagers than uninjured children.

Evidence in the literature puts this connection down to the fact that brain injuries can negatively impact on romantic relationships, involvement in extracurricular activities, and employment – all of which are linked to a lower risk of alcohol abuse.

The literature also suggests that traumatic brain injuries can lead to impulsiveness and make people less aware of the consequences of their actions. Furthermore, brain injury survivors may turn to alcohol to cope with the effects of their injury.

Other explanations offered in the literature point to the inflammatory effect of both traumatic brain injury and alcohol in the brain, which, according to animal studies, might encourage further drinking, as well as the damaging consequences of TBI on the dopaminergic system, which plays an important role in alcohol dependence.

Weil suggests that greater efforts to address alcohol abuse among people with traumatic brain injuries could go a long way to improving outcomes in terms of health and quality of life; however, he cautions that more work needs to be done to establish a definitive link between TBI and alcohol dependency.

“This has not been completely confirmed in humans, but there is a lot of suggestive evidence,” he concludes.

Traumatic brain injuries and drinking behaviour

The Ohio study was unable to find clear evidence that traumatic brain injuries in adulthood are a risk-factor for alcohol abuse, but there is more promising news from researchers in Albuquerque, who have determined that brain injuries do not worsen drinking behaviour in people who use alcohol heavily.

Not only are heavy drinkers more likely to experience accidents, but injuries to the head often cause damage to regions of the brain that are also involved in addictive behaviour. Researchers at the Mind Research Network and University of New Mexico therefore wanted to see if the combination of heavy alcohol use and TBI worsens the damage to the brain already caused by chronic alcohol exposure.

The results were published in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

The study centred on two groups of people: those with a recent history of heavy alcohol use and TBI, and a control group with a similar level of lifetime alcohol exposure but no brain injury.

In addition to analysing the participants’ drinking behaviour – for instance how much alcohol they consumed and how often – the researchers also employed imaging techniques to measure the structure of the brain and its activity when the participants were given a taste of their favourite drink.

The results were surprising: not only did the TBI-affected group display no worse drinking behaviour than those without a history of TBI, they also exhibited no more severe neurocircuitry dysfunction.

“On average, the brains of the two groups were similar both in terms of the amount of lost tissue, as well as how each person’s brain responded to their favourite drink,” explained Dr Andrew Mayer, who led the research.

According to Dr Cameron Carter, a professor of psychiatry and psychology at the University of California, Davis and the editor of Biological Psychiatry CNNI, this finding could translate into “greater therapeutic optimism for the treatment of individuals with a combination of TBI plus heavy drinking histories”.

How can we improve TBI diagnosis?

Can biomarkers detect pitch-side brain injury?

Elsewhere, scientists at the University of Birmingham, UK, have identified inflammatory biomarkers that indicate whether or not the brain has sustained an injury. They are now hopeful that the discovery can form the basis of a test to be used at the side of a sports pitch or by paramedics to detect brain injury at the scene of an incident.

The study, which was led by Professor Antonio Belli, of the university’s College of Medical and Dental Sciences, could represent an important step forward in the diagnosis of TBI, which is at present extremely challenging.

“Being able to detect compounds in the blood which help to determine how severe a brain injury is would be of great benefit to patients and aid in their treatment,” explained Dr Lisa Hill, of the university’s Institute of Inflammation and Ageing.

“Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries that impair function, damage other brain structures and promote further cell death.

“Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions.”

The study, which was originally published in the journal Scientific Reports, examined blood samples from 30 injured patients taken within the first hour of injury before the patient had arrived at hospital. Blood samples were also taken at intervals of four, 12, and 72 hours after the injury had been sustained.

The researchers then used protein detection methods to simultaneously screen the samples for inflammatory biomarkers which correlated with the severity of the injury (either mild TBI with extracranial injury, severe TBI with extracranial injury, or extracranial injury only), and compared the results to those of a control group of healthy volunteer patients.

They identified three inflammatory biomarkers – CST5, AXIN1, and TRAIL – as novel early biomarkers of TBI.

While CST5 was able to distinguish patients with severe TBI from all other cohorts within the first hour of injury, AXIN1 and TRAIL were both able to discriminate between TBI and uninjured patient controls in less than an hour.

These findings have significant implications for the detection and subsequent management of TBI, and could inform how hospitals respond to cases of traumatic brain injury in future.

Dr Valentina Di Pietro, also of the Institute of Inflammation and Ageing, explained: “Early and objective pre-hospital detection of TBI would support clinical decision making and the correct triage of major trauma.

“Moreover, the correct diagnosis of TBI, which is one of hardest diagnosis to make in medicine, would allow clinicians to implement strategies to reduce secondary brain injury at early stage, for example by optimising blood and oxygen delivery to the brain and avoiding manoeuvres that could potentially increase intracranial pressure.”

She added that the findings might also hold promise for future drug development, provided that there is sufficient confidence in the diagnosis of TBI, “as novel compounds could be given immediately after injury and potentially commenced at the roadside.

“We conclude that CST5, AXIN1 and TRAIL are worthy of further study in the context of a pre-hospital or pitch-side test to detect brain injury.”

Evaluating mild traumatic brain injury

Meanwhile, in the US, the Food and Drug Administration (FDA) has recently authorised the marketing of an in vitro diagnostic blood test to evaluate mild traumatic brain injury (mTBI) in adults.

Patients with suspected head traumas are currently examined using the 15-point Glasgow Coma Scale, a neurological scale which assesses patients according to their eye, verbal and motor responsiveness, and a CT head scan to detect any possible brain tissue damage that may have occurred.

However, the vast majority of patients evaluated for mTBI have negative CT scans.

The Banyan BTITM (Brain Trauma Indicator) could help overcome this problem by enabling healthcare professionals to better determine whether a CT scan is needed in patients with possible mTBI. This would also help to prevent unnecessary neuroimaging and associated radiation exposure – a key goal of the FDA.

“A blood-testing option for the evaluation of mTBI/concussion not only provides healthcare professionals with a new tool, but also sets the stage for a more modernised standard of care for testing of suspected cases,” explains FDA commissioner Scott Gottlieb, MD.

“In addition, availability of a blood test for mTBI/concussion will likely reduce the CT scans performed on patients with concussion each year, potentially saving our health care system the cost of often unnecessary neuroimaging tests.”

The Banyan BTITM works by measuring levels of UCH-L1 and GFAP, two brain-specific protein biomarkers that are rapidly released from the brain into blood after a head injury. The levels of these proteins can give an indication of which patients may have intracranial lesions visible by CT scan and which won’t, and the results of the test can be available in as little as 3-4 hours.

Ahead of the FDA application, Banyan Biomarkers, Inc evaluated the performance of the Banyan BTITM by comparing its results to head CT scans in a multi-centre, prospective clinical study (ALERT-TBI) of 2,011 suspected mTBI patients in the US and EU.

The test was able to predict the presence of intracranial lesions on a CT scan 97.5% of the time. Its success at identifying those who did not have intracranial lesions was even more impressive, at 99.6%.

The FDA thus concluded that the test can be incorporated into the standard of care in order to rule out the need for a CT scan in at least one-third of patients with suspected mTBI.

“Brain biomarkers will change the practice of emergency care for mild TBI and will greatly assist a large number of patients. The impact will be improved medical care by reducing radiation exposure to the patient and improving efficiency in the emergency department,” says Andy Jagoda, MD, professor and chair in the Department of Emergency Medicine at the Icahn School of Medicine at Mount Sinai.

In addition to being used in civilian medicine, the blood test could also have an important military application, given that combat wounds and improvised explosive devices are common causes of traumatic brain injuries.

“A blood test to aid in concussion evaluation is an important tool for the American public and for our service members abroad who need access to quick and accurate tests,” says Jeffrey Shuren, MD, the director of the FDA’s Center for Devices and Radiological Health.

“The FDA’s review team worked closely with the test developer and the US Department of Defense to expedite a blood test for the evaluation of mTBI that can be used both in the continental US as well as foreign US laboratories that service the American military.”

Banyan Biomarkers, Inc is now investigating whether UCH-L1 and GFAP could also be used to monitor recovery after injury or for other degenerative conditions of the brain.

References

  1. http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002496
  2. https://www.frontiersin.org/articles/10.3389/fnbeh.2017.00135/full
  3. http://linkinghub.elsevier.com/retrieve/pii/S245190221730174X
  4. https://www.nature.com/articles/s41598-017-04722-5
  5. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596531.htm

This article will appear in SciTech Europa Quarterly issue 26, which will be published in March.

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