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Welcome to the Biome podcast, this time in association with the Alzheimer’s Research & Therapy special series on traumatic brain injury.

Public interest in traumatic brain injury has grown considerably in recent years, with increased awareness of the scale of its burden on public health, especially in those involved in contact sports or in the military. In light of this growing focus, we’ll be talking to four experts involved in different aspects of research in the field. First off, we spoke to Series Editor Robert Stern from Boston University in the USA, to ask why he thinks traumatic brain injury has been subject to such great public and media interest.


RS: There’s been such tremendous increase in the last five years in both public and scientific interest in this area for many reasons. I think, like so many complex issues, it’s a confluence of variables that have come together. Probably, however, the most important issues have evolved around former NFL players – American football players – who have died and whose brains have been examined and were found to have the neurodegenerative disease Chronic Traumatic Encephalopathy. When those neuropathological examinations are shown visually, it is quite striking – the picture of neuropathology in these individuals. Because our society focuses so much on sports, and in particular football, to have relatively young former players who die in many cases tragically and in many cases from suicide, and then found to have a brain disease, it’s really had a tremendous impact on awareness.

Fortunately there has been an increase in funding to study the long-term effects of repetitive brain trauma. The funding has come in part by a gift from the National Football League to the foundation at the National Institutes of Health, that has resulted in funding through NIH to support this kind of research. Because this also has a direct effect on what we’re trying to understand in the military, in terms of the long term effects of repetitive brain trauma, there’s been Department of Defense and VA funding specifically for this area of research as well.


So neurodegenerative disease relating to brain trauma is currently in the public eye, but for how long has this been the case? Stern explains the history of Chronic Traumatic Encephalopathy, or CTE, and recent changes in where the disease is thought to be prevelant.

RS: Perhaps a key point in the history was a journal article by Martland in the Journal of the American Medical Association in 1928 called ‘Punch Drunk’, in which he described the clinical picture of behavioural and mood and cognitive changes in boxers. ‘Punch drunk’ as a description and term to describe that neurobehavioural syndrome then started having other terms used as well, for example ‘Dementia pugilistica’ for the dementia of boxers, and ‘boxers dementia’ – a variety of interesting terms used to describe what seems to be the same thing, which are mood, behavioural, cognitive and motor changes associated with boxing. Then around the 1940s especially, and 50s, the term Chronic Traumatic Encephalopathy was first used to describe that same syndrome, but from a neuropathological standpoint eventually.

But it wasn’t until 2002, when Bennet Omalu, a coroner and neuropathologist first described CTE in a former NFL player, that it really started to expand beyond boxers. I think because our society really just expected that something would happen to the brains of boxers, people didn’t really pay attention to it. Then over the last several years, there have been more and more cases that have gone to the media – of former NFL players, former hockey players, and then also military veterans who were exposed to blast trauma in the Afghanistan and Iraqi conflicts.


Given that CTE appears to affect individuals involved in a range of contact sports as well as other professions, what can we learn from this and how will this inform future research directions? Stern explains.

RS: What we know now, from the neuropathological cases is that every neuropathologically confirmed case of CTE has had a history of repetitive brain trauma.

That includes boxers from early on, and now football players, hockey players, other athletes. But it’s not just athletes; we’ve now seen it in, as I mentioned earlier, military veterans who’ve had traumatic brain injuries including those from blast trauma. But it’s also been seen in people who have no sports or military history, including a woman who sadly was a victim of physical violence – domestic abuse with repetitive hits to the brain, as well as an individual with a seizure disorder who had a lot of falls through life.

So that’s what we know – that every case of CTE has had a history of repetitive brain trauma. But obviously not everyone who hits their head over and over again is going to get this neurodegenerative disease. What we now need to understand is why one person gets it and another person doesn’t. We need to understand what the additional risk factors are, above and beyond repetitive brain trauma, so we can understand why it develops, what the underlying mechanism is, and then that should hopefully lead to some prevention approaches as well.

There are critics that have said CTE doesn’t even exist, or it’s a concept. That’s been a very silly view of things – it’s been known as a disease for many many years, from a neuropathological standpoint, and it’s been accepted now as a unique neuropathological disease. But what we don’t know are the specifics of who gets it and why, other than there’s an association with repetitive brain trauma.


CTE has been shown to be a more widespread disease than initially thought, however original insights into the condition came specifically from boxers. We therefore spoke to Charles Bernick from the Cleveland Clinic’s Lou Ruvo Center for Brain Health in the USA, about why studying the effects of repetitive head trauma on the brain in boxers is especially useful.

CB: Well, boxers in particular offer a somewhat unique group. So this is in some sense a human model of repetitive head trauma. Fighters are exposed to thousands of blows to the head. Most, sub-concussive blows; some that are concussive. You know when they’re getting these blows, so you can actually follow these people in sparring. You know when their competition’s going to be, so you can predict when that trauma is going to happen. Nowadays of course, there could be techniques, either with mouth guards or in training – things that you could put in head gear that in some sense can monitor movement and blows to the head to give you some more precise measure of the impact the head is receiving.

What’s also unique about boxers as opposed to perhaps other sports is that you have just about a whole cross-section of society to some degree. You have weight classes going from the flyweight to heavyweights, so people ranging from 118 pounds to 250 pounds. You have all ethnicities that have been represented in fighting. So you really get a very broad look across society, as opposed, for example, to maybe football players here in the US – these are big guys going at each other at a very fast speed and that’s one form of head trauma but that may not give you a true representation across all, as I say, ethnicities and weight classes and so on. So there are a number of features of boxing that allow it again – at least in humans, in vivo – to really study the effects of repetitive head trauma.


With much to be learnt about CTE from research on boxers, Bernick is leading a landmark study on the brain health of professional fighters. He tells us more.

CB: This was designed in some sense to try to fill the gap of that absence of longitudinal precise measurement, starting from when people are first exposed to injury and then over time to understand what happens to the brain with repetitive head trauma. This study has been conducted by the Cleveland Clinic here in Las Vegas. It is a longitudinal cohort study of professional fighters. So these are boxers and mixed martial arts fighters that are participating and they are evaluated on a yearly basis with a variety of tests. We do MRI imaging with a variety of measures within that – so we do volumetric measures on the brain, we do resting state conductivity, we can do diffusion weighted images, we look at just general morphology, blood flow – so we get a variety of measures from the MRI scan. Then we have psychometric testing we do on these fighters as part of the session. We get a sample of their speech. We do some sophisticated balance testing. We do get blood samples for genetics and looking at other peripheral biomarkers. And then they get, of course, behavioural assessments and then a neurological examination. So they get this battery on a yearly basis, and the hope is to at least keep them in for four years, and of course if we can follow them longer, we will.


The results from the first year of this study were recently discussed in a review in Alzheimer’s Research & Therapy, as part of the traumatic brain injury series. What do these results tell us?

CB: One is that education may have a protective effect. That is, those fighters that have higher levels of education, given the same levels of exposure, had less change on cognitive functions, despite having the same or similar relationships with volumes. So even though the volumes were decreasing with exposure, the cognitive function in more educated fighters wasn’t. We weren’t seeing that relationship as much. It seems that the younger age where you start participating in a combat sport is associated with lower volumetric measures, again given the same amount of professional exposure. So it certainly is not good, is not an advantage, to start fighting at a young age perhaps any contact sport. And perhaps some of the lighter weight fighters, fighting at a lighter weight, also there’s a stronger association between exposure and lower volumes. We did a calculation just of the number of punches fighters get at various weight classes and there’s no question the lower weight classes get hit more. I mean, they just get more punches! Even though you’d think that the heavier guys may be hitting harder, it just may be the volume of punches that has an effect – and nobody knows this but it’s just raised by that analysis.


Further to these findings, the study also touched upon the speculated link between CTE and an apolipoprotein allele, which has been previously implicated in neurodegeneration. But the study didn’t find an association.

CB: We didn’t – or haven’t yet – seen an association between carrying a certain genetic marker, which is the APOE4 gene risk factor for Alzheimer’s disease, that has been reported in other studies to be a risk factor for CTE. But at least in the active fighters, and at least in the number that we’ve looked at, it doesn’t seem to be a modifying factor whether you carry the APOE4 gene or not. All this stuff is going to have to be really replicated as we follow these people over time and see what happens longitudinally.


So it’s clear that not only boxers are susceptible to the effects of CTE as a result of their profession. We spoke to Thor Stein from Boston University in the USA about the importance of studies in other athletes and military personnel. Stein first explained what we currently know about the clinical symptoms of CTE.

TS: The clinical symptoms of CTE can really be quite varied. Many symptoms are common and non-specific, such as headaches, but behavioural issues are frequent and include impulsivity and aggression, and there are mood changes such as depression and a tendency for suicide. Cognitive deficits can in some ways be similar to Alzheimer’s disease and frontotemporal dementia, with memory problems and executive dysfunction, for instance. And virtually all patients eventually will exhibit these cognitive issues. Bob Stern, has done some great work suggesting that there are really two distinct subtypes of CTE – and this is also seen early on in the boxers – there are those that first present with the behaviour or mood symptoms, and then a second subtype are those with cognitive symptoms at onset. I think this is probably very likely related to where the pathology starts and how it progresses.


With an increasing number of studies into the effects of repetitive head trauma on the brain in athletes and military personnel, Stein also gave us some perspective on the extent to which these studies have implications.

TS: In the US alone, almost two million individuals require evaluation every year from a traumatic brain injury, with a mild injury accounting for about three quarters of these cases. It happens in sports that millions participate in at all levels, including boxing, wrestling, American football, rugby, hockey and soccer. Also, traumatic brain injury is really considered the signature wound of military service members and up to 20 per cent of currently deployed soldiers experience it.

Traditionally concussion, and especially sub-concussive hits or a ‘ringer’ was considered part of the game and something to just walk off. The thought was that these are transient or non-serious injuries that some folks can just shake off and go back to play or back to the battlefield. But the truth is that there can be lasting repercussions and physical damage to the brain that really takes time to heal, and this can further predispose to additional injury and long-term dementia and eventually CTE.

So I think studying the physical changes in the brain can help us understand the severity of these injuries and better appreciate the risks involved in these various activities. Hopefully in the near term, we can take steps to prevent head injury, and then treat it properly when it does occur. And in the long term, we need to understand the mechanisms of this disease and identify targets for therapies.


Keeping in mind the need for a better understanding of the pathology of CTE in order to develop treatments, we asked Alexander Lin from the Brigham and Women’s Hospital in the USA what neuroimaging can tell us about the long-term effects of repetitive brain trauma, and why is this useful.

AL: As a non-invasive technique, it really allows clinicians to open a window to visualise the underlying morphological, pathophysiological and biochemical changes that are occurring in the chronic stages of repetitive brain trauma. So, not only can it be used to diagnose disease – as it has been used across a number of other different neurodegenerative diseases – but hopefully it will allow us to also monitor disease progression and, most importantly, to monitor potential treatments for these diseases. Furthermore, I think neuroimaging also provides insight into underlying mechanisms of head trauma, which also will be useful in helping us identify potential targets for treatment.


We also asked what neuroimaging techniques are most widely used for identifying brain trauma, and why?

AL: In regards to this question, it’s important to note the distinction between different types of brain trauma. So, for example in severe head trauma, the most widely used neuroimaging techniques are definitely computer tomography (or CT) and magnetic resonance imaging to identify obvious bleeding or damage to the brain. However, when we talk about repetitive brain trauma, some of which is asymptomatic, the injury is much more mild in comparison. And this is where conventional CT and MRI are not sensitive enough to identify injury, and so we really need to work on developing more sensitive advancements that are necessary to try to capture what happens with repetitive brain trauma: development of more advanced positron emission tomography (or PET) ligands, more advanced MRI imaging techniques such as diffusion tensor imaging (or DTI) which can visualise the damaged fibril tracts of the brain, or susceptibility weighted imaging (or SWI) which can identify micro-bleeds that are not visualised by conventional MRI.

Currently, CTE can only be diagnosed post mortem, so there’s a definitive need then to try to identify those individuals that will go on to develop CTE, and to really try to do this while they’re still alive. And so this is why neuroimaging has the important role of trying to identify the necessary biomarkers for CTE.


So the development of more sensitive neuroimaging imaging techniques is key to identifying CTE during an individual’s lifetime, and opens the door for appropriate care and treatments to be administered. Stein explains what challenges need to be overcome to help achieve this goal.

TS: Repetitive brain trauma by nature is very heterogeneous. For example, it’s unclear whether it’s the severity of the trauma that plays a role in development of CTE, or perhaps just the repetitiveness of potential sub-concussive blows that might have an impact on it. So trying to characterise the nature of the injury itself is a bit challenging.

The other challenge is – particularly in the chronic stages of CTE in head injury – the comorbidity of other different diseases such as Alzheimer’s disease or depression that may confound the clinical presentation of the disease. So I think in trying to meet these challenges for neuroimaging, the real benefit is to be able to apply the different modalities of neuroimaging, which I think together combined using a multi-model approach will help us to solve this problem of specificity.

I think one of the surprising challenges that we’ve come across in the field of sports-related head injury is actually trying to find appropriate healthy controls. Initially, we thought it would be quite easy to find professional athletes without a history of head injury, but you find that actually a lot of professional athletes either they played football when they were younger, or they participate really in contact sports and so it’s been challenging to find control subjects and we’re kind of always on the look out for professional athletes without concussion.


Developments both in neuroimaging technology and in studies looking to uncover the basis for the neuropathology of CTE will provide much needed insights into the condition. We asked all four of our experts what they thought the most important questions in the field are that remain to be answered – starting with Bernick and Stein.

CB: Understanding the risk factors: are there genetic risk factors? Are there lifestyle risk factors? Do performance-enhancing drugs influence this condition any? We don’t know. How do we diagnose it? We have no diagnostic test for it now. In fact we don’t really have an accepted clinical criteria for it now. So this has to be developed, particularly if we’re going to move ahead with really being able to identify individuals and follow them over time. And then of course the final part is developing therapies that prevent progression in those that may be on that trajectory to decline.

TS: Biologically, I think one of the most fascinating questions is how mechanical injury can lead to a tauopathy. I mean, this is the only example where a physical injury leads to a degenerative disease. So understanding the early mechanisms at play is really going to be key to identifying biomarkers that we can use to follow progression and develop treatments to stop it.

Treatment is going to be a tougher issue to tackle, so to speak. But biomarkers are going to let us treat earlier and give us a better chance of getting a result, I think. This is really another lesson we’ve learned from the Alzheimer’s field, where treatments are generally or historically believed to be tried much too late. Tau has got to be a focus for this disease and already there are tau therapeutics that are in clinical trials so once we can identify our patient base and follow disease progression, we’re going to have ten other drugs that we can try.


Stern similarly echoed thoughts over targeted drug treatments, with the Alzheimer’s field of research providing a starting point.

RS: We need to really understand the epidemiology. How common is it? Is this really a public health issue? We think it likely is, but we don’t know yet, so we must understand the epidemiology of this disease. And we need to be able to figure out how to treat it and how to prevent it and there are some very important compounds being developed already that are anti-tau compounds, that are being developed for other diseases such as Alzheimer’s disease and frontotemporal dementia and cortical basal degeneration etcetera. These compounds could be used in clinical trials for CTE, but we have one very important thing we need to be able to do before we start those clinical trials, and that is to diagnose the disease while someone’s alive. To answer all of those important questions, that seems to be the key issue – we do need to come up with ways to diagnose the disease, both through clinical diagnostic criteria that we’re working on as well as objective biomarkers to have a better certainty of disease.


Biomarkers were also top of Lin’s list of research priorities.

AL: I think CTE research is still very much in its infancy, so there remain many questions that need an answer. Obviously the first question is to try to identify biomarkers for CTE so that it can be diagnosed during life. The second question after we identify those biomarkers is – can we treat the disease? I think it’s in this role that neuroimaging can play a really vital role, by not only providing the means to monitor the treatment, but also to potentially identify targets for treatment.

For example, our studies have shown that repetitive brain trauma results in increases of glutamate in the brain. Again we should note that it’s unclear whether this is the result specifically of CTE or this is the result of repetitive brain trauma. We’re still working out those details. But the important thing to note is that glutamate is an excitatory neurotransmitter, so that when it’s increased to high levels it becomes toxic, killing off brain cells. So if we could drive down the level of glutamate in the brain – whether through pharmaceutical interventions or other potential interventions – perhaps we can reverse or at the very least prevent further progression of the disease.


The Alzheimer’s Research & Therapy special series on traumatic brain injury brings together a range of insights discussing several of the questions raised by our four experts. Series Editor Stern tells us more about what the special series has to offer.

RS: This has been a real honour to be able to play a role in this Traumatic Brain Injury series. There have been wonderful contributions looking at everything from the potential epidemiology in former NFL players, to the neuropathology of the disease, to magnetic resonance spectroscopy findings, to some basic science approaches, to potential even diet focus on treatment, to the clinical diagnosis of the disease. What the series has been able to do, I think, is for the first time to really bring together basic scientists, clinical scientists, epidemiologists, from a variety of fields, coming together to hopefully lead to improved answers for the long-term effects of repetitive brain trauma and in particular the development of this disease Chronic Traumatic Encephalopathy.


Looking to the future, we asked Lin and Stern what progress they thought researchers will be able to make in the field of CTE research in the next ten years

AL: I think, given the importance of this problem to the public, and obviously if funding of this research continues, there’ll be really rapid progress in this field. I think there’s a lot of attention that’s been poured towards this issue and I think that many of the world’s best researchers and clinicians are focussing on this very important problem. So I think even perhaps within the next five years we’ll see some major breakthroughs that will help us better understand the long-term impact of repetitive brain trauma. I think also at the same time, the technology for neuroimaging is always rapidly evolving so hopefully in the near future we should be able to answer many of the challenges and the questions that we’ve discussed here.

RS: This is going to be a tremendously exciting decade. In part, because we’re now ready to fully take advantage of existing and future technical and neuroscientific developments because of everything that’s happened in the last few years in the study of CTE. There’s now funding, there’s now interest, there’s now the beginnings of an understanding of this disease.

So I think in the next ten years, we’re going to be able to diagnose CTE very clearly, accurately, during life, as well as other neurodegenerative diseases like Alzheimer’s disease. And I think with all of the new compounds in the pipeline, and those already in clinical trials, there’s going to be terrific advances in the treatment and hopefully early diagnosis leading to early treatment that would then lead to, ultimately, prevention of the clinical manifestation of the disease.


It seems then that the field of traumatic brain injury is poised to see some fascinating developments in the next few years, not least because of the increased public awareness of the diseases that they cause, and the pursuits that are implicated with their onset. More insights can be found in the traumatic brain injury series can be viewed online here.


The interviews in this podcast were conducted by Alzheimer’s Research & Therapy in-house Editor Kathryn Smith, and was produced in London by Kathryn Smith, Lux Fatimathas and Jo Barrat. Our thanks to Robert Stern, Thor Stein, Charles Bernick and Alexander Lin.

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