(3 of 4) Traumatic brain injury (TBI) and the post-mortem diagnosis of chronic traumatic encephalopathy (CTE) are the focus of Dr. Kornguth’s current research. In our third podcast, he shares cutting edge research that suggests that CTE has an autoimmune component. Dr. Kornguth describes how a combination of repeated significant trauma to the brain and the immune system’s imperfect matching function can come together to allow for a perfect storm in which self attacks brain in the form of CTE. That said, only 35% of professional football players develop CTE. Dr. Kornguth uses this example to illustrate the differences between individuals in their vulnerability or resilience to stressors. Using evidence from data collected from both athletes and warriors, he presents a model of how some individuals with TBI can develop CTE with the hope that early diagnosis of vulnerability will reduce exposure to the long-lasting, devastating effects of injury.
Karen French: Alright, I'm here again today with Dr. Steven Kornguth talking about his undergraduate course, then you put together the University of Texas at Austin called Autoimmune Disease As a Window Into Medical Principles.
Today's topic is TBI leading to chronic traumatic encephalopathy, can you tell me what traumatic brain injury is?
Steven Kornguth: Thank you Karen, this is always fun. Traumatic brain injury is essentially synonymous, from a clinical perspective, with concussion. And it is when you have neurological psychiatric and somatic changes from a non-penetrating strong head impact on individuals. Typically, we're talking about the disease that shows the long term cognitive shifts, the psychiatric shifts and the somatic shifts 10 to 15 years after the initiation of the events. So we are discussing it in soldiers who have been exposed to traumatic brain injury from improvised explosive devices, football players from head bangs, soccer players, women in particular, who are heading the ball repetitive times with a ball is coming to the Head 30 to 40 miles an hour multiple times.
It's where you have essentially, repetitive head impacts significant in force that would be as an example deceleration of 5 meters per second and where intervals between these exposures are in days to weeks. So that's what the definition of the traumatic brain injury. Its a non-penetrating forceful impact on the head resulting in loss of consciousness briefly or loss of situational awareness or loss of reasoning for very short periods of time extending long. Where in the end, the population we are concerned with will develop long-term cognitive deficits with a time delay of 10 to 15 years and the injuries did not involve any rupturing of the skull which is called a penetrating brain injury.
Karen: Ok, how is traumatic brain injury diagnosed?
Steve: For the coach on the field, for instance, or for the commander in a combat environment first thing is that the individual has he or she lost situation awareness of consciousness. Did they fall down? How long are they out? Did the individual get up. Could they walk/stagger free around the field? If it's a soccer player or football player. For the combatant, do they know where they are in time and place? Now, the majority of people who have the traumatic brain injury that we're dealing with are typically the agent who fall or people from motorcycle accidents or automobile accidents where there is a bang on the head or people working on the roof and falling off. Now, this is a very wide range of populations our interest is particularly in the young people the athletes and the soldier. Who are active, who are cognitively at the highest stage of the life and by the age of 30 to 50 are showing now sudden cognitive shifts that are to the disadvantage.
Can't concentrate, can't read very well, become unruly with family members or assaultive to their family members or have sudden outbursts of anger. So we have these different components of the neurological , psychiatric, and somatic manifestations that will be seen. As the patient comes into the emergency room. If they have lost consciousness. What we looking for is reflex of the eye, to shining of light, is the person still disoriented in space and time? As you're talking to them in the ER. Following that, we have the neurologist who can do specific tests looking for materials from the brain, typically proteins from the brain that have entered the blood compartment from the banging of the head. Rupturing small vessels and causing material exiting from the cells into the blood. That's a laboratory test relatively quickly done today.
And then we have magnetic resonance imaging, so you can say is there sufficient microbleeds in the brain that I can see the products of the blood that has seeped into the cerebrospinal fluid or the brain substance itself. So we have these five different ways of measuring it, in a given time. But it's a question of interest to ask: how long does the state of disorientation or dysfunction last? If it's 3 to 5 days or 3 days or less, I should say, and in that case we're assuming that person can return to their normal activity. If it's longer than 3 days or longer than 5 days, we have to hold a person out from continuing exposure to repetitive head bags so they can recover.And then we have to ask: is there a likelihood of long-term injury and that's going to be the majority of the discussion will have today?
Karen: So this is making me think about in professional football they do the concussion protocol.
Steve: This is exactly what they are talking about.
Karen: Is that what they are doing?
Steve: Yes, it is Karen, that is exactly what we are talking about.
Karen: So with chronic traumatic encephalopathy, what are the characteristics of those that go on to have that disorder? Tell me more about that.
Steve: Traumatic brain injury (TBI) is essentially in the live individual and continues today in 2018 going from the traumatic event non-penetrating injury to the development of the cognitive disorders and to the psychiatric disorders and somatic disorders. There is another stage which is the end stage of the disease, which is a post-mortem diagnosis. You make that diagnosis on the basis of brain tissue that is removed at death of the individual.
That stage which has particular pathology is called chronic traumatic encephalopathy. So it is an end stage marker of traumatic brain injury in that percentage of the people who went on to develop this long-term disorder. We have to recognize that of all of the individuals that we have looked at with significant TBI, what we call moderate TBI, 1/3 of them gone on to develop the chronic traumatic encephalopathy end stage. The majority of individuals with concussions events do not exhibit any long-term injury.
All of us by the age of 20 or even lower have banged our heads at one time or another and we go on to lead perfectly healthy lives.
Of the people who are exposed to repetitive head injuries, it's a third of them; and that's with the blast exposure to IEDs, it's with the football playing, it's with the soccer playing. It's about 1/3, at most 40%, that go on to develop the long-term cognitive disabling disease of traumatic brain injury and chronic traumatic encephalopathy.
Karen: Thinking about that some more. We hear on the news a lot about CTE. CTE is only diagnosed post-mortem?
Steven: That's correct.
Karen: S0 player that are active might have a TBI?
Steve: That's correct.
Karen: They don't have CTE?
Steve: In our diagnosis in 2018 it is limited. CTE is limited to post mortem.
Karen: Okay. Okay. So, why is it useful to identify what individuals may develop CTE?
Steve: It's important to understand that in my understanding of disease, disease results from two factors interacting with each other. The first of
these is a significant stress on the host. Be that where the stress can be a virus. It can be a bacterium. The vulnerability is the second element. That is what is it in the host that makes them vulnerable to develop the disease. Diseases not alone a vulnerability or alone a stressor. It is an interaction between these two. So, by understanding what are the mechanisms involved in progressing the traumatic brain injury from a common occurrence, which occurs in all of us, and we get up and live perfectly well the rest of our lives. To those individuals who are now engaged in forceful impacts of the body either from explosions, or from the impact with other players, or from automobile accidents and motorcycle accidents understanding which internal factors of that individual predisposes them to develop a long-term disabling disease of TBI leading to CTE.
From those of us who go on to live a perfectly healthy life, we can now begin to introduce mitigating factors which protect them. So the mitigating factors could be as simple as stop playing the football if you have bang your head and your a vulnerable person. A second thing is a pharmacological treatment. So with the research we have done and the proposal that the TBI leading to CTE is fundamentally an autoimmune disease. In which the body's immune system responds to proteins released from the brain with every impact to develop antibodies for those protein. Very similar to the paraneoplasia. we talked about last week. Where these antibodies with every subsequent impact are able to cross the blood-brain barrier because the blood-brain barrier is permeablised with every significant bang to the body.
Steve: These antibodies produced to the brain proteins can now access the brain compartment as the same way the proteins can exit the brain compartment during the bang. The antibodies coming into the brain tissue now can react with neuronal cells and with glial cells to cause silencing of the nerve cells and long-term cognitive changes.
Karen: Okay, let me make sure I understand you. This is complex to me and I'm new to it.
Steve: Yes, that's good.
Karen: So what you are saying is each time there is a hit there are microbleeds...
Karen: that opens the blood-brain barrier. Some of the proteins leak out...
Karen: and that's what you were able to test for when you test for a TBI?
Karen: That same leak, the microbleed, also allows those antigens to go into the brain? Explain it to me.
Steve: The proteins exiting the brain from the micro bleed are called the antigens. The body begins to make antibodies to those antigens.
Steve: As the antibodies build up in the body, with every subsequent bang in the near-term. Those antibodies are crossing the blood-brain barrier and entering the compartment and beginning to see the antigens that are still in the brain compartment and that gives rise to potential silencing of neurons when you have what's called inflammation in microglia, a particular cell which is an immune kind of cell releases a molecule, protein molecules, that can silence neurons together with the antibodies and the immune sensitive self.
Karen: Let me make sure I understand the words that you're using. When you say "silence", what does "silence" mean.
Steve: Typically your neurons are electrically firing cells. So the way the brain works is neurons, the information processing elements of the brain, can either fire and tell another cell to fire more frequently or less frequently. I call that activation or it can inhibit the cells firing and we call that an inhibition.
All the information processing is due to electron firing up axonal firing neuronal firing. "Silencing" means when these cytokines, one of them is called interferon-gamma, is produced in large amounts, it causes the neuron in its immediate vicinity to become silenced when you have hyper sensitive cells present in that domain. If the cells are silent they're not communicating and those cells die.
Karen: Cytokines is antibody.
Karen: Help me understand it
Steve: A cytokine is an immunomodulator you have many different sorts of what we call molecular messengers and they tell the body to either increase an inflammatory response or inhibit an inflammatory response. A cytokine is one of these kind of messengers, and antibody is a very specific molecule that is structured chemically, it's a protein.
Steve: To interact with a very specific sequence of something else. It's designed to react with viruses and that's what protects you. That's what we do with immunization or protect you from bacteria. In this case, the immune response is responding to itself and that immune response instead of being helpful to the foreign stressor, or virus bacteria is harmful to cell function. That's what the basis of an autoimmune disease is.
Steve: And so in this case, as you have the permeabilized blood-brain barrier with every subsequent impact on the body, antigen is released from the neurons and from the glia. The self antigens come into the blood compartment; kick up the immune system. The immune system produces more antibodies; and more cells that have the ability to interact with particular proteins in the brain.
Every subsequent permeabilization of the blood-brain barrier let's the cells, immune cells, and the antibodies cross into the brain compartment and compromise neural function in the area where the blood-brain barrier compromise occurred.
Steve: Giving you disease
Karen: And that disease is CTE
Steve: And that disease is traumatic brain injury...
Steve: Because remember CTE is an end-stage disease. Only in post-mortem, so, we can't see it. We can see the proteins going in by a variety of measures, we can see the cells going in to the brain. But the CTE is by definition and end-stage measure.
Karen: Okay, so when I'm seeing in the news that they're able to diagnose CTE before people are dead it is a misunderstanding.
Steve: It is a misunderstanding, yes. A study that has been done in Boston by a very excellent group,the Mckee Group, has shown that in the individuals with very advanced traumatic brain injury the overwhelming number almost all of them have CTE, but the definition of CTE is end-stage post-mortem tissue.
Karen: It sounds like there is almost a need for a new term.
Karen: Something between TBI and CTE
Steve: Yes, that is right. Think of it as a linear progression in disease. T he same way with all the diseases we have what I would call the initiation of a disease be it cancer, be it infection and so on. This progresses to become a more compromised body, a more vulnerable body to whatever the insult is or what the stressor is. You can have what I will call multiple hits then in the compromised body, so, for instance: If you have an individual with traumatic brain injury and there is a sudden infection by a virus which now has access to the central nervous system because of the compromised blood-brain barrier, you end up now with infection of the brain, subsequent to the TBI. These can interface with each other to give you more rapid or less rapid vulnerability to long-term illness.
Steve: But in our case we are talking about the development going from initial impacts, multiple of these with initial loss of situational awareness, of human consciousness and progressing over a 10 to 15 year period; with what's called the cognitive shifts, psychiatric shifts, and somatic shift.
Karen: So how did you get involved with this research? Whats the process? You've mentioned a little bit about soccer players, tell me more about what you've done.
Steve: Where we came from in the 1990s, we were studying the effect of long term sleep deprivation, a stressor, on cognitive function in military soldiers. This was people who were deployed abroad to Middle East or to Asia and experienced combat. And what happened when the person was awake for 20 hours and slept for 4 hours and did this over a period of 6 to 8 months. We saw cognitive shifts in alertness, which is... the stressor was fatigue. But then it became of interest to ask, as we entered the 2000s, we had a significant number of Troopers who were exposed to improvised explosive devices.
And so, the stressor now which led to a cognitive shift not due to fatigue but to blast injury became of interest to me. So we initiated studies at that point on looking at soldiers initially, but more controllable were athletes because the athletes were exposed to much lower forces, blast forces, if you will. That is you have one person of 270 lbs to 300 lbs crashing into another 200 to 300 lbs individual at 5 meters per second. And that's now... you can follow them in time because we know when the impacts occurred and now we ask the question what is a shift in cognitive ability? What's the shift in brain structure?
Steve: So, all of my studies are involved with that and how can we understand whether a particular force of impact resulted in changes in the brain that could be predictive of developing long-term traumatic brain injury and cognitive shifts. The reason we were interested in this is because you can then determine from a paradigm of correlating brain structure shifts with cognitive shifts with force of impact and with vulnerability factors. Things within the individual herself or himself that would make them more susceptible to the disease and that are not amenable to treatment. Where the treatment of separation from the sport or a pharmacological treatment that would be beneficial to that patient. That's how I got into this study. And so we were blessed to be able to work with the athletic department at University of Texas with the women's soccer team and have done this over a five-year period, Looking at each player longitudinally and with respect to specific impacts and concussion of events.
Karen: Where do you see the field, the research, going over the next five years? The next ten years? The next direction.
Steve: There is a very major... effort today do understand how to mitigate the disease occurrence. The reason for this is we are talking about a budgetary requirement of billions of dollars. The estimate is in the 3 to 7 billion dollars annually and that's from the TBI and that's with involving the one third of the players. If we fold in an associated disorder, post-traumatic stress disorder, which is primarily psychiatric. We are looking at just from the military force alone on the order of 500,000 people affected.
Steve: Over a 15-year period. So there is a major, several major studies, both in the athletic community and in the military and in the aging population how to mitigate the disorder. From our studies, recognizing where the brain lesions are in the patients... Typically, if you think of a bang of the head, deceleration of the head, you would think that the injury should occur at the crown of the brain it is called the top of the gyrus. So you have folds in the brain, called sulci, and peaks. We would imagine the stress should occur at the apex or the peak ... the surface... outer surface of the brain
Karen: Right where is touches the skull, right?
Steve: The gyris, [cross talk] touching the skull. Actually, where you will see the major sheer injury is at the base of the cavity of the invagination...
Karen: The foldy part?
Steve: Of the sulcus, called the sulcus. Right.
And that's number one, you can see that by magnetic resonance imaging.
Steve: And you see that at the interface between the gray and the white matter.
Steve: You also see a widening of the sulci and that's because as the brain is hitting a rigid surface, we call the skull, the bone, so, which is not compressible effectively and the spinal fluid, which is non compressible. As a brain is impacting into the skull, the spinal fluid is driven into the sulcus, that cavity, that invagination and the only place it has to dissipate its energy without tearing the brain, and the brain is not torn, is at the base of the sulcus. This gives rise to then the primary injury that we're seeing. Because of this and because of the 10 to 15 year delay and because we see antibodies produced of the brain proteins, and we know from our studies on a variety of autoimmune disorders and paraneoplasias that the antibodies cause neuronal silencing and cell death we have proposed that this is an autoimmune disorder, primarily in those individuals who have been delayed in the development of long-term injury for 10 to 15 years.
Why is that important? It's important because there are several factors we know that are correlated with vulnerability to autoimmune disease. And, we can begin to examine the patient in advance... or the athlete and military soldier and the older individual for presence of these particular markers in the brain that would render that person more susceptible to traumatic injury. In the same ways we're going to be discussing next week, these markers make the individual more susceptible to multiple sclerosis or to systemic lupus erythematosus two classic autoimmune disorders.
Karen: Interesting, and a lovely tie-in to next week. Thank you Steve. This was great today.