How Does Traumatic Brain Injury Affect Dementia Risk?

Researcher Dr. Bruce Lamb shares his insights on the connection between traumatic brain injury, cognitive functioning and dementia.

A concussion may cause headaches, fatigue and difficulty concentrating, but could a blow to your head also lead to more serious consequences decades later? According to Dr. Bruce Lamb, head of the Stark Neurosciences Research Institute at Indiana University, evidence suggests that experiencing a traumatic brain injury could increase someone’s chances of developing dementia later in life.

• Researchers are still unsure if a single hit to the head or the type of traumatic brain injury could affect how likely someone is to develop dementia years later
• New clinical trials are tracking athletes over time to determine what head injuries may cause dementia
• Researchers are exploring why some people appear to have a greater risk of developing neurodegenerative diseases after a head injury than others

Being Patient spoke to Lamb about different types of head injuries, what happens to the brain after a head injury, why researchers think a blow to the head could lead to dementia, as well as current and future studies on the link between traumatic brain injuries and dementia. 

Being Patient: You focus on the connection between a traumatic brain injury and long-term brain health. Can you tell us about your research?

Dr. Bruce Lamb: There are a wide variety of brain injuries that can happen: an injury from a concussion—which is the typical injury we think of regarding sports—injuries from car accidents, or from blast injuries among individuals who have been in the military. Each one of those has a very different outcome for people who are impacted by them and their families. There’s been interest in understanding how those different types of injuries may impact someone later in life by developing into dementia or other neurological disorders.

For a very long time, we’ve been looking at chicken-and-egg-type questions, like “If you get a brain injury, are you really at a higher risk of developing late-onset neurodegenerative diseases?” and that’s been a very difficult thing to study. But recently, there have been some very large studies. One was a Danish study that looked at this, and one in the United States looked at the veterans’ community out of the VA health care system. The latter study looked at individuals who have been exposed to a brain injury—and this is usually a moderate to severe traumatic brain injury, so this is not a concussion. These studies suggested that there’s an increased risk of later-life development of dementia. That includes a memory impairment later in life that could be Alzheimer’s disease, but also Parkinson’s disease as well as some of the other late-life neurodegenerative diseases. I think those are the studies that have led us to start thinking, OK, what could be the biological link? Why would a brain injury lead to this increased risk for dementia many, many decades later? That’s what my lab is focused on: trying to understand that biology.

Being Patient: Can we compare a traumatic brain injury to a scar? Inflammation is meant to heal our brains to an extent, but does the inflammatory process cause something to go terribly wrong in the long-term?

Dr. Bruce Lamb: Yes. There’s increasing evidence that immunity is a double-edged sword. On the one hand, it’s activated following a brain injury, and also peripherally. This activation of the immune system is really critical for protecting us and helping us to survive an immediate injury. However, especially in the nervous system, there’s now accumulating evidence that more of a chronic activation of that immune system can ensue, which is the thing that can lead to detrimental outcomes—neurodegeneration or dementia. I think it’s trying to understand how that happens and the balance between these really important aspects of the immune function versus those we think ultimately might lead to dementia.

Being Patient: The presumed pathology of Alzheimer’s disease is the plaques and tangles in our brain and then later, inflammation. Is there something we can equate with traumatic brain injury that leads to more plaques, tangles or inflammation in the brain? Do we know that yet?

Dr. Bruce Lamb: Sure, there have been some animal studies. For the most part, that’s where this work is being done—looking at different types of brain injuries. And again, the models of brain injuries are different—including what humans are exposed to, there’s a whole variety of types of injury models that are done with animals as well. Most of those animal studies have suggested that there are potential interactions between brain injury and an ultimate development of amyloid and tau pathology.

There certainly are some links. For example, one of the things that’s well known to occur following brain injury is induction of this one protein called amyloid precursor protein (A.P.P.), which is actually the precursor to amyloid, the thing that gets deposited in the brain of Alzheimer’s patients. So just the fact that you get this activation of A.P.P. expression following brain injury is a really significant effect of injury and may have this impact later on, which is what the animal models suggest.

And then in terms of tau, we have some data we’re currently working on in models where we have a genetic mutation that produces this one immune molecule we focus on that’s been associated with Alzheimer’s disease—it’s called TREM2—this gene and protein is not actually expressed on neurons and other brain cells. We have now looked at whether mutating that particular gene, as seen in Alzheimer’s disease, will impact the brain injury response. It definitely affects that immune response—that activation of immunity following brain injury—but it also affects the development of tau pathology much later in life. Again, it suggests that there is this early event, which is impacting, but that’s having an effect much, much later in your life, at least in the animal studies.

Being Patient: What criteria is used to differentiate between various brain injuries? Is one bad blow to the head enough to set off a process that could increase your risk of getting dementia later in life?

Dr. Bruce Lamb: That’s a really important question and one we still don’t have a great answer to yet. Again, most of the studies that have been done so far are retrospective, where you just try to associate, OK, based on the health records, this person was exposed to a brain injury and now, you say, “Are they at an increased risk of developing dementia?” but that’s all retrospective.

There are currently some big trials underway, what we call “prospective studies,” which means enrolling people who are at an increased risk for head injuries and then following them and seeing if they are at an increased risk for dementia. That will help us determine what types of injuries are likely to be the ones that might be the most problematic. For example, there is a big study of the N.C.A.A., college athletics, that’s headquartered at Indiana University, led by Tom McAllister, the chair of psychiatry at IU school of medicine, that’s really looking at this. They’re enrolling NCAA athletes from all across the country. They’re then following them as they get exposure to a variety of different types of injuries, including concussion, and then studying what impact that has on them over time. I think those are really important questions that we don’t have a great answer to. We know certainly, especially for concussions, evidence is increasing that multiple concussions over a prolonged period of time, for example in some of the N.F.L. players, clearly can lead to this chronic traumatic encephalopathy (C.T.E.), which is another neurodegenerative disease, although it’s different from Alzheimer’s. But we still don’t know what types of injuries ultimately lead to C.T.E. Some people seem to develop it and others don’t. Why is that? Those are things we still don’t really understand.

Being Patient: Are any studies further down the pipeline? We know there’s a percentage of football players who get dementia, so what have we learned so far about the football population?

Dr. Bruce Lamb: Both football players and professional athletes or fighters—boxers and mixed martial artists—are definitely at an increased risk for developing dementia later in life. Chronic traumatic encephalopathy is the one biggest risk for those two populations. But again, it’s not all of them. So we still don’t really understand—why is it that some of these athletes do ultimately develop this neurodegenerative condition, while others don’t? Is it, as you suggested, the type of injury that they’re getting, or the frequency of that injury, or other factors like genetics and factors that we don’t really understand?

I think these longitudinal studies are important because one of the big problems has been that there’s no way to really quantify brain injuries. How can we quantify brain injury in a way that’s helpful? That is starting to change now because they have new technologies for helmets and mouth guards that have accelerometers, and other types of devices that can real-time quantify the type of injury. Is it a rotational injury? What types of injuries are really occurring in real time? The technology can send that to the sidelines for physicians to look at and to start assessing, OK, they just got an injury that’s really significant and we need to take them off the field to not play anymore. So that’s where the field is definitely moving. Over the next five to ten years, I think we’ll have a much better idea of what type of injury is the one that’s really problematic, and that will be helpful because it will allow us to make decisions about whether somebody should go back into—for the military, whether they should go back into the field, or for athletes, whether they should go back to playing sports.

Being Patient: There have been a lot of articles written about the repeated impact of heading a ball in soccer. Is that action enough to actually cause damage?

Dr. Bruce Lamb: There are what we call sub-concussive injuries, which include an even wider variety of people getting hit in the head by a ball. My daughter is a volleyball player and she was hit by a ball in the head and dropped to the ground. I immediately had the wrong response, which was, “Oh, she should get back in and play.” It is a risk in a variety of sports. There’s not a lot of data yet on soccer players in particular, though there are a couple of case reports on soccer players who then went on to develop this chronic traumatic encephalopathy, but it’s very few and we don’t know how this relates to the entire group of soccer players. We just know there’s a couple of cases, so we don’t really know the true incidence of this in people who have played soccer for a living or for many, many years. So that’s another area where we don’t have a lot of information yet: what the real risk is.

Being Patient: You said that you had the wrong reaction when your daughter was hit in the head by a ball. What is the right thing to do if you suffer a blow to the head?

Dr. Bruce Lamb: If you have a concussion and then you have a second one, particularly within a close proximity, outcomes across the board are much worse. That is the one thing that we know fairly clearly. The recommendations are, if you have a concussion, and maybe some of these sub-concussive blows, that athletes should sit out and get evaluated for whether they have a concussion and how bad it is. They can go through these tests of balance, memory, language and all of those tests that can access whether someone has a concussion. In my daughter’s case, during the next day or weeks, it followed that she indeed had a concussion and all of the typical features of a concussion: light sensitivity, headaches and the very traditional symptoms of a concussion. But immediately, afterwards, I think our response is, “Oh, you have to go back in,” and that’s the thing I think we really have to work on as a community and society to say, “There are situations where we need to pull people out and assess how they’re doing before people can go back in.”

Being Patient: Does traumatic brain injury affect the ability of the brain to get the energy it needs through the blood-brain barrier? Studies report that traumatic brain injury decreases the ability of glucose to cross the blood-brain barrier. Are there any differences in the type and extent of inflammation found within the brain after a traumatic brain injury, compared to in an Alzheimer’s patient’s brain?

Dr. Bruce Lamb: The blood-brain barrier is the area which protects our brain from the peripheral immune system so that we’re not having peripheral immune cells entering and causing damage in the brain. After an injury, it can get damaged and lead to leakage of the blood-brain barrier, so then peripheral immune cells and all different kinds of things can come into the brain. There is certainly evidence that that could potentially be part of what’s happening in traumatic brain injury.

For chronic traumatic encephalopathy, where the pathology occurs later on, after many years of concussions, the tau protein begins to form around blood vessels in the brain, so it really suggests that there’s something locally about how those blood vessels are responding to injury, which is then inducing that type of pathology. One of the big problems we have with studying the immune system in the brain is that we don’t have a lot of great ways to study this in living people. There are starting to be some ways to do brain imaging to look at the immune system, but we’re still at the infancy of being able to assess, “Is the immune system activated, and what does that mean for patients?”

Being Patient: Articles suggest that traumatic brain injury can trigger depression and increase the risk of suicide. Is there a mechanism that causes that, and how does memory loss factor into these conditions?

Dr. Bruce Lamb: We don’t really know. This is where it gets into the complexity of this. There’s also evidence, especially in the military with brain injuries, that those folks are at an increased risk for post traumatic stress disorder (P.T.S.D.) and a variety of things related to that, including depression and suicide. They’re obviously linked together somehow, in terms of how these folks are at an increased risk for P.T.S.D., but they’re also at an increased risk for dementia, so how do those two intersect? I don’t think we have a good idea yet of what those different levels of intersection are. It’s one of the difficult things for us to study this, again, because we’re usually, based on these retrospective studies, looking backwards, as opposed to following people over time.

Being Patient: Have any studies looked at people who have dementia and have suffered a traumatic brain injury or multiple concussions after their diagnosis?

Dr. Bruce Lamb: Yes, there’s definitely a lot of work being done there. Falls in general in the elderly are one of the biggest risk factors we have for outcomes of all sorts. There is evidence that if dementia patients are exposed to a brain injury through a fall, their outcomes become worse. That is pretty clear and in those folks, brain injury is definitely not a good thing. We should try to figure out how to reduce falls at all costs. I think there’s starting to be some interesting new technologies, like watches and electronic devices that are being used in some early studies—and can monitor people off-site—to track things like a participant’s gait. Researchers can look at how someone is walking and interacting with the world, and whether that’s causing them to be at an increased risk for a fall. If you can identify patients who are at an increased risk for a fall, I think all the evidence suggests that could dramatically impact whether those patients go into a nursing home. Those are some interesting areas right now with a lot of research.

Being Patient: When should you get neuropsychological testing or brain scans to determine whether you have a concussion or head injury and need to recover from it?

Dr. Bruce Lamb: I think for athletes, there are more and more physicians or physician’s assistants who are on the sidelines, especially in the NCAA and professional sports. They’re there primarily to provide those levels of assessments, so most of that right now is done by clinical assessment: certain features that we know are part of concussions, like balance, memory, language and a variety of tests to track symptoms. Typically, in professional sports, and I think in college sports, they will assess people in the pre-season, before they’ve actually started. That way, when they get into a game, they can assess their function relative to how they were performing before they started the season. That’s how this is done: an assessment of how they’re performing relative to their baseline before. The key there is that that baseline has to be performed honestly. I’ve heard rumors that some of the athletes perform poorly on that pre-season test intentionally so then, if something does happen, they’ll be more likely to continue to play, especially among professional athletes, where this is their livelihood.

As I mentioned, I think the field is developing ways to assess the type of injury that’s occurring and making assessments based on that. So if we have mouth guards with accelerators and gyrometers, which are in our phones, or on helmets, and different things like that, then can assess on the sidelines, “OK what was that hit?”, “What was the rotation or acceleration?” and “Based on that, should that person be pulled out of the game?” I think that’s where the field is going, but right now, it’s done by clinical assessment. So in a high school sport, which is where my daughter was, we then relied on her reporting her symptoms. The minute she was talking about the clinical symptoms of photophobia, light sensitivity, headaches, nausea and classic signs of a concussion, we realized, “OK, we should take her to the pediatrician or pediatric neurologist, who specializes in concussions, and can develop a plan for helping her.” The other aspect of a concussion is obviously the follow up. Some people respond and can function again very quickly, but others struggle with this for many months or years, in some cases. We still don’t understand why some of these people who have concussions don’t respond positively,  whereas others do.

Being Patient: Have there been any studies on where the impact is on your head, and whether that puts you more at risk of developing dementia later in life?

Dr. Bruce Lamb: There’s starting to be. In the past, this wasn’t really monitored in any clever way. With some of these new technologies, I think we’re going to start seeing this, especially, for example, in some of these more recent studies, where they’re now using ways to assess how to quantify and localize where the injuries are occurring. I think that’s going to be the key for moving forward.

Being Patient: There are people who have an elevated genetic risk for Alzheimer’s, namely the ApoE4 community, depending on whether they have one or two variants. Are we studying that population in the context of traumatic brain injury?

Dr. Bruce Lamb: There’s been a bunch of work done there: trying to look at the risk relative to brain injury in the ApoE4 community. There’s a bit of a controversy. There’s some data that certainly suggests that those people are also at an increased risk for negative outcomes with regards to brain injuries, but other studies have shown that there’s really no effect. We are currently doing some studies in animals that we’ve generated, who carry the ApoE isoforms, and we’re looking particularly at this. One of the interesting things about ApoE, which I think may relate to the risk in terms of brain injury, is that it’s recently come out that ApoE is one of the genes that’s the most up-regulated in the immune cells in Alzheimer’s disease, so this is a new and interesting finding. It’s only been within the past year that we’ve appreciated this, and so I think that suggests ApoE is potentially playing a role in the immune system, which I think previously, we didn’t appreciate. That is a brand new area, and you’re going to see a lot more relationships to brain injury and how the immune system is activated, but also in Alzheimer’s disease as well.

Being Patient: How do you know whether or not symptoms are related to a traumatic brain injury versus that they’ve developed into dementia, especially in elderly patients?

Dr. Bruce Lamb: It’s difficult with that age population [people in their early 60s] because that’s right about the age when dementia starts to increase in incidence. Before that, it’s not normally seen, so it would be very, very abnormal to see. Once you get to 60 or 65, 5 to 10 percent of that population already has dementia, so that’s a very difficult thing to assess because we don’t know what a person’s functioning at that age would’ve been anyway, if they hadn’t been exposed to a traumatic brain injury. The only things we can figure out are what we can do to support people who have those types of injuries—by seeing physicians and following the patients—but also things we recommend for Alzheimer’s patients at this point, including physical exercise, since all of the evidence has supported that that’s something that’s good for our brain and potentially, may help reduce risk of dementia of all causes. A heart-healthy diet is important as well; the evidence strongly suggests that that’s also good for our brains in a variety of situations, including potentially following brain injury. My sister has had multiple, significant injuries, including head injuries, so she’s self-reporting self-confusion, but you can’t really know if that’s related to the brain injury, or something that would’ve happened irrespective of that. I think it’s a huge challenge.

Being Patient: What have we learned in recent years that we didn’t know and where should the focus be in the next five or ten years?

Dr. Bruce Lamb: Earlier on, as a field, we were struggling and sort of asking, “How do we assess whether this topic is really important or not?” I think the field has just been trying to assess, “Is there really an association between brain injury and neurodegeneration, more generally?” I think it’s starting to become clearer from some of the most recent studies that are so large, with tens of thousands of patients over many decades being studied, that there are significant changes in the brain for sure; that evidence is pretty strong. The same thing with chronic traumatic encephalopathy. We now are pretty confident that this is a real phenomenon that is occurring, so the questions now become, “What are the types of injuries that move us towards that condition?”, “Can we identify what those are and figure out what the biology is?” and “Why does it occur in some people and not others?” We think that there’s definitely a link here and now we need to understand, “What is that link?”  

Being Patient: People often ask how they can participate in trials if they’ve had a series of brain injuries. Who’s the perfect candidate and how do they get involved in a trial?

Dr. Bruce Lamb: I would argue that most academic medical centers have a program of research going on relating to brain injury, including some clinical trials, depending on the location, across the country. There are ongoing clinical studies, including observational studies that follow people and try to understand how they’re exposed. Some of these longitudinal studies, like I mentioned for the NCAA, are occurring nationwide. There’s other studies of professional fighters out in Las Vegas, and then there’s just studies going on at academic medical centers. Typically, for a lot of the brain injuries, the studies are occurring in departments of neurosurgery, because that’s where people arrive with more moderate to severe injuries, or in the departments of psychology and neurology—those are where you see people coming in. 

Being Patient: Do researchers focus on behavioral studies, or is there a type of medication that can treat traumatic brain injury?

Dr. Bruce Lamb: There are clinical trials going on right now and that have been going on for a variety of different [treatments]. I wouldn’t say there’s anything out there yet that’s shown enough promise to get approved by the F.D.A. and to be offered to patients. That’s something we’re still struggling with. It’s similar to the Alzheimer’s field right now; we are still struggling to come up with a therapy that really works well, but there are certainly lots of clinical trials going on that cover a wide variety of different drugs and interventions. They’re not only looking at drugs, but questioning how to help people recover from these types of injuries. A lot of the research is going on in rehab facilities. There are all different types of tools, including robots, to help with rehab for these patients.

This interview has been edited for length and clarity.