Welcome to Rusk Insights on Rehabilitation Medicine, a top podcast featuring interviews with thought leaders in the field of PM&R from Rusk Rehabilitation at NYU Langone Medical Center and other prominent rehab medicine institutions. Your host for these interviews is Dr. Tom Elwood. He will take you behind the scenes to look at what is transpiring in the exciting world of rehabilitation research and clinical services through the eyes of those involved in making dynamic breakthroughs in healthcare. So listen, learn, and enjoy. Hello, and welcome back to part two of the presentation by Dr. Stephen DiKosti in the Rusk Rehabilitation Institute podcast series. He concluded part one of his presentation by discussing how the relationship between TBI and neurodegeneration has affected the Department of Defense and the Alzheimer's Association in the United States. In part two, he discussed how CTE is not a new disease, but its pathology is seen in various contact sports and how when patients currently arrive for rehabilitation, their injury is a lot better described now than it was the case previously. And of interest is the fact that these are from 2014, here's the Journal of the Alzheimer's Association, Alzheimer's, and dementia with the soldier on the front because of the blast and traumatic injuries that occur to them and the risk down the line of neurodegenerative disease. And then another one with the scientific end on it, here's a, I believe that's a red breasted woodpecker, but it was there because people started to examine how animals that would be able to traumatize themselves so many times like pecking into wood, but did not hurt their brains and what could we learn from that to try and prevent disease from coming later. So one of the other places beside woodpeckers that in which trauma occurs are in mountain goats in the spring, they fight endlessly to see who will rule the herd and it became so commonly known, this disease that no one had ever heard of before, that in 1915, this cartoon appeared in the New Yorker and the one mountain goat is saying to the other, I'm weighing the risk of brain damage against a life of celibacy because the winner was the one who got to guard the herd of female animals in the herd. So what are the path mechanisms that would lead you from an acute to a chronic neurodegenerative disease? One is diffuse axonal injury, which leads to decreased connectivity in the reserve and a slow degeneration of axonal connections due to altered components, especially tau. This is important because we all know about the acute things that can happen, but how does it lead to something that manifests itself several decades later? For the short term with let's call it a mild to moderate traumatic injury, you can have altered synaptic structure and function. For the longer term, chronic inflammation and chronic oxidative stress can lead to subsequent degeneration and also some chronic microglial activation, which may turn on mechanisms that you don't necessarily want, including cleaning up partially injured neurons that might recover. And the other interesting thing is, although we're not sure how that happens or why it happens, amyloid precursor protein, beta amyloid, the peptide that puts itself into plaque in the brain and AD, and subsequent Alzheimer's cascades may also lead to chronic disorders that lead that manifest themselves later. Well, here's an example of how inflammation can occur. This is a 37-year-old who died and four years later, following one severe TBI, still had inflammatory foci around the brain, and activated microglia disruption of myelin basic protein, but you see they're both in the same places. So these activated microglia are eating white matter in this region. And then this is what we saw. This is from Ann McKee and Bob Stern in the group at the Boston VA who have done fabulous work in the pathology and the behavior changes of CTE, the characteristic picture, which most of us learned as dementia-pugilistica, is this curious deposition at the base of the salsi, the valley, and the bottom of the valley that ends in a V that goes back up to the top of the gyrus. And in these areas is where TAL collects. It's for the most part perivascular, but it gathers itself in the depths of the salsi. It's not just neurons, interestingly enough, it's also in astrocytes, one of the few disorders in which there's TAL in astrocytes. And another interesting part of what this means is a study from David Brody who's now at NIH. If they took thin slices and looked in an area where there was not a deposition at the bottom of the gyrus, they found that the evidence of disruption of myelin was not present on fusion tensor imaging, which tells you about whether the axons are lined up correctly or not. But if you look in a sulcus where there is evidence of this TAL deposition, as I showed you in the previous slide, there is massive disruption of the white matter underneath the cortex. So this is obviously a significant disruption of the activity. And this is in this region of the brain. So TAL positive salsi had disrupted myelin. If there's not TAL in that area, it is not, it doesn't disturb the white matter. But we have a way to now look at high special resolution and diffusion MR and we can tell, I mean, this was done with an 11T MR scanner, but we can now see the microscopic level of effect, although this is not yet able to be done in humans. There are a number of 17 magnets now being assessed, and I suspect that those studies will be out sometime in the reasonably near future. The other thing is, especially in the people who get the disease in an older age, there's other pathology in the CTE, there's neurofibrillary tangles. There's a TDP-43 deposition, this is what you see usually in dementia with lewy bodies, and then there are lewy bodies. The distribution of their fibrillary tangles in CTE is different than AD, and I've already mentioned how it's at the bottom of the salsi. Whereas in Alzheimer's disease, there's a laminar distribution that's continuous, it doesn't just care at this, in the sulcus, and in there. If you look at the comorbid pathology in CTE, remember most, but not all of these people in these earlier studies were from an older age group. Over half of them had Alzheimer's disease pathology. A significant number had lewy body disease, and they may have had AD as well. A number of them had phototepal degeneration, FTD, and a number of them had ALS, had motor neuron disease, which we also see now frequently in people with, not necessarily with the cognitive changes of CTE, but who developed motor neuron disease after a lifetime of playing sports, especially Lou Gehrig of being one of the most famous people, but he didn't have a lot of head trauma, but there also were people with ALS in a lot of the early studies. The number of people who had CTE without any disease was, you know, half of them, so lots of them have other things going on in the brain besides just evidence of CTE. Now animals, models show up regulation of amyloid beta after traumatic brain injury in humans. It also happens in mice, so they can be, amyloid beta can be elevated both in white matter and gray matter, and might add to the cascades that we think amyloid leads to, which leads to degeneration, especially the Alzheimer's disease, but we have not been able to prove that, but we also know that in contact sports, it is all a significant, these people are all at significant risk. I guess we should put MMA in because although there's not as much boxing now, MMA and full contact karate will probably be the next wave of people who have this disorder who will come to be rehabilitated, and then the long-term neuropsychological impairments correlate not with the number of knockouts, but the number of rounds boxed, and when I told you there was not much oversight of boxers back in the early days, you could fight as early as frequently in as often as you wanted to, and if you lost your skills, I'm told to be a competitive fighter, you would just sometimes hire yourself out to be a sparring partner with a person who was on the way up, and you would just be head traumatized even more because you weren't up to the task of fighting with these people. APOE4, I told you, increases the risk of Alzheimer's disease, and I said it also increases the risk of tell deposition, and here is the cognitive score of someone who had either APOE or not, and did a lot of boxing or a little boxing. When you have a lot of boxing, that effective APOE shows up, and you have more evidence of brain injury. Both neurofilament light, which is a marker of neurons, it's an intracellular protein, so that it shouldn't be out in this biofluid. Same way with tell, there should be low levels of it, but if they're elevated, it means that amyloid has, or these proteins have leaked out of an injured neuron, and it's also upregulated in spinal fluid, in soft purple areas, who do headers a lot, and in ice hockey. So we find these, although we don't know how much of these might cause damage that would lead to some cognitive impairment, at least at this point, although there are some people with CTE with both of these, they don't appear to be as common as in football players. And I believe I've told you that severity of impairment in boxers relates to whether they have APOE4, and even then you have to box a lot before it can happen. So here's evidence of trauma leading to diffuse amyloid plaques. This is a 34 year old male after a TBI. Two hours after the TBI, his temporal lobe was removed, and this was present. So at 34, he won't have plaques that were Alzheimer in development, and two hours post TBI means that they formed right away, and we've seen this now in animals as well. The neuropathology is characterized by a misfolded hyperphosphorylated form. This is what forms those tangles, both astrocytic and neuronal, that are at the base of the salsi. And the pathonomonic findings are those findings as the depth, and as I showed you before, the tau deposit surrounding small blood vessels, which almost surely implies a leakage one way or the other, but we have not yet nailed that down. The prevalence of the disease is unknown, and it's controversial. And many of you may have seen this. This is a paper by people who work with the NFL, Joe Maroon was the sealer's neurosurgeon, and they reported that in 153 cases, they didn't see a relationship to the apoelia or to age of death, and they said the incidence remains unknown. Well, we know that, but it doesn't question the widespread existence of CTE. And widespread is the problem, because especially when the Boston Group says, well, we've examined 110 cases of football players whose brains came to us, and 98% of them have CTE. Keep in mind that of all the hundreds and thousands of people who play football, the ones who came to them were people who had a cognitive complaint. So you would expect that you have a very high level of pathology if they were cognitively impaired like that, which is where a lot of the distribution of the other pathologies came from in that circle got pie chart that I showed you a few minutes ago. Why is this so important? Well, tau is a microtubule associated protein. You can think about it as it holds together. The axons specifically holding together the microfibers that make up the axon by keeping them together like this. They are essentially like railroad ties for the train tracks. And if you were to cut these, you could tell that with a train when over them, it would display. And in fact, that's what happens when you get too much phosphorylated tau, it comes off the axon and bind the microtubules anymore, and they disseminate themselves into the extracellular space. And some of these you can pick up in the spinal fluid. So the tau phosphorylation and the crosslinking stops it from binding, and you get disruption of connectivity. Now in Alzheimer's disease, the spread of neurofibillary pathology like this is very regular. It starts in the mesial temporal lobe. This is where a lot of the memory difficulties, early memory difficulties are based, comes onto the hippocampus, spreads out into the anterior temporal lobe, and then onto the inferior lateral temporal lobe, and then up to many other parts of the brain, although interesting enough, it doesn't bother the post-central virus sensory cortex. But it's always the same way. CTE does not look like that. You see most of it early in the anterior portions of the frontal lobe, and wouldn't that be expected? Inferior portions of the frontal lobe, and some parts of the brainstem. And then when it spreads, you start to see it in different parts of the cortex, and also in the basal ganglia of the brain, and as it moves, you can see it involves the entire frontal lobe, and eventually everywhere. Not the same as the spread of neurofibillary tunnels. But of course, these are what these red markings show you, is where they're seeing the frequent perivascular abnormalities, and the social deposition of tau. It's not just the counts of neurofibillary tangles in the cortex, which is what the prior Alzheimer's distribution was made of. So if you go back, which people did, and look in your autopsy cases, and you could do this at NYU if you wish, they find that CTE is rare, and it's only seen in cases with history of repetitive head injury. This was one of the things thrown back at the deniers that this had any relationship to boxing. So looking into one, I think this was for Mayo Clinic, a minor article, 21 of the 66 former athletes had cortical tau pathology, wasn't detected in almost 200 people who had no contact sports, including 33 people with only a single incident TBI, but the people who in which it was detected, those 21 people all had documented participation in contact sports. So exposure to contact sports was the greatest risk for CT pathology. And of course, these are just the data from autopsies done at an academic medical center. They weren't looking for cases of repetitive traumatic head injury. They just took what came, and then if you look back, this is what you find. Oh, yes, we have some people who were diagnosed with what probably would have been dementia pugilistica. But if it had that diagnosis, they had a history of repetitive head injury. I think the connection is pretty clear. How can neural imaging help? Well, we're getting better and better with this. When people come to you in rehabilitation, they're going to have things a lot better described than we used to. We can look at disruption of structures. We can see hemorrhage. We can determine whether the volume changes both in the ventricles and in the gray matter. Inflammation, such as the microcleial deposition I showed you in the young man four years after he died. TSPO is a pet ligum, and it binds to the mitochondrial position. It's used to be called the benzodiazepine receptor. But if TSPO is up, that means that cell is in trouble. But you can now see these on a PET scan with TSPO. Connectivity with diffusion tensor imaging as I showed you before with the 11-team magnet showing that if there's traumatic injury, we can't see the tau on the MR scan. But the DTI will tell you that right beneath that, there is disruption. And functional MR, which would show you that if you were giving tasks to expect specific circuitry to light up, it would or would not light up. And now, of course, with molecular imaging, we can tell number one, where the amyloid is. If there's amyloid and tau distribution, it's probably AD or AD+. But we don't yet have a definitive marker in tau pet that people will firmly call due to or diagnostic of CTE. And I want to show you that before we stop. Here's an example with diffusion tensor imaging of the kinds of injuries that you can pick up. This is corpus callosin, obviously disruption. But we can see it now on DTI studies. And then this is a person with activated glia. This is a TSPO, sorry, this is a TSPO ligand. And what it shows you is all of this disrupted deposits of this activation. Here's a normal person and virtually nothing to disturb you. And then here's the former NFL player. This is one of the papers, this is one of the papers that we had published a while ago of a person with CTE with these drops here. Not only can you see them, but for the most part, they look like they're at the bottom of SELSI. And then with subsequent additional cases, 62-year-old with a hockey player, a 63-year-old hockey player who looks like he didn't mix it up so much, a 44-year-old football player who looks pretty clean, a 39-year-old football player who doesn't. And then a 68-year-old football player with CTE, so one of the mysteries is why he waits so long to present with cognitive impairment, who's got a little bit of noise in the area. Then boxers, 39-year-old boxer looks pretty clean, 45-year-old boxer has some issues, especially inferior from a 45-year-old boxer who boxed a lot, and you can see that the deposition is pretty diffuse. And then a control who has virtually nothing in the way of deposition. So we know that CTE is not a new disease, but we do see the pathology in other contact sports, and we don't see it in autopsy series unless the person had a history of repetitive head injury. We know that it involves structural change in disrupted circuitry, as well as of tauopathy, and a lot of overlapping pathologies. And keep in mind that those little deposits of tau in the cell cell are not, could not possibly cause the extent of the cognitive impairment of CTE. So almost surely it's the white matter damage that leads to the cognitive impairment, not so much the tau deposition areas themselves. We know that neuroimaging will aid evaluation and treatment outcomes like that. Anybody will come to you from now on with a diagnosis of possible CTE, or what we now call in the absence of pathology traumatic encephalopathy syndrome, because CTE is a pathological diagnosis, not a clinical diagnosis. We know that there are some relationships to risk factors for Alzheimer's disease, but no smoking gun here to say how related they are other than the fact that TBI increases the risk for Alzheimer's disease significantly. And it is quite likely that whatever therapeutic interventions we develop for Alzheimer's disease, especially for tau protein, for removing tau protein, and those studies are now cranking up, and if you look them up in clinical trials.gov, whatever we find will be used in CTE for treatment, and potentially for prevention, depending on the person's history and how much they had had an abnormality in our frequency of boxing and head trauma. So CTE and Alzheimer's disease in a way are strange research bedfellows, and they're going to stay that way, because they both have scientific discoveries that I think will help the others. The takeaway message here, I think for you all, is that CTE is a pathology about which we have learned a lot and then look back at the history to see what has happened that caused this strange deposition, this new finding, but because it only can happen as an autopsy, the only way to know it, those scans as I showed you, are not enough to make that diagnosis. All of these cases that come in with cognitive impairment that's been progressive are due to our term traumatic encephalopathy syndrome and not CTE until there is pathological proof in that person that they have the distribution of tau in the expected places. So I'll stop there, and I would be happy to answer any questions that I could. It's been a strange chase of this disorder. We played very little, if any, attention to it until the early 2000s, even though it was known about for 100 years before that, and the fascinating problem, because it represents a kind of change in pathology that we didn't know existed, or the why that is existence, and I'll leave you with the last clearly very important abnormality and mystery. If people develop the disease at a relatively younger age, let's say in their 30s, think Junior Seow, the football player who committed suicide in his late 30s, those people who get the disease relatively soon after they finish playing football have much more of a neuropsychiatric presentation, and maybe they're never quite well. The people who get the disease at mid 50s to 60s, maybe 70, have a progressive slow cognitive change, not so much of them as a neuropsychiatric change, but these are people who may have played football football for 10 years, stop going to business, have a lifetime of success with family and friends, and then begin to have a dementia, or a cognitive decline, isn't necessarily Alzheimer's disease, and we don't know why they have waited so long, but they are ones who have more of a classical cognitive impairment dementia, as opposed to the young people who have a much greater incidence of depression and neuropsychiatric feelings, and neuropsychiatric abnormalities. So if anybody wants to sort that one out, we will be delighted to see it. So if there are any questions, I would be happy to answer them. We're going to get some more answers for this disease, I think, over the next five to 10 years, and when the drugs come for tau from Alzheimer's disease, they'll be going into these people before they die. Right, great. Thank you so much, Dr. Tkoski. If anyone has any questions to ask him, you may do so now, and if not, I guess we can have the great rest of our day. I'm happy it was all so clear. Thank you very much. Thank you so much again, everyone. Have a great time. Thank you again for joining us. You can learn more about Rusk at NYULangone.org/Rusk. Also be sure to follow this podcast on Twitter at Rusk Podcast.
