Dr. Shuvro Roy talks with Dr. Daniel Daneshvar about the prevalence of CTE at death among NFL players and the association between CTE severity and the risk of dementia. Read the related article in the BMJ. Disclosures can be found at Neurology.org. Podcast Transcript: Dr. Jose Merino: This is Jose Merino, Editor-in-Chief of the Neurology family of journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening, and have a great week. Dr. Shuvro Roy: Hi, this is Shuvro Roy from the University of Washington, and welcome to today's Neurology Podcast. We'll be covering a study titled Prevalence of Chronic Traumatic Encephalopathy and Death in National Football League Players: A Retrospective Population-Based Cohort Study from 2008 to 2001, published in BMJ. We're joined by lead author Daniel Daneshvar, Chair of Spaulding Rehabilitation at Harvard Medical School. Dan, thanks for joining us. Dr. Daniel Daneshvar: Great to be here. Thanks for having me. Dr. Shuvro Roy: So Dan, this study has already received widespread national attention, but please give us the headline. What did you find and what's the number one thing that you want listeners to remember? Dr. Daniel Daneshvar: So this was a study looking at how commonly this specific neurodegenerative disease called chronic traumatic encephalopathy or CTE, how commonly this occurs in a cohort with a lot of repeated traumatic brain injury exposure, namely former National Football League professional football players. And what we found was that between the years of 2016 and 2021, so for that five-year period, the absolute minimum prevalence of CTE at death in this group was 25%. The absolute maximum was 98%, and the true rate is somewhere in that range. Now, for context, in the general population in community cohort studies, the prevalence of this pathology is somewhere south of 1%. Dr. Shuvro Roy: And what does this study add to our current understanding of CTE and neurologic disease associated with head trauma? Dr. Daniel Daneshvar: So we've long known that individuals who have experienced repeated traumatic brain injury exposure, whether through sports like NFL, NHL players, professional soccer players, whether through occupational exposures like in the military or as in individuals who experience intimate partner violence, we've long known that these individuals have higher rates of neurodegenerative disease. But what we haven't known is just how much higher that rate is. And what this study has shown us is first off that this is alarmingly high in former professional football players at death. And then the second thing that this study shows us is that this pathology is unsurprisingly very linked to clinical symptoms, including with more severe disease, cognitive impairment that's so severe it results in dementia, meaning impairment in someone's ability to perform activities of daily living, including feeding, bathing, dressing, grooming, toileting, those kinds of things. Dr. Shuvro Roy: As you pointed out, your primary finding was that there was this maximum versus minimum prevalence, which ranged from anywhere from 98% to 25%, so obviously a wide range. But to help us understand this study, can you walk us through that methodology, the minimum and maximum prevalence approach? Why a range rather than a single estimate? And you mentioned that the number is likely somewhere in between. Where do you think that true number sits, if we even can estimate? Dr. Daniel Daneshvar: So to understand why there's a range, it's helpful to understand how we got to these numbers. And so when we looked at the individuals who had CTE who played in the NFL across three brain banks, mostly the BU CTE Center, but also the Mount Sinai Brain Bank and the UCSF Alzheimer's Disease Center Brain Bank, when we combined all NFL players across these brain banks, we found that NFL players had a 93% prevalence of CTE at death, but that 93% represents a selected cohort. These individuals who chose to donate their brains more often than not chose to donate because they or a loved one had some concerns about them, not always, but many times. And so we don't believe that the true prevalence in NFL players is 93%, but what we wanted to get at is what could that true prevalence look like? And so we took advantage of the fact that amongst the NFL community, brain donation is something that has been less stigmatized over the past couple decades and is something that is very common. And so we said for the lowest, the conservative minimum prevalence of CTE, let's say that everybody who was not studied by one of our brain banks, that every single professional footballer who died during that time period had no CTE at all in their brain. If we make that assumption, then the absolute minimum over those last six years of the study is that 25%. Now, it's important to note what that assumption entails. That assumption assumes that, for example, the people who were diagnosed with CTE at other brain banks that were not included in this study, it assumes that they did not have CTE, even though they were diagnosed with CTE at other brain banks. That conservative minimum assumes that the 16% of people with dementia so severe, it was listed as the actual cause of death on their death certificates, the 16% who didn't donate, that they did not have CTE either. Now, of the people who did donate, for the folks who had dementia, 96% of them had CTE. So that's quite an assumption. We're assuming that they were all clean too. Despite those assumptions, the conservative minimum of CTE prevalence amongst these NFL players is one in four. Now, the maximum on the other side assumes that the only individuals who played in the NFL who died during that time period that didn't have CTE were the ones that we laid eyes on, and so that everybody else, they did have CTE. That's how we get the upper bound. And so when I say that range is somewhere in the middle, based on those assumptions, it's almost certainly higher than that 25% and likely substantially higher. Dr. Shuvro Roy: So essentially trying to maybe correct for the possibility that maybe there's a "sick bias" or selection bias of the brains that were donated, but even the 25% is almost certainly too conservative, considering it is likely that those folks with dementia, at least some of them had some degree of CTE. To that point, beyond prevalence, you showed that stage four CTE was strongly tied to dementia with 90 plus percent of those donors affected. What does that add to the argument about CTE pathology mattering clinically? Can you speak a little bit more to that? Dr. Daniel Daneshvar: It's pretty clear at this point that CTE pathology is associated with a substantial cognitive impairment, especially as it gets severe. In a different study, we took a look at individuals who had CTE in the absence of any other neurodegenerative disease, and we found in that study that individuals with more severe pathology were more likely to have dementia and specifically with stage three and stage four CTE. In this study, similarly, we also found that in individuals with CTE in the absence of other neurodegenerative pathology, which represented 53% of donors who had CTE that had no other neurodegenerative disease had dementia too. So CTE clearly can result in dementia when the pathology is severe. But that's, again, not surprising for anybody in the neurodegenerative disease space because the pathologic marker that's most closely linked to cognitive impairment in a disease like Alzheimer's disease, it's not the amyloid pathology, it's the tauopathy, it's the phosphorylated tau, the same neurofibrillary tangle pathology that we see in Alzheimer's. When that disease occurs in a different pattern, but also in CTE, it's not surprising that we see individuals with cognitive impairment. Dr. Shuvro Roy: You also looked at the death certificates of the donors in these cases, and death certificates missed roughly 70% of the dementia that your clinicians identified. I think about CTE in the news and how many prior players who have since been found to have CTE posthumously were not necessarily identified to have dementia at the time. What does this finding mean for some of the earlier NFL mortality studies that relied on these numbers of the percentage of players who had dementia? Dr. Daniel Daneshvar: Again, it's not particularly surprising for anybody in the neurodegenerative disease space that death certificates under-report the prevalence of dementia, because many individuals die with dementia but may die of say an MI or something else. But we've both been the beleaguered intern in the ICU in the middle of the night that has unfortunately had to write a death certificate for a patient of ours. And oftentimes what we're writing is the most proximal cause of death. So we might write that sepsis or pneumonia was the cause of death, but might not include on the death certificate that the sepsis was due to urosepsis related to dysphagia related to dementia. Those factors aren't typically what we are including in the death certificates. And so we know that death certificates are under-counting the rate of neurodegenerative disease. But what this study allowed us to do was put a number to it to let us know that we're missing the vast majority of individuals who are dying with dementia but of other processes if we only look at the death certificates. And so when we look at death certificates and we try to ascertain the causes of death for individuals, we might erroneously think that something like a heart attack is a bigger issue for NFL players than something like dementia, but that's why it's so important to take a look at what the population averages are. And so when we look at something like MI for NFL players, they die with MI, as we showed in
