The Science of CTE: Have We Rejected the Null Hypothesis?

Aug 2, 2019

By William B. Barr, Ph.D., ABPP, Associate Professor of Neurology & Psychiatry, NYU School of Medicine.
Media reporting on chronic traumatic encephalopathy (CTE) continues on a nearly daily basis, perpetuating a narrative that individuals competing in contact sports are destined to develop a distinct pattern of neurodegeneration and associated behaviors resulting from repetitive blows to the head. While the media reporting has been successful in capturing the public’s attention, most members of the scientific community have remained somewhat skeptical about the status of the prevailing CTE narrative while awaiting publication of more substantial scientific evidence. The aim of this article is to take a step back from the media hype and review the basic premises underlying the presumed diagnosis of CTE and methodology used to support its status as a distinct clinical condition.
In exploring the basic premises, it is good to start with a brief review of the methodology typically accepted and used in the scientific community. Origins of these scientific methods date back to the early part of the 17th Century when academicians, attempting to break away from philosophical speculation, began to systematically collect and analyze data to support the establishment of scientific facts. Over time, the methodology evolved to testing pre-established hypotheses. The idea is to establish a new alternative hypothesis prior to initiating an experiment, in favor of the null hypothesis, which is the assumption that the results of the experiment will not be true. Formal statistical procedures were developed in the early part of the 20th Century to formally reject the null hypothesis, forming the basis of the methods that continue to be used in contemporary research.
Prior to highly publicized neuropathological reports of former NFL players in the mid-2000’s, the assumption had been that some retirees from professional football and other contact sports would develop neurodegenerative diseases in the context of aging, in a manner that was similar to that which had been observed in non-athletes. When looking at the numbers, the lifetime risk of developing dementia is 15 percent in older males from the general population and 10 percent in males reaching age of 45 years. Going back in time, the null hypothesis was that NFL retirees and other aging professional athletes would be as susceptible as the general population to neurodegenerative diseases such as Alzheimer’s disease (AD), Vascular Dementia (VaD), Frontotemporal Dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).
The well-known story is that Bennet Omalu and colleagues, performing neuropathological studies on brains from retired NFL players, described the first cases of CTE associated with football competition beginning in 2005. The conclusion was that that these players were exhibiting a unique form of neuropathology that was atypical for their age and was similar in nature to a form of brain pathology had only been observed previously in former boxers. Publication of those initial cases was followed by a series of reports from Ann McKee and her colleagues at Boston University who described a series of individuals progressive tauopathy believed to be associated with repetitive brain injury. The argument was that this particular form of tauopathy produced a neurodegenerative condition with clinical and neuropathological characteristics that could be distinguished from other more common and well-described disorders associated with abnormal tau deposition, such as AD or FTD.
The assumption is that the pattern and characteristics of tau deposition and other neuropathological changes identified in cases of CTE are distinct from those observed in other conditions. Results published in a consensus panel report from 2016 are commonly used as supporting evidence (Acta Neuropath 2016; 131: 75-86). The findings from that report were based on analyses from a panel of seven neuropathologists who evaluated digitized images of neuropathological specimens from 25 individuals having the most severe stages of CTE in comparison to those from individuals with other neurodegenerative conditions. Upon detailed examination of the published data, one finds that abnormalities characteristic of AD were identified by members of that panel in eight of the 10 specimens from individuals purported to have CTE while alleged CTE changes were identified in eight of 15 cases without clinical features of that condition. Although the findings from this study are often cited as evidence supporting the neuropathological diagnosis of CTE, one sees that there is clearly overlap between the changes associated with CTE with those seen in other conditions, questioning whether the proposed brain changes associated with CTE are truly distinct from AD and other related conditions.
Extending beyond the neuropathology, the clinical presentation of CTE has also been associated with a broad spectrum of cognitive, mood, behavioral, and motor symptoms that are known to overlap significantly with those that are commonly observed in a variety of other neuropsychiatric and neurodegenerative conditions. It is argued that individuals exhibiting clinical symptoms of CTE have a history of exposure to repetitive brain injury causing a set of highly visible behaviors, including impulsivity, explosiveness, and violence that distinguish them from individuals experiencing prolonged forms of post-concussion syndrome or other forms of neurodegeneration. It is also argued that the individuals exhibiting clinical features of CTE develop symptoms at an earlier age than what is commonly seen in other conditions such as AD and have a less rapid course of progression than non-AD conditions such as the behavioral variant of FTD. However, contrary to the situation with neuropathology, no studies have been performed to support these claims or to disentangle the proposed clinical characteristics of CTE from those associated with other conditions in NFL retirees or other subjects, although research is currently underway (
One of the major gaps in the study of CTE is that its prevalence remains unknown. The estimates offered thus far have ranged widely, from four percent to 87 percent and there are currently no epidemiologic studies underway to address this question in any scientifically rigorous manner. Attempts to study rates of dementia in retired athletes have produced mixed results. One study demonstrated that, while the general death rate in retired NFL players from all causes was lower than what is observed in men from the general population, the rate of death associated with neurodegenerative disease was nearly three-times higher; however, this study is limited by its reliance on a relatively limited number of deaths attributed to neurodegenerative causes and no conclusive link between these conditions and head trauma (Neurology 2012; 79: 1970-1974). Those findings have not been replicated in other studies on professional athlete samples. Moving to non-professionals, multiple studies have shown no increase in the rate of dementia of former high school football players compared to non-athlete controls. There is obviously a need for more controlled studies using larger athletes samples before any strong argument can be made regarding increased rates of neurodegenerative disease in former football players.
There remains a possibility that retired athletes exposed to many years of repetitive head contact and a genetic propensity might develop symptoms of neurodegeneration earlier than similarly predisposed individuals who did not play professional sports. Prior to Omalu’s neuropathological reports on individual NFL players, other investigators had identified through questionnaire methods, a trend toward earlier onset of AD in NFL retirees relative to the general population (Neurosurgery 2005; 57: 719-726). This contributed to a proposal made by Randolph and Kirkwood that cumulative exposure to repetitive brain injury from a career in professional football could potentially reduce cognitive reserve, causing affected individuals to exhibit cognitive changes earlier than would otherwise be expected for their age (JINS 2009; 15: 512-250). However, it was predicted that, if this were true, the affected individual would be more likely to develop symptoms of more commonly reported conditions, such as depression, mild cognitive impairment (MCI) or AD, rather than any newly defined syndrome, such as CTE. In fact, a number of studies using neuropsychological test batteries with retired NFL players conducted outside of Boston have demonstrated that the pattern of cognitive and behavioral changes seen in NFL retirees resembles what is seen more commonly in depression and MCI, raising questions about the need to invoke the potential effects of any “new” or less prevalent condition, such as CTE.
In the end, there is no doubt that some former participants of contact sports develop neurodegeneration with advancing age. The questions are whether this occurs more commonly than what is seen in the general population and whether there is something new and unique about the pattern of neurodegeneration resulting specifically from their participation in the sport. The null hypothesis is that aging athletes remain as susceptible to developing AD and similar conditions as others. The scientific findings, to date, are insufficient to adopt an alternative hypothesis that aging professional athletes exposed to the effects of repetitive brain injury develop CTE, a condition that is distinct in the combination of its clinical presentation and neuropathological characteristics from other more commonly observed neurodegenerative diseases, such as AD. While the media continues to advance the CTE narrative, the current state of the science is that there continue to be no definitive findings on the prevalence or cause of the abnormal neuropathological findings that have been reported in limited studies of athlete samples and there is no consensus on the neuropathological or clinical criteria required to make a diagnosis of CTE or any accepted means to distinguish it from other more commonly occurring conditions. Efforts at making laws or public policy based on CTE science will have to await publication of more definitive findings before any truly informed decisions can be made.


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