CTE: Tackling the high incidence and possibility of a premortem diagnosis in NFL players

Are you ready for some football? As the Super Bowl—the most watched sporting event in the world—draws closer, most fans are thinking about the Philadelphia Eagles facing off against the New England Patriots. But some researchers, clinicians, the National Football League (NFL), and perhaps even players have been forced to consider the sobering possibilities of football’s damaging effects.

One of these is chronic traumatic encephalopathy (CTE), a degenerative brain disease that occurs in athletes, military veterans/service members, and individuals with a history of repetitive brain trauma. The hallmark of CTE is the presence of clumps of tau, which slowly spreads and kills healthy brain cells.

CTE has been getting a lot of press, as well as a lot of research effort as of late.

For example, recent research published in the Journal of the American Medical Association showed that up to 99% of professional football players whose brains were studied had CTE.

In this study, senior author Ann C. McKee, MD, Boston University Alzheimer’s Disease and CTE Center, Boston University School of Medicine, Boston, MA, and colleagues set out to assess both the neuropathological and clinical features of deceased football players with CTE. They used a case series of 202 football players who donated their brains for research and conducted neuropathologic evaluation, as well as retrospective telephone clinical assessments.

Refined neuropathologic criteria for CTE diagnosis from a 2015 consensus panel of neuropathologists organized by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB) were used.

They found neuropathologic evidence of CTE in 177 of the 202 players (87%), which included 110 of 111 former NFL players (99%). Median age at death was 67 years, and mean years of football participation was 15.1 years, as follows:

• 21% high school
• 91% college
• 64% semi-professional
• 88% Canadian Football League
• 99% NFL.

Median age at death for those with mild CTE pathology (stages I and II) was 44 years. For those with severe CTE pathology, it was 71. The most common cause of death for participants with mild CTE pathology was suicide (27%), and for those with severe CTE pathology, neurodegenerative, including dementia-related and parkinsonian-related causes of death were the most common (47%).

The neuropathological severity of CTE was distributed across the highest level of play. All three former high school players exhibited mild pathology, while 56% of former college, 56% of semi-professional, and 86% of professional players had severe pathology.

In all subjects, researchers found CTE lesions—perivascular clusters of ptau immunoreactive neurofibrillary tangles (NFTs) —in the cerebral cortex. In all stages of CTE pathology (stage I-IV), TDP-42 and alpha-synuclein deposition were evident. In a full 91% of those with stage IV CTE (91%), amyloid-beta deposition was present.

Dr. McKee and fellow researchers also found that cognitive symptoms were common in cases with mild (85%) as well as severe CTE pathology (95%). Among mild cases, 73% exhibited memory symptoms, 73% executive function symptoms, and 69% attention symptoms. In severe cases, these rates were 92%, 81%, and 81%, respectively.

Among severe cases, language and visuospatial symptoms occurred in 66% and 54%, respectively, and premortem AD diagnosis (25%) and postmortem consensus diagnosis of dementia (85%). Motor symptoms were also common at this stage, occurring in 75%, as were gait instability (66%) and movement slowness (50%).

“The strengths of this study are that this is the largest CTE case series ever described to our knowledge, more than doubling the size of the 2013 report,¹ and that all participants were exposed to a relatively similar type of repetitive head trauma while playing the same sport. In addition, the comprehensive neuropathological evaluation and retrospective clinical data collection were independently performed while blinded to the findings of the other investigators,” wrote Dr. McKee and colleagues.

Limitations included ascertainment bias, lack of a comparison group, and brain bank selection bias.

After this study was published in JAMA, the NFL released the following statement:

"We appreciate the work done by Dr. McKee and her colleagues for the value it adds in the ongoing quest for a better understanding of CTE. Case studies such as those compiled in this updated paper are important to further advancing the science and progress related to head trauma. The medical and scientific communities will benefit from this publication, and the NFL will continue to work with a wide range of experts to improve the health of current and former NFL athletes. As noted by the authors, there are still many unanswered questions relating to the cause, incidence, and prevalence of long-term effects of head trauma such as CTE. The NFL is committed to supporting scientific research into CTE and advancing progress in the prevention and treatment of head injuries.”

In addition, they noted: "In 2016, the NFL pledged $100 million in support for independent medical research and engineering advancements in neuroscience related topics. This is in addition to the $100 million that the NFL and its partners are already spending on medical and neuroscience research."

A big problem with managing CTE is that it can only be diagnosed after death. But recently, researchers presented the plausibility of using [F-18]FDDNP-PET imaging in the premortem diagnosis of CTE. [F-18]FDDNP is a molecular imaging probe that has an affinity for binding to amyloid and tau proteins.

Their study was conducted in an American football player with CTE who underwent [F-18]FDDNP-PET imaging 52 months before his death. Their results, to be published February 2018 in Neurosurgery, showed that [F-18]FDDNP-PET binding levels may correlate with neuropathological patterns of tau deposition in CTE (r_s=0.59; P=0.02), with the highest relative distribution volumes located in the parasagittal and paraventricular regions of the brain and brain stem. Researchers correlated [F-18]FDDNP-PET imaging findings and neuropathologic findings upon autopsy.

They called for future studies to assess the utility of differential and selective [F-18]FDDNP-PET in establishing a diagnosis of CTE in at-risk persons.

So whether you are rooting for the underdog Eagles or the favored Pats in Super Bowl LII, know that researchers and the NFL are channeling an increased awareness and significant research toward unraveling the mysteries of CTE diagnosis, treatment, and prevention, to improve the safety and health of all football players—from high school to pro, from Nick Foles to Tom Brady, and everyone in between.

This study received support from NINDS (grants U01 NS086659, R01 NS078337, R56 NS078337, U01 NS093334, and F32 NS096803), the National Institute on Aging (grants K23 AG046377, P30AG13846 and supplement 0572063345-5, R01 AG1649), the US Department of Defense (grant W81XWH-13-2-0064), the US Department of Veterans Affairs (I01 CX001038), the Veterans Affairs Biorepository (CSP 501), the Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (grant B6796-C), the Department of Defense Peer Reviewed Alzheimer’s Research Program (grant 13267017), the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association (grants NIRG-15-362697 and NIRG-305779), the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL.

References

1. McKee AC, Stern RA, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013;136(Pt 1):43-64.