Editorial pubs.acs.org/chemneuro
Chronic Traumatic Encephalopathy (CTE): A Brief Historical Overview and Recent Focus on NFL Players some debate in the literature regarding the role of the APOE ε4 allele as increasing susceptibility for CTE, but more studies are required to definitively establish a correlation.8−15 The slow progression and possible risk gene involvement is attractive from an intervention standpoint; however, at present, the only way to confirm CTE is through post-mortem pathological assessment. Tau imaging probes (PET) are in development, and may offer an ability to diagnose early in the disease course, which will be essential for drug discovery efforts. The link to professional football, and high profile attention from the media, began with a report from Omalu and coworkers in 20059 that CTE was diagnosed postmortem in a symptomatic NFL football player, and he highlighted a second NFL player the following year.10 In 2009, McKee and coworkers reported on five NFL players with classical symptoms (depression, memory loss, paranoia, aggression, confusion, and agitation) that were neuropathologically verified with CTE at autopsy.11 Interestingly, all five were offensive/defensive linemen or linebackerspositions with significant helmet-tohelmet contact. These findings led McKee and co-workers to pursue a larger study of 85 subjects with RHI and displaying classical CTE symptoms. From this group, 34 were NFL football players, and McKee found that the stage of CTE correlated (in this manuscript, McKee proposed a staging criteria, Stages I−IV, that correlate with progressive disease and companion symptoms at each stage) with duration of football play.12 Alarmingly, 89% of the NFL players in this study had stage III−IV CTE with a mean onset of 54 years of age.12 Once again, CTE was more prevalent in NFL players with positions subjected to more RHI (offensive/defensive linemen (40%), running backs (20%), linebackers (14%), and quarterbacks (6%)). After this initial proposal of CTE of stages, two subsequent efforts (UNITE and the NINDS-NIBIB panel) formally established CTE stages and neuropathological criteria for CTE diagnosis.13,14 In July 2017, McKee and co-workers published a paper in JAMA that caught the world by storm. In one of the largest CTE studies to date of all levels of football players (202 subjects), 86% (177 subjects) were neuropathologically diagnosed with CTE.1 Moreover, they reported that 110 out of 111 deceased NFL players were neuropathologically diagnosed with CTE (and were symptomatic), and 86% of these had severe pathology.1 As in the earlier studies, offensive/ defensive linemen accounted for 41% of the subjects, running backs and linebackers accounted for 33%, while punters/kickers accounted for only 1% - again trending with nature of position and RHI via helmet-to-helmet contact.1 Every major news outlet ran with headlines that 99% of NFL players have CTE, and several young players, with less than 5 years in the league announced their retirement due to the risk of CTE. Importantly, there were some facts and study limitations that
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recent JAMA paper by McKee and co-workers1 on the incidence (110 out of 111 subjects, or 99%) of Chronic Traumatic Encephalopathy (CTE) in National Football League (NFL) players has garnered a great deal of attention in the lay press and raised concerns about the safety of the sport for younger children. While the report does indeed seem conclusive in the cause and effect of CTE, a progressive tauopathy and neurodegenerative disease, there are caveats and other considerations to bear in mind. However, before delving into the study in question, let us review the origin of CTE (Figure 1), along with its clinical presentation and neuropathological diagnosis en route to its recent association with NFL players. Boxing in the early 20th century was a brutal sport. The equipment was poor, and boxers would participate in hundreds of fights in their careers and over decades (unlike today). Martland, in 1928, was the first to describe the concept of CTE, when he coined the term “punch drunk” to describe the complex behavioral, motor, and cognitive symptoms of progressive neurological deterioration experienced by boxers from years of repetitive, nonlethal blows to the head.2 A decade later, Millspaugh3 redefined the syndrome as dementia pugilistica, and later it was further amended by Courville4 as psychopathic deterioration of pugilists. It was not until 1949 that the term employed today, chronic traumatic encephalopathy (CTE), was cemented as the medical diagnosis (though briefly referred to as progressive traumatic encephalopathy) by Critchley.5−7 Over the next 30 years, CTE was diagnosed (postmortem, Figure 2) beyond boxers, and encompassed athletes from multiple contact sports (football, hockey, rugby wrestling, extreme sports, etc.) as well as military personnel where repetitive sublethal blows to the head occurred over time.8−15 The symptoms of CTE begin to emerge 8−10 years after experiencing repetitive head injury (RHI), and include headache, personality changes, impulsivity, irritability, shortterm memory loss, aggression, depression, parkinsonism, speech and gait abnormalities, and suicidal thoughts and actions.8−15 While bearing some overlap with Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), traumatic brain injury (TBI), and numerous other neurodegenerative disorders, CTE is distinct.8−15 At a high level, experiencing repetitive blows to the head, in essence repetitive mild traumatic brain injury, initiates CTE, a progressive neurodegenerative condition with widespread deposition of neurofibrillary tangles of hyperphosphorylated tau (and spindle-shaped and threadlike neutrophil neuritis throughout the brain), as well as other aggregated, neurotoxic peptides (such as Aβ and TDP-43).8−15 There is also general atrophy of key brain regions (cerebral cortex, temporal lobes, thalamus, mammillary bodies, and brain stem) that leads to lower brain weight.8−15 CTE initiates focally, deep in the sulci in the cerebral cortex and spreads slowly over decades to eventually spread tau pathology across multiple brain regions. There is © 2017 American Chemical Society
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DOI: 10.1021/acschemneuro.7b00291 ACS Chem. Neurosci. 2017, 8, 1629−1631
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Editorial
Figure 1. Timeline of major defining events in the evolution of CTE as a progressive tauopathy and neurodegenerative disease, recently associated with NFL football players.
imaging (selective tau PET tracers). I challenge my neuroscience colleagues to consider developing research programs aimed at innovative imaging modalities for early detection and therapeutic strategies to delay/manage CTE and ultimately disease modifying therapies. Could existing efforts in Alzheimer’s disease, tau-based diseases, and other neurodegenerative disorders be repositioned for CTE? Can we develop robust preclinical models for CTE as we have for TBI? At ACS Chemical Neuroscience, I welcome your Letters, Articles, Reviews, Perspectives, and Viewpoints on any aspect of CTE (preclinical/clinical). Figure 2. Cross section of a normal brain on the left, and cross section of an advanced CTE brain on the right, highlighting significant atrophy and tau pathology in multiple brain regions. Reproduced with permission from BU CTE Center
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Craig W. Lindsley, Editor-in-Chief AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445
were not widely publicized. First, of the 202 subjects, 25 players displayed no pathological abnormalities.1 Why? It would be interesting to know their APOE ε4 allele profiles. Second, this study and those that preceded it have inherent limitations of the generality of the subjects. To be a subject, the patient’s brain had to be donated for study, and this is usually done when the subject displayed CTE symptoms before death, and the subject, or their families, donates their brain to understand/ rationalize the aberrant behavior.1 Thus, a control group of NFL players, with a history of RHI, but no clinical symptoms of CTE, need to be studied postmortem and ascertain neuropathology to identify patterns and/or exceptions that could hopefully explain why some players develop CTE and others do not. Third, the VA-BU-CLF brain bank is not representative of all those that have played American football−the bank is biased toward college and professional football.1 Thus, the findings of this study can not necessarily be extended to high school/ middle school football players. Finally, the majority of the NFL players in this study (from which 99% were definitively diagnosed with CTE), played professionally when helmets and protective gear were not as safe as they are today, and today’s concussion guidelines were not in place. Still, these findings are alarming, but there are caveats for which I hope additional studies will be pursued to understand why some players with a history of RHI develop CTE while others do not. CTE is a slowly progressing neurodegenerative disorder with well pronounced neuropathology and clear etiology, which offers many opportunities for therapeutic intervention, and
Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
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DOI: 10.1021/acschemneuro.7b00291 ACS Chem. Neurosci. 2017, 8, 1629−1631
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