RESEARCH ARTICLE Premortem Chronic Traumatic Encephalopathy Diagnoses in Professional Football Rachel Grashow, PhD, MS ,1,2 Marc G. Weisskopf, PhD, ScD,1,2 Aaron Baggish, MD,1,3 Frank E. Speizer, MD,1,2,4 Alicia J. Whittington, PhD, MPH,1 Lee Nadler, MD,1,5 Ann Connor, RN,1,6 Robyn Keske, MSW, MPH,1 Herman Taylor, MD,1,7 Ross Zafonte, DO ,1,8† and Alvaro Pascual-Leone, MD, PhD 1,6,9,10† Objective: American-style football (ASF) has gained attention because of possible links between repetitive head injury and neurodegenerative diseases. Although postmortem pathologic changes consistent with chronic traumatic encepha- lopathy (CTE) have been reported in ASF players, there are currently no established premortem diagnostic criteria for CTE. Nevertheless, presented with symptoms of cognitive impairment, clinicians treating former players may be inclined to suggest CTE without a thorough exploration of comorbid factors that demonstrate similar clinical phenotypes to putative CTE. Methods: A survey of 3,913 former ASF players aged 24 to 89 was conducted for those who responded by March 2019. Results: Despite being a postmortem diagnosis, 108 players (2.8%) self-reported clinician-diagnosed CTE. The percent- age of players under age 60 years reporting a CTE diagnosis was 2.3% versus 3.7% in participants age 60 or older. Com- orbidities in participants self-reporting CTE were significantly more common, including sleep apnea, hypercholesterolemia, obesity, indicators of past or current depression, hypertension, prescription pain medication use, heart conditions, and low testosterone when compared to non-CTE respondents. Patterns of reporting for obesity, hypertension, heart conditions, or hypercholesterolemia differed between older and younger participants. Cognitive impairment symptoms were significantly higher in participants self-reporting CTE. Interpretation: Some former professional football players have been clinically diagnosed with CTE, a postmortem con- dition. Comorbidities that can affect cognition were associated with CTE diagnoses in both older and younger players. Although underlying neuropathology cannot be ruled out, treatable conditions should be explored in former athletes demonstrating CTE-linked clinical phenotypes or symptoms as a means of improving cognitive health in these patients. ANN NEUROL 2020;88:106–112 syndrome,2 chronic traumatic encephalopathy (CTE) is a S cientific and news media have paid considerable attention to the idea that cognitive impairment in American-style football (ASF) players may be a consequence of repeated head neurodegenerative disease pathologically defined at autopsy by deposition of phosphorylated tau (P-tau) in neurons, astro- trauma.1 First reported by Martland in 1928 as punch drunk cytes, and cell processes around perivascular structures at the View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.25747 Received Sep 16, 2019, and in revised form Apr 7, 2020. Accepted for publication Apr 9, 2020. Address correspondence to Dr Ross Zafonte, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts Gen- eral Hospital, Brigham and Women’s Hospital, Harvard Medical School, 300 First Avenue Boston, MA 02129. E-mail: rzafonte@mgh.harvard.edu † These authors contributed equally to this work and should be considered as senior authors. From the 1Football Players Health Study at Harvard University, Harvard Medical School, Boston, MA; 2Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; 3Cardiovascular Performance Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA; 4Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 5Dana Farber Cancer Institute, Boston, MA; 6Department of Neurology, Harvard Medical School, Boston, MA; 7Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA; 8Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women’s Hospital and Harvard Medical School Boston, Boston, MA; 9Center for Memory Health and Marcus Institute for Aging Research, Hebrew Senior Life, Harvard Medical School, Boston, MA; and 10Institut Guttmann, Universitat Autónoma, Barcelona, Spain 106 © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Grashow et al: Premortem CTE Diagnoses in Football depths of the cortical sulci.3 Recent work has noted postmor- league transitioned from soft leather to hard plastic hel- tem pathologic changes consistent with CTE in 177 of mets.19 We explicitly considered active players ineligible. 202 ASF players.4,5 The 177 affected ASF players had a We obtained email and residential information for 16,089 median age at death of 67 years and retrospective analysis eligible former players from the NFL Players Association. found that the majority had shown cognitive, emotional, and Of these, return-to-sender address errors or unopened behavioral symptoms for over a decade prior to autopsy. email messages were documented for 1,675 unique former However, the relationship between CTE pathology players. Of the remaining 14,414 former players, 3,913 and clinical phenotypes among former ASF athletes (27.1%) had enrolled as of March 2019. This study was remain incompletely understood.6,7 A series of clinical approved by the Institutional Review Board of the Beth diagnostic criteria have been proposed that include behav- Israel Deaconess Medical Center and the Harvard ioral, cognitive, and motoric features.8–10 Yet, the agree- T.H. Chan School of Public Health, and participants pro- ment between the clinical features of these proposed vided informed consent prior to participation. criteria is modest.11 in vivo flortaucipir positron emission tomography (PET) imaging has revealed higher tracer Outcome and Other Data retention in former professional ASF players with cogni- Participants completed either a paper or online question- tive and neuropsychiatric symptoms in brain regions naire about demographics, football careers, and health con- affected by CTE.12 Nonetheless, there was no association ditions. Body mass index (BMI) was calculated from self- between tau deposition as registered on imaging and reported weight (lbs) and height (inches) as (lbs*0.45/ scores on cognitive and neuropsychiatric tests. (inches*0.025).2 Players on the offensive or defensive line The specificity13 and progressive nature of CTE5 have were categorized as linemen, and all others were categorized not been fully elucidated, and some evidence suggests that as non-linemen. Participants were asked to select categories CTE may not be solely unique to repeated head trauma.13,14 that described their racial identity: black/African American; Additionally, in former ASF players with cognitive symp- white; American Indian/Alaskan Native; Native Hawaiian/ toms, CTE pathology—even when present—might not be Pacific Islander; Asian and other. Black was defined as the sole contributor of cognitive decline.6,15 Thus, while players who self-identified as black or African American. National Institute of Neurological Disorders and Stroke Former players who self-selected “black” in addition to (NINDS) pathologic criteria exist,3 continued refinement of another race were categorized as black, based on lived experi- these criteria is needed to better differentiate CTE from other ence studies that have shown that perceivers strongly tend to neurodegenerative diseases, such as aging-related tau characterize multiracial individuals as belonging to a minor- astrogliopathy. The limitations of in vivo diagnostic tests, ity status.20 White was defined as players who self-identified absence of clear links between neuropathology, and cognitive only as white. Participants who declined to answer this ques- symptoms,6,7 the multifactorial nature of cognitive decline tion were categorized as “missing.” All remaining partici- in older age groups, and the impact of possible com- pants were categorized as “other.” Number of seasons of orbidities on clinical presentations often impede the identi- professional NFL play was divided into 1 to 4 seasons, 5 to fication of definite etiological factors in CTE. As a result, 9 seasons, and 10+ seasons. the clinical criteria for antemortem CTE or traumatic We considered several different health conditions as encephalopathy syndrome remain proposed16,17 but not reported by the former players. Heart attack, sleep apnea, yet established.6,7,11 stroke, dementia, and CTE was based on a yes/no While clinical criteria for CTE or traumatic encepha- response to the question for the given condition phrased lopathy syndrome remain in debate, few studies have as “Has a Health care provider ever told you that you addressed the potential comorbid factors that can impact have had any of the following diagnoses or health out- cognitive function.11 In the Football Players Health Study comes?” followed by options that included: heart attack; (FPHS), we investigated the self-reporting of CTE diagnoses sleep apnea; stroke; dementia (Alzheimer’s disease); and by former players, as well as comorbidities relevant to CTE. Further definitions for these conditions were not cognition.6,7 provided. We considered a yes response to the question phrased as “Has a medical provider ever recommended or prescribed medication for any of the following condi- Methods tions?” for “high blood pressure,” “diabetes or high blood Study Population sugar,” “high cholesterol,” “low testosterone,” “erectile Starting in 2014, the FPHS18 recruited former football dysfunction (ED),” and “pain” as an indicator of hyper- players who had received compensation from any National tension, diabetes, hypercholesterolemia, low testosterone, Football League (NFL) team starting in 1960, when the erectile dysfunction, and chronic pain, respectively. We July 2020 107 ANNALS of Neurology defined having a heart condition as reporting any of the Statistical Analysis following: (1) diagnosis of “heart attack,” (2) medication We used chi-square tests to determine statistically signifi- recommendations or prescriptions for “heart failure” or cant differences in health conditions between former “heart rhythm problems (atrial fibrillation, supraventricu- players who did and did not report diagnoses of CTE. Sta- lar tachycardia [SVT], or other),” or (3) positive tistical significance was considered at a 95% level of confi- responses to the question “Since leaving active profes- dence and evaluated using R Statistical Software.23 sional play have you had any of the following surgical procedures?” specifically for heart bypass, angioplasty, or Results stent replacement? The mean age was 52.4 (SD = 14.3; range: 24–89) in the We defined indicators of past or current depression 3,913 former ASF players who responded to the question- as having (1) a current prescription or prescription rec- naire. The frequency of self-reported CTE diagnoses was ommendation for an antidepressant, or (2) a score >3 108 (2.8%) among all players, and 59 (2.3%) in players on the depression-related Patient Health Questionnaire under age 60 versus 49 (3.7%) in players age 60 or older (PHQ-4).21 The Quality of Life in Neurological Disor- (Table 1). Black former players reported a higher percent- ders (NQOL) instrument for Applied Cognition-General age of CTE than white or other categories. In both age Concerns22 was used to measure cognitive symptoms. The groups, the percentage of linemen self-reporting CTE was frequencies of 8 symptoms over the previous week were higher than in non-linemen. The percentage of CTE summed and T-scored according to a standardized US reporting did not increase monotonically with more sample. Participants who scored 2 or more SDs below the playing seasons: CTE reporting was highest in the 5 to mean were considered to have cognitive impairment. 9 season category, but not with 10+ seasons (see Table 1). TABLE 1. Demographic and Football-related Characteristics in Former ASF Players by Age and Self-reported CTE Status (N = 3,913) Ages 24–89 Ages 24–59 Ages 60–89 No CTE CTE No CTE CTE No CTE CTE N = 3805 N = 108 N = 2,518 N = 59 N = 1287 N = 49 Characteristic N (%) N (%) N (%) N (%) N (%) N (%) Age <60 2,518 (97.7) 59 (2.3) - - - - 60+ 1,287 (96.3) 49 (3.7) - - - - Racea Black 1,413 (96.6) 50 (3.4) 1,116 (97.1) 33 (2.9) 297 (94.6) 17 (5.4) White 2,234 (97.6) 56 (2.4) 1,299 (98.1) 25 (1.9) 935 (96.8) 31 (3.2) Other 110 (98.2) 2 (1.8) 83 (98.8) 1 (2.9) 27 (96.4) 1 (3.6) Position Non-linemen 2,492 (97.4) 66 (2.6) 1,640 (98.0) 34 (2.0) 852 (96.4) 32 (3.6) Linemen 1,313 (96.9) 42 (3.1) 878 (97.2) 25 (2.8) 435 (96.2) 17 (3.8) b Seasons played in NFL 1–4 Seasons 1,258 (97.7) 29 (2.3) 914 (97.9) 20 (2.1) 344 (97.5) 9 (2.5) 5–9 Seasons 1,633 (96.8) 54 (3.2) 1047 (97.6) 26 (2.4) 586 (95.4) 28 (4.6) 10+ Seasons 914 (97.3) 24 (2.7) 557 (97.7) 13 (2.3) 357 (96.7) 12 (3.3) a Racial identity was not reported for 48 players, none of whom reported CTE. bYears played for one player could not be ascertained. ASF = American-style football; CTE = chronic traumatic encephalopathy; NFL = National Football League. 108 Volume 88, No. 1 Grashow et al: Premortem CTE Diagnoses in Football TABLE 2. Current Health Conditions and Neurological Quality of Life Impairment Status in Former ASF Players by Age and selS-reported CTE Status (N = 3,913) All ages (24–89) Ages 24–59 Ages 60–89 No CTE CTE No CTE CTE No CTE CTE N = 3,805 N = 108 N = 2,518 N = 59 N = 1,287 N = 49 Characteristic N (%) N (%) N (%) N (%) N (%) N (%) Obese (>30.0 kg/m2)a 1,976 (51.9) 71 (65.7)** 1,373 (54.5) 38 (64.4) 603 (46.9) 33 (67.3)** Sleep apnea 817 (21.5) 52 (48.1)*** 468 (18.6) 25 (42.4)*** 349 (27.1) 27 (55.1)*** Indicators of past or current depression 631 (16.6) 73 (67.6)*** 426 (16.9) 42 (71.2)*** 205 (15.9) 31 (63.3)*** Diabetes 336 (9.1) 14 (14.0) 156 (6.3) 4 (7.4) 180 (14.7) 10 (21.7) b Hypertension 1,414 (37.5) 54 (50.5)** 685 (27.4) 24 (41.4)* 729 (57.4) 30 (61.2) c Low testosterone 654 (17.7) 40 (37.4)*** 373 (15.1) 25 (43.1)*** 281 (22.9) 15 (30.6) Stroke 101 (2.7) 7 (6.5)* 34 (1.4) 2 (3.4) 67 (5.2) 5 (10.2) Rx pain medication 1,016 (26.7) 62 (57.4)*** 591 (23.5) 35 (59.3)*** 425 (33.0) 27 (55.1)*** Heart conditiond 696 (18.3) 26 (24.1) 233 (9.3) 11 (18.6)* 463 (36.0) 15 (30.6) High cholesterole 1,284 (34.3) 50 (48.1)** 598 (24.1) 26 (45.6)*** 686 (54.7) 24 (51.1) Dementia 97 (2.5) 41 (38.0)*** 30 (1.2) 20 (33.9)*** 67 (5.2) 21 (42.9)*** Cognitive impairmentf 434 (11.4) 60 (56.1)*** 311 (12.4) 34 (57.6)*** 123 (9.6) 26 (54.2)*** a Twenty-eight players were missing body mass index data. b Thirty-five players were missing hypertension data. c Ninety-two players were missing low testosterone data. d Heart condition includes self-reported heart rhythm issues, myocardial infarction, heart failure, or cardiac surgery. e Seventy-four players were missing cholesterol data. f Ten players were missing neurological quality of life scores. *p < 0.05; **p < 0.01, ***p < 0.001 on chi-square test. ASF = American-style football; CTE = chronic traumatic encephalopathy. Men of all ages self-reporting a CTE diagnosis were been raised regarding the specificity of many symptoms significantly more likely to also report obesity, sleep apnea, attributed to CTE.13 Thus, it is disconcerting that a percent- indicators of past or current depression, stroke, hyperten- age of former players report being told they have a condition sion, use of prescription pain medication, low testosterone, that can only be diagnosed postmortem. hypercholesterolemia, dementia, and cognitive impairment Participants may have reported CTE because clinicians (Table 2). Obesity was associated with CTE reporting in told them they have CTE. This is concerning in the absence older but not younger participants, whereas hypertension, of validated diagnostic methods, and may imply that expo- any heart condition, and hypercholesterolemia were signifi- sure to professional football is driving the suggestion of cantly more common in younger but not older former CTE rather than differential diagnoses based on systematic players (see Table 2). evaluation. Previous research has linked elements of profes- sional ASF exposure to mood disorders,24 aggression,25 and hormonal and sexual dysfunction.26,27 Recently, years of Discussion professional play, concussion history, and position were sig- We found that a number of former ASF players reported nificantly associated with neuropsychiatric symptoms in the clinician-diagnosed CTE. Participants reporting CTE also fre- largest study of living ASF football players to date.28 These quently disclosed other comorbidities with well-established results align with prior work in nonprofessional football independent adverse cognitive effects. There is currently no cohorts suggesting a link between cumulative head impacts validated way to clinically diagnosis CTE,6 and concerns have and neurobehavioral symptoms.29 Using either exposure to July 2020 109 ANNALS of Neurology football as a proxy for repetitive head injury, or using mood lower bound of clinician-diagnosed CTE reporting in for- and behavioral changes as a phenotypic marker of brain mer football players. Nevertheless, it is important to note degeneration, clinicians familiar with this literature may be that no player should have received a clinical diagnosis of inclined to suggest CTE before considering other contribu- CTE. It is possible that cognitive status could have tors to cognitive symptoms. affected the likelihood that a former football player joined Alternatively, former players may infer the presence our study; participation among those with a disease or of CTE when other explanations for cognitive impairment more severe disease may be higher than among those with- are not provided.30 The common reporting of com- out because they have an interest in understanding their orbidities that can affect cognition among players disclos- condition.36 On the other hand, it is known that cognitive ing a CTE diagnosis raises the concern that treatable impairment tends to inhibit study participation.37 Impor- conditions are going untreated or undertreated. For exam- tantly, though, if that participation is not also related to ple, players younger than age 60 reporting CTE also other factors (eg, linemen who report CTE participate at a reported significantly more sleep apnea, indicators of past different rate than non-linemen who report CTE) then or current depression, hypertension, chronic pain, low tes- the differences by CTE that we see in this study should tosterone, heart conditions, and hypercholesterolemia. still be reflective of the whole player population. For Participants reporting prior depression or current symp- example, the higher prevalence of low testosterone among toms of depression were more likely to report CTE diag- former players with CTE would not be caused by former noses. We note that our definition combines medical players who report CTE participating more (or less) than history of diagnosis or treatment for depression and cur- players not reporting CTE. This would only be errone- rent symptoms. Therefore, the percentage of those meet- ously caused if participation was based on both CTE ing our criteria is likely greater than that of either of those reporting and low testosterone (ie, if players who both two considered alone. Given that there are no established report CTE and have low testosterone were more likely to premortem clinical criteria for CTE,11 it is possible that participate than former players who report CTE and do the self-reported diagnosis of CTE was a misinterpretation not have low testosterone). If such jointly based participa- by former players of what they had been told by their cli- tion did occur, then the differences we report and their nicians, or assumed even when CTE was not explicitly associated p values would not reflect the true differences mentioned. It seems unlikely, however, that this would in the larger population of former players, including those occur in the absence of cognitive symptoms. who did not enroll in our study. Former player participants reporting CTE were more The use of self-report represents another limitation likely to self-identify as black than white or other. This of this study: medical records were not obtained, and may be because some comorbidities known to cause cogni- there was limited survey space for defining procedures, ill- tive problems are more prevalent in black men (eg, hyper- nesses, and condition severity. Furthermore, data were not tension31 and diabetes32). Additionally, because black collected on clinician and medical facility types (eg, aca- players are more likely to play high-impact positions,33 pre- demic hospital specialists vs community providers), which sumed exposure may be driving the suggestion of CTE in introduces additional variability into the meaning of clinical contexts. A recent study of symptomatic former reported diagnoses. Because we do not know the clinical professional football players has noted that black players setting and level of diagnostic workup that were used to had significantly higher indices of head injury, higher blood support the suggestion of CTE, it is challenging to under- pressure, higher BMI, and lower right hippocampal volume stand the clinical criteria used for such a diagnosis. than white participants.34 In our study, participants who Comorbidity data based on self-report could even rep- played between 5 and 9 seasons showed a higher percentage resent an under-reporting in some instances; for example, of self-reported CTE than those who played both fewer sleep apnea, often goes unrecognized.38 Other factors, such and more seasons. Although we cannot say for certain why as number of anesthesia exposures, have been posited as this is, it is possible that healthy worker bias may be at play potential risks for dementia and should also be considered in where the most injured players aren’t represented in this population39 as many players often have undergone a populations of players with longer careers.35 number of surgical procedures to address sports-related A limitation of our study is that the overall response orthopedic injuries. It must also be kept in mind that many rate was relatively low (27.1%). If none of the nonpartici- of the comorbidities that could increase risk of cognitive pants would have reported clinician-diagnosed CTE, then impairment may begin early in life40,41 and may ultimately the overall percentage of reported CTE would be only not be consequences of exposure to professional ASF. 0.76%, instead of the 2.8% among those players who par- The data presented in this study were observational, ticipated in our study. Thus, 0.76% should be viewed as a cross-sectional, and based on self-report and it is, 110 Volume 88, No. 1 Grashow et al: Premortem CTE Diagnoses in Football therefore, not possible to make true inferences on the role acknowledge the study participants, advisors, and staff of of comorbidities in CTE or cognitive decline for these the Football Players Health Study for their time and participants. Further research using longitudinal data, effort. All of the authors named on this study are or were medical records, and in-person neuropsychological testing either partially or fully supported by the Football Players is necessary to better elucidate the relationships between Health Study at Harvard University which is, in turn, perceived CTE diagnoses and comorbid conditions. How- sponsored by the NFL Players Association (NFLPA). ever, until those data become available, it is important to Please note that the NFLPA had no role in: the design draw attention to treatable conditions that may have been and conduct of the study; collection, management, analy- overlooked or eclipsed by the suggestion of CTE. sis, and interpretation of the data; preparation, review, or We cannot tell whether self-reported CTE diagnoses approval of the manuscript; and decision to submit the represent an actual diagnosis given or recorded in a medi- manuscript for publication. cal chart, or just an articulated suspicion on the part of the medical provider. We also cannot rule out that some Author Contributions of the participants may demonstrate neuropathological A.P.L., R.Z., R.G., M.W., A.B., L.N., and changes associated with postmortem CTE. Furthermore, H.T. contributed to the conception and design of the such pathology may or may not be directly linked to their study. R.G., A.C., A.B., H.T., R.Z., M.W., R.K., and reported symptoms. Nevertheless, the possibility of incor- F.S. contributed to the acquisition and analysis of data. rect reporting of diagnosis or just an impression left with A.P.L., R.G., R.Z., M.W., F.S., A.W., H.T., and the player that he has CTE is of great concern. Such neb- A.B. contributed to the drafting the text and preparing ulous diagnoses could produce a nocebo effect and trigger the tables. mental health challenges, discourage further diagnostic efforts for potentially treatable conditions, and lead to Potential Conflicts of Interest tragic consequences. 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