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Figure 1.
Representative Images of Phosphorylated Tau Pathology at CTE Pathological Stages I and II
CTE indicates chronic traumatic encephalopathy; NFT, neurofibrillary tangle; ptau, phosphorylated tau. For all images, 10-µm paraffin-embedded tissue sections were immunostained with microscopic mouse monoclonal antibody for phosphorylated tau (AT8) (Pierce Endogen). Positive ptau immunostaining appears dark red, hematoxylin counterstain; calibration bar indicates 100 µm. Stage I CTE is characterized by 1 or 2 isolated perivascular epicenters of ptau NFTs and neurites (ie, CTE lesions) at the depths of the cortical sulci. In stage II, 3 or more cortical CTE lesions are found. All hemispheric tissue section images are 50-µm sections immunostained with mouse monoclonal antibody CP-13, directed against phosphoserine 202 of tau (courtesy of Peter Davies, PhD, Feinstein Institute for Medical Research; 1:200); this is considered to be an early site of tau phosphorylation in NFT formation.28Positive ptau immunostaining appears dark brown. A, Former college football player with stage I CTE. Two perivascular ptau CTE lesions are evident at sulcal depths of the frontal cortex; there is no neurofibrillary degeneration in the medial temporal lobe (open arrowhead). Perivascular CTE lesion: neurofibrillary tangles and dot-like and threadlike neurites encircle a small blood vessel. B, Former NFL player with stage II CTE. There are multiple perivascular ptau CTE lesions at depths of sulci of the frontal cortex; there is no neurofibrillary degeneration in the medial temporal lobe (open arrowhead). Perivascular CTE lesion: a cluster of NFTs and large dot-like and threadlike neurites surround a small blood vessel.
Figure 2.
Representative Images of Phosphorylated Tau Pathology at CTE Pathological Stages III and IV
CTE indicates chronic traumatic encephalopathy; NFT, neurofibrillary tangle; ptau, phosphorylated tau. For all images, 10-µm paraffin-embedded tissue sections were immunostained with microscopic mouse monoclonal antibody for phosphorylated tau (AT8) (Pierce Endogen). Positive ptau immunostaining appears dark red, hematoxylin counterstain; calibration bar indicates 100 µm. In stage III CTE, multiple CTE lesions and diffuse neurofibrillary degeneration of the medial temporal lobe are found. In stage IV CTE, CTE lesions and NFTs are widely distributed throughout the cerebral cortex, diencephalon, and brain stem.6All hemispheric tissue section images are 50-µm sections immunostained with mouse monoclonal antibody CP-13, directed against phosphoserine 202 of tau (courtesy of Peter Davies, PhD, Feinstein Institute for Medical Research; 1:200); this is considered to be an early site of tau phosphorylation in NFT formation.28Positive ptau immunostaining appears dark brown. A, Former NFL player with stage III CTE. There are multiple large CTE lesions in the frontal cortex and insula; there is diffuse neurofibrillary degeneration of hippocampus and entorhinal cortex (black arrowhead). Perivascular CTE lesion: a dense collection of NFTs and large dot-like and threadlike neurites enclose several small blood vessels. B, Former NFL player with stage IV CTE. There are large, confluent CTE lesions in the frontal, temporal, and insular cortices and there is diffuse neurofibrillary degeneration of the amygdala and entorhinal cortex (black arrowhead). Perivascular CTE lesion: a large accumulation of NFTs, many of them ghost tangles, encompass several small blood vessels.
Figure 3.
Phosphorylated Tau Pathology for Each Brain Region by CTE Neuropathological Stage
CTE indicates chronic traumatic encephalopathy; NFT: neurofibrillary tangle, SI: substantia innominata, SN: substantia nigra; LC: locus coeruleus. Cerebellum indicates dentate nucleus of the cerebellum. In each region, 0 = no NFTs (yellow); 1 = 1 NFT per 20× field (orange); 2 = 2 to 3 NFTs per 20× field (amber); and 3 = ≥4 NFTs per 20× field (red). The color scale is based on the distribution of all values, not by each individual stage. Values represent means of phosphorylated tau pathology among participants in each stage.
Table 1.
Demographic and Exposure Characteristics of 177 American Football Players Diagnosed With CTE, Stratified by Neuropathological Severitya
Table 2.
Neuropathological Findings in 177 American Football Players, Stratified by Severity of Phosphorylated Tau Pathology (CTE Stage)a
Table 3.
Clinical Features Reported in 111 American Football Players Diagnosed as Having CTE, Stratified by Neuropathological Severitya
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Author Video Interviews. Evaluation of Chronic Traumatic Encephalopathy in Football Players
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Evaluation of Chronic Traumatic Encephalopathy in Football Players
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Understanding Chronic Traumatic Encephalopathy
Editorial
July 25, 2017
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Traumatic Brain InjuryNeurologySports MedicineTrauma and Injury
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Original Investigation
July 25, 2017
Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football
Jesse Mez, MD, MS1,2; Daniel H. Daneshvar, MD, PhD1,3; Patrick T. Kiernan, BA1,2; et alBobak Abdolmohammadi, BA1,2; Victor E. Alvarez, MD1,4,5; Bertrand R. Huber, MD, PhD1,2,4,5; Michael L. Alosco, PhD1,2; Todd M. Solomon, PhD1; Christopher J. Nowinski, PhD1,6; Lisa McHale, EdS6; Kerry A. Cormier, BA1,2; Caroline A. Kubilus1,2; Brett M. Martin, MS1,7; Lauren Murphy, MBA1,2; Christine M. Baugh, MPH8,9; Phillip H. Montenigro, BA1,2; Christine E. Chaisson, MPH1,7; Yorghos Tripodis, PhD1,10,11; Neil W. Kowall, MD1,2,4,12; Jennifer Weuve, MPH, ScD11,13; Michael D. McClean, ScD11,14; Robert C. Cantu, MD1,2,6,15; Lee E. Goldstein, MD, PhD1,2,12,16,17,18,19; Douglas I. Katz, MD2,20; Robert A. Stern, PhD1,2,21,22; Thor D. Stein, MD, PhD1,4,5,12; Ann C. McKee, MD1,2,4,5,12,23
Author Affiliations Article Information
JAMA. 2017;318(4):360-370. doi:10.1001/jama.2017.8334
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Evaluation of Chronic Traumatic Encephalopathy in Football Players
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Evaluation of Chronic Traumatic Encephalopathy in Football Players
Key Points
Question What are the neuropathological and clinical features of a case series of deceased players of American football neuropathologically diagnosed as having chronic traumatic encephalopathy (CTE)?
Findings In a convenience sample of 202 deceased players of American football from a brain donation program, CTE was neuropathologically diagnosed in 177 players across all levels of play (87%), including 110 of 111 former National Football League players (99%).
Meaning In a convenience sample of deceased players of American football, a high proportion showed pathological evidence of CTE, suggesting that CTE may be related to prior participation in football.
Abstract
Importance Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE).
Objective To determine the neuropathological and clinical features of deceased football players with CTE.
Design, Setting, and Participants Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history.
Exposures Participation in American football at any level of play.
Main Outcomes and Measures Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia.
Results Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia.
Conclusions and Relevance In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.
Introduction
Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head trauma.1- 8 In 2013, based on a report of the clinical and pathological features of 68 men with CTE (including 36 football players from the current study), criteria for neuropathological diagnosis of CTE and a staging scheme of pathological severity were proposed.6Two clinical presentations of CTE were described; in one, the initial features developed at a younger age and involved behavioral disturbance, mood disturbance, or both; in the other, the initial presentation developed at an older age and involved cognitive impairment.9 In 2014, a methodologically rigorous approach to assessing clinicopathological correlation in CTE was developed using comprehensive structured and semistructured informant interviews and online surveys conducted by a team of behavioral neurologists and neuropsychologists.10 In 2015, the neuropathological criteria for diagnosis of CTE were refined by a panel of expert neuropathologists organized by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB).8
Using the NINDS-NIBIB criteria to diagnose CTE and the improved methods for clinicopathological correlation, the purpose of this study was to determine the neuropathological and clinical features of a case series of deceased football players neuropathologically diagnosed as having CTE whose brains were donated for research.
Methods
Study Recruitment
In 2008, as a collaboration among the VA Boston Healthcare System, Bedford VA, Boston University (BU) School of Medicine, and Sports Legacy Institute (now the Concussion Legacy Foundation [CLF]), a brain bank was created to better understand the long-term effects of repetitive head trauma experienced through contact sport participation and military-related exposure. The purpose of the brain bank was to comprehensively examine the neuropathology and clinical presentation of brain donors considered at risk of development of CTE. The institutional review board at Boston University Medical Campus approved all research activities. The next of kin or legally authorized representative of each brain donor provided written informed consent. No stipend for participation was provided. Inclusion criteria were based entirely on exposure to repetitive head trauma (eg, contact sports, military service, or domestic violence), regardless of whether symptoms manifested during life. Playing American football was sufficient for inclusion. Because of limited resources, more strict inclusion criteria were implemented in 2014 and required that football players who died after age 35 years have at least 2 years of college-level play. Donors were excluded if postmortem interval exceeded 72 hours or if fixed tissue fragments representing less than half the total brain volume were received (eFigure in the Supplement).
Clinical data were collected into a Federal Interagency Traumatic Brain Injury Research–compliant database. Since tracking began in 2014, for 98 (81%) brain donations to the VA-BU-CLF Brain Bank, the next of kin approached the brain bank near the time of death. The remaining brain donors were referred by medical examiners (11 [9%]), recruited by a CLF representative (7 [6%]), or participated in the Brain Donation Registry during life (5 [4%]) (eFigure in the Supplement).
Clinical Evaluation
Retrospective clinical evaluations were performed using online surveys and structured and semistructured postmortem telephone interviews between researchers and informants. Researchers conducting these evaluations were blinded to the neuropathological analysis, and informants were interviewed before receiving the results of the neuropathological examination. A behavioral neurologist, neuroscientist, or neuropsychologist (J.M., D.H.D., T.M.S., M.L.A., or R.A.S.) obtained a detailed history, including a timeline of cognitive, behavioral, mood, and motor symptomology. Additionally, other neuropsychiatric symptoms, exposures and symptoms consistent with posttraumatic stress disorder, features of a substance use disorder, neurodegenerative diagnoses made in life (Alzheimer disease [AD], frontotemporal dementia, vascular dementia, dementia with Lewy bodies, Parkinson disease, CTE, or dementia of unknown etiology), headaches that impaired function, symptoms and diagnoses made in life of sleep disorders, and causes of death were assessed. Clinicians qualitatively summarized the participants’ clinical presentation (eg, presence and course of symptoms, functional independence) into a narrative and presented the case to a multidisciplinary consensus team of clinicians, during which it was determined whether the participant met criteria for dementia. To resolve discrepancies in methods that evolved over time, only clinical variables ascertained after January 2014 using a standardized informant report were included because of the larger subset of participants recruited during this time frame (n = 125).
Prior to January 2014, demographics, educational attainment, athletic history (type of sports played, level, position, age at first exposure, and duration), military history (branch, location of service, and duration of combat exposure), and traumatic brain injury (TBI) history (including number of concussions) were queried during the telephone interview. Beginning in January 2014, demographics, educational attainment, and athletic and military history were queried using an online questionnaire. Informant-reported race was collected as part of demographic information so that neuropathological differences across race could be assessed. To be considered a National Football League (NFL) athlete, a participant must have played in at least 1 regular-season NFL game. Professional position and years of play were verified using available online databases (http://www.pro-football-reference.com, http://databasefootball.com, http://www.justsportsstats.com). History of TBI was queried using informant versions of the Ohio State University TBI Identification Method Short Form11 and 2 questionnaires adapted from published studies that address military-related head injuries and concussions.12,13 With the addition of these questionnaires, informants were read a formal definition of concussion prior to being asked about concussion history, which was not the case prior to January 2014.
Neuropathological Evaluation
Pathological processing and evaluation were conducted using previously published methods.14,15 Brain volume and macroscopic features were recorded during initial processing. Twenty-two sections of paraffin-embedded tissue were stained for Luxol fast blue, hematoxylin and eosin, Bielschowsky silver, phosphorylated tau (ptau) (AT8), α-synuclein, amyloid-β, and phosphorylated transactive response DNA binding protein 43 kDa (pTDP-43) using methods described previously.16 In some cases, large coronal slabs of the cerebral hemispheres were also cut at 50 μm on a sledge microtome and stained as free-floating sections using AT8 or CP-13.16,17
A neuropathological diagnosis was made using criteria for CTE recently defined by the 2015 NINDS-NIBIB Consensus Conference8 and well-established criteria for other neuropathological diseases, including AD,18,19 Lewy body disease,20 frontotemporal lobar degeneration,21- 25 and motor neuron disease.26,27 Neuropathological criteria for CTE require at least 1 perivascular ptau lesion consisting of ptau aggregates in neurons, astrocytes, and cell processes around a small blood vessel; these pathognomonic CTE lesions are most often distributed at the depths of the sulci in the cerebral cortex and are distinct from the lesions of aging-related tau astrogliopathy.8Supportive features for the diagnosis of CTE include ptau pretangles and neurofibrillary tangles (NFTs) in superficial cortical layers (layers II/III) of the cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and CA4 of the hippocampus; subpial ptau astrocytes at the glial limitans; and dot-like ptau neurites.8
Chronic traumatic encephalopathy ptau pathology was classified into 4 stages using previously proposed criteria.6 Briefly, stage I CTE is characterized by 1 or 2 isolated perivascular epicenters of ptau NFTs and neurites (ie, CTE lesions) at the depths of the cerebral sulci in the frontal, temporal, or parietal cortices. In stage II, 3 or more CTE lesions are found in multiple cortical regions and superficial NFTs are found along the sulcal wall and at gyral crests. Multiple CTE lesions, superficial cortical NFTs, and diffuse neurofibrillary degeneration of the entorhinal and perirhinal cortices, amygdala, and hippocampus are found in stage III CTE. In stage IV CTE, CTE lesions and NFTs are densely distributed throughout the cerebral cortex, diencephalon, and brain stem with neuronal loss, gliosis, and astrocytic ptau pathology. Chronic traumatic encephalopathy pathology in stages I and II is considered to be mild and in stages III and IV is considered to be severe.
Neuropathological evaluation was blinded to the clinical evaluation and was reviewed by 4 neuropathologists (V.A., B.H., T.D.S., and A.M.); any discrepancies in the neuropathological diagnosis were solved by discussion and consensus of the group. In addition to diagnoses, the density of ptau immunoreactive NFTs, neurites, diffuse amyloid-β plaques, and neuritic amyloid-β plaques; vascular amyloid-β; pTDP-43; and α-synuclein immunoreactive Lewy bodies were measured semiquantitatively (0-3, with 3 being most severe) across multiple brain regions.
Descriptive statistics were generated using SPSS software version 20 (IBM Inc).
Results
Among the 202 deceased brain donors (median age at death, 66 years [interquartile range [IQR], 47-76 years]), CTE was neuropathologically diagnosed in 177 (87%; median age at death, 67 years [IQR, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]; 140 [79%] self-identified as white and 35 [19%] self-identified as black), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 NFL (99%) players.
The median age at death for participants with mild CTE pathology (stages I and II) was 44 years (IQR, 29-64 years) and for participants with severe CTE pathology (stages III and IV) was 71 years (IQR, 64-79 years). The most common cause of death for participants with mild CTE pathology was suicide (12 [27%]) and for those with severe CTE pathology was neurodegenerative (ie, dementia-related and parkinsonian-related causes of death) (62 [47%]). The severity of CTE pathology was distributed across the highest level of play, with all former high school players having mild pathology (3 [100%]) and the majority of former college (27 [56%]), semiprofessional (5 [56%]), Canadian Football League (6 [86%]), and NFL (95 [86%]) players having severe pathology. The mean duration of play for participants with mild CTE pathology was 13 years (SD, 4.2 years) and for participants with severe CTE pathology was 15.8 years (SD, 5.3 years) (Table 1).
