BOSTON (Reuters) - The brains of 99 percent of former National Football League players studied showed signs of a disease linked to repeated hits to the head that can lead to aggression and dementia, according to research published in a medical journal on Tuesday.

The findings were based on the broadest review yet of the brains of former football players for signs of chronic traumatic encephalopathy. The condition, also known as CTE, is linked to the sort of head-to-head hits that were long a part of the sport, although the NFL and school leagues have been tweaking the game in recent years to limit blows to the head.

“The data suggest that there is very likely a relationship between exposure to football and risk of developing the disease,” said Jesse Mez, a Boston University School of Medicine assistant professor of neurology, who was lead author of the study published in the Journal of the American Medical Association.

The researchers studied the brains of 202 former athletes who had played football in the NFL, the Canadian Football League or at the college or high school level and found signs of CTE in the brains of 110 of the former 111 NFL players.

The condition, which currently can be diagnosed only by taking brain tissue from a dead subject, has been diagnosed in former players including Hall of Fame linebacker Junior Seau and Pro Bowl safety Dave Duerson, who both committed suicide.

The researchers noted that the study had limitations including, that the subjects’ brains were donated by their families and that families are more likely to opt into the study if the players had showed symptoms of CTE.

They also noted that behavioral symptoms of CTE, including depression, anxiety and memory loss, had been reported in subjects whose brains showed little sign of damage, and suggested that other factors including substance abuse could contribute to the condition.

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The NFL, which last year pledged $100 million for neuromedical research, said the study would help the league and players to understand the condition.

“The NFL is committed to supporting scientific research into CTE and advancing progress in the prevention and treatment of head injuries,” said NFL spokesman Brian McCarthy, in an email.

The study found signs of CTE in the brains of 91 percent of the 53 former college players whose brains were studied and 21 percent of the former high school players.</s>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

Quiz Ref IDChronic 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.6 Two 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

Quiz Ref IDIn 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.8 Supportive 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).

In all cases, perivascular clusters of ptau immunoreactive NFTs diagnostic for CTE (ie, CTE lesions)8 were found in the cerebral cortex (Figure 1 and Figure 2). In cases with mild CTE pathology (stages I and II), isolated perivascular CTE lesions were found at the sulcal depths of the cerebral cortex, most commonly in the superior and dorsolateral frontal cortices, but also in the lateral temporal, inferior parietal, insula, and septal cortices (Figure 1). Neurofibrillary tangles were sparse in other cortical regions, and there was no diffuse neurofibrillary degeneration of the medial temporal lobe structures (Figure 1, open arrowheads). Neurofibrillary tangles were also found in the locus coeruleus, substantia nigra, and substantia innominata (Figure 3) in mild CTE. In cases with severe CTE pathology, perivascular CTE lesions were large and confluent (Figure 2). Neurofibrillary tangles were widely distributed in the superficial laminae of cortical regions and there was severe neurofibrillary degeneration of the medial temporal lobe structures, including the hippocampus, amygdala, and entorhinal cortex (Figure 2, black arrowheads, and Figure 3). Neurofibrillary tangles were also frequent in the thalamus, nucleus basalis of Meynert, substantia innominata, substantia nigra, and locus coeruleus in severe CTE (Figure 3).

Deposition of amyloid-β was present in a subset of participants at all stages of CTE pathology, predominantly as diffuse amyloid-β plaques, but neuritic amyloid-β plaques and amyloid angiopathy were also present. In stage IV CTE, amyloid-β deposition occurred in 52 cases (91%). Deposition of TDP-43 and α-synuclein were found in all stages of CTE pathology; TDP-43 deposition occurred in 47 (83%) and α-synuclein deposition occurred in 23 (40%) stage IV CTE cases (Table 2).

Among the 25 football players without CTE, 9 showed no pathological abnormalities and 7 showed nonspecific changes; eg, hemosiderin-laden macrophages (n = 7) and axonal injury (n = 5). Other diagnoses included vascular pathology (n = 4), unspecified tauopathy not meeting criteria for CTE (n = 3), AD (n = 2), argyrophilic grain disease (n = 1), and Lewy body disease (n = 1).

Data on informants were collected beginning in 2014. The median number of participating informants was 2 (IQR, 1-3) per participant. Among all of the interviews, 71 (64%) included a spouse/partner, 56 (51%) included an adult child, 27 (24%) included a sibling, 16 (14%) included a parent, 13 (12%) included a non–first-degree relative, 8 (7.2%) included a neighbor or friend, and 4 included other informants. Among the informants who knew the participant the longest, the mean relationship length was 45.8 years (SD, 1.5 years).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, a reported progressive clinical course was common in participants with both mild and severe CTE pathology, occurring in 23 (85%) mild cases and 84 (100%) severe cases (Table 3). Behavioral or mood symptoms were common in participants with both mild and severe CTE pathology, with symptoms occurring in 26 (96%) mild cases and 75 (89%) severe cases. Impulsivity, depressive symptoms, apathy, and anxiety occurred in 23 (89%), 18 (67%), 13 (50%), and 14 (52%) mild cases and 65 (80%), 46 (56%), 43 (52%), and 41 (50%) severe cases, respectively. Additionally, hopelessness, explosivity, being verbally violent, being physically violent, and suicidality (including ideation, attempts, or completions) occurred in 18 (69%), 18 (67%), 17 (63%), 14 (52%), and 15 (56%) mild cases, respectively. Substance use disorders were also common in participants with mild CTE, occurring in 18 (67%) mild cases. Symptoms of posttraumatic stress disorder were uncommon in both groups, occurring in 3 (11%) mild cases and 9 (11%) severe cases.

Cognitive symptoms were common in participants with both mild and severe CTE pathology, with symptoms occurring in 23 (85%) mild cases and 80 (95%) severe cases. Memory, executive function, and attention symptoms occurred in 19 (73%), 19 (73%), and 18 (69%) mild cases and 76 (92%), 67 (81%), and 67 (81%) severe cases, respectively. Additionally, language and visuospatial symptoms occurred in 54 (66%) and 44 (54%) severe cases, respectively. A premortem diagnosis of AD and a postmortem (but blinded to pathology) consensus diagnosis of dementia were common in severe cases, occurring in 21 (25%) and 71 (85%), respectively. There were no asymptomatic (ie, no mood/behavior or cognitive symptoms) CTE cases. Motor symptoms were common in severe cases, occurring in 63 (75%). Gait instability and slowness of movement occurred in 55 (66%) and 42 (50%) severe cases, respectively. Symptom frequencies remained similar when only pure CTE cases (ie, those with no neuropathological evidence of comorbid neurodegenerative disease) were considered (eTable in the Supplement).

Among the 111 CTE cases with standardized informant reports on clinical symptoms, 47 (42.3%; median age at death, 76 years [IQR, 63-81 years]) initially presented with cognitive symptoms, 48 (43.2%; median age at death, 66 years [IQR, 54-73 years]) initially presented with behavior or mood symptoms, and 16 (14.4%; median age at death, 65.5 years [IQR, 39-78]) initially presented with both cognitive symptoms and behavior or mood symptoms. Forty (85%) of those initially presenting with only cognitive symptoms were reported to have behavior or mood symptoms at the time of death and 43 (90%) of those initially presenting with only behavior or mood symptoms were reported to have cognitive symptoms at the time of death. Dementia was present at the time of death in 36 (77%) of those initially presenting with cognitive symptoms, 33 (69%) of those initially presenting with behavior or mood symptoms, and 11 (69%) of those initially presenting with both cognitive and behavior or mood symptoms.

The most common primary cause of death was neurodegenerative for all 3 groups (cognitive, 26 [55%]; behavior or mood, 16 [33%]; both cognitive and behavior or mood, 6 [38%]). Substance use disorders, suicidality, and family history of psychiatric illness were common among those who initially presented with behavior or mood symptoms, occurring in 32 (67%), 22 (47%), and 23 (49%) cases, respectively.

Discussion

Quiz Ref IDIn a convenience sample of 202 deceased former players of American football who were part of a brain donation program, a high proportion were diagnosed neuropathologically with CTE. The severity of CTE pathology was distributed across the highest level of play, with all former high school players having mild pathology and the majority of former college, semiprofessional, and professional players having severe pathology. Behavior, mood, and cognitive symptoms were common among those with mild and severe CTE pathology and signs of dementia were common among those with severe CTE pathology.

Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe. These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden. Several other football-related factors may influence CTE risk and disease severity, including but not limited to age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits. Recent work in living former football players has shown that age at first exposure may be related to impaired cognitive performance29 and altered corpus callosum white matter30 and that cumulative hits may be related to impairment on self-report and objective measures of cognition, mood, and behavior,31 although it is unclear if any of these outcomes are related to CTE pathology. Furthermore, it is unclear if symptomatic hits (concussions) are more important than asymptomatic hits resulting in subconcussive injury. As with other neurodegenerative diseases, age may be related to risk and pathological severity in CTE. It will be important for future studies to resolve how different measures of exposure to football and age influence the outcome.

Quiz Ref IDIn cases with severe CTE pathology, accumulations of amyloid-β, α-synuclein, and TDP-43 were common. These findings are consistent with previous studies that show deposition of multiple neurodegenerative proteins after exposure to TBI32 and with work showing that neuritic amyloid-β plaques are associated with increased CTE neuropathological stage.33 Diagnoses of comorbid neurodegenerative diseases, including AD, Lewy body disease, motor neuron disease, and frontotemporal lobar degeneration, were also common in cases with severe CTE pathology. Overall, 19% of participants with CTE had comorbid Lewy body disease, which aligns with a recent observation by Crane et al34 regarding the increased prevalence of Lewy body pathology after single TBI. Chronic traumatic encephalopathy was not assessed in the analysis by Crane et al; to investigate the possibility of CTE after single TBI would require more extensive sampling of the depths of the cortical sulci with ptau immunostaining, as silver stains typically do not detect CTE pathology.

Quiz Ref IDBehavioral, mood, and cognitive symptoms were common among participants with either mild or severe CTE pathology. In participants with severe CTE pathology, there was marked ptau pathology in brain regions that have been associated with symptoms frequently reported: impulsivity, depressive symptoms, apathy, anxiety, and explosivity (prefrontal cortex, amygdala, locus coeruleus); episodic memory symptoms (hippocampus and entorhinal and perirhinal cortices); and attention and executive function symptoms (prefrontal cortex). Participants with mild CTE pathology often had these symptoms despite having relatively circumscribed cortical pathology and absence of ptau pathology in the hippocampus, entorhinal cortex, or amygdala. This may suggest that other pathologies not captured by the pathological data set, such as neuroinflammation, axonal injury, or astrocytosis, or pathologies in neuroanatomical regions not evaluated contribute to these clinical symptoms. Microglial neuroinflammation appears to precede tau accumulation in CTE,35 suggesting it may play a role in early symptoms.

Informants reported that 43% of participants had behavior or mood symptoms as their initial presentation. Many of these participants had a substance use disorder, demonstrated suicidality, or had a family history of psychiatric illness. Behavior or mood symptoms may be the initial presentation for a subset of individuals with CTE, or alternatively, CTE ptau pathology may lower the threshold for psychiatric manifestations in susceptible individuals. These clinical observations confirm and expand on previous reports of 2 primary clinical presentations of CTE.9

There is substantial evidence that CTE is a progressive, neurodegenerative disease. In this study, 107 participants (96%) had a progressive clinical course based on informant report. In addition, pathological severity of CTE was correlated with age at death (Table 3). However, a postmortem study evaluates brain pathology at only 1 time point and is by definition cross-sectional. In addition, the participants were not observed longitudinally during life. Although associations with age in cross-sectional samples can result from age-related progression within individuals, they can also arise from birth cohort effects, differential survival, or age-related differences in how individuals were selected into the study. Population-based prospective studies are needed to address the issue of progression of CTE pathology and age at symptom onset.

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,6 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.

This study had several limitations. First, a major limitation is ascertainment bias associated with participation in this brain donation program. Although the criteria for participation were based on exposure to repetitive head trauma rather than on clinical signs of brain trauma, public awareness of a possible link between repetitive head trauma and CTE may have motivated players and their families with symptoms and signs of brain injury to participate in this research. Therefore, caution must be used in interpreting the high frequency of CTE in this sample, and estimates of prevalence cannot be concluded or implied from this sample. Second, the VA-BU-CLF brain bank is not representative of the overall population of former players of American football; most players of American football have played only on youth or high school teams, but the majority of the brain bank donors in this study played at the college or professional level. Additionally, selection into brain banks is associated with dementia status, depression status, marital status, age, sex, race, and education.36 Third, this study lacked a comparison group that is representative of all individuals exposed to American football at the college or professional level, precluding estimation of the risk of participation in football and neuropathological outcomes.

Conclusions

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.

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Corresponding Author: Ann C. McKee, MD, Neuropathology Service, VA Boston Healthcare System, CTE Center, Boston University Alzheimer’s Disease Center, Boston University School of Medicine, 150 S Huntington Ave, Boston, MA 02118 (amckee@bu.edu).

Accepted for Publication: June 20, 2017.

Author Contributions: Drs Mez and McKee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mez, Daneshvar, and Mr Kiernan are co–first authors.

Concept and design: Mez, Daneshvar, Abdolmohammadi, Murphy, Montenigro, Kowall, Cantu, Stern, McKee.

Acquisition, analysis, or interpretation of data: Mez, Daneshvar, Kiernan, Abdolmohammadi, Alvarez, Huber, Alosco, Solomon, Nowinski, McHale, Cormier, Kubilus, Martin, Murphy, Baugh, Montenigro, Chaisson, Tripodis, Weuve, McClean, Goldstein, Katz, Stern, Stein, McKee.

Drafting of the manuscript: Mez, Daneshvar, Abdolmohammadi, Alosco, Martin, Murphy, Montenigro, McKee.

Critical revision of the manuscript for important intellectual content: Mez, Daneshvar, Kiernan, Abdolmohammadi, Alvarez, Huber, Alosco, Solomon, Nowinski, McHale, Cormier, Kubilus, Baugh, Chaisson, Tripodis, Kowall, Weuve, McClean, Cantu, Goldstein, Katz, Stern, Stein, McKee.

Statistical analysis: Mez, Daneshvar, Abdolmohammadi, Huber, Montenigro, Tripodis, Weuve.

Obtained funding: Mez, Nowinski, McKee.

Administrative, technical, or material support: Daneshvar, Kiernan, Abdolmohammadi, Alvarez, Huber, Alosco, McHale, Cormier, Kubilus, Murphy, Baugh, Montenigro, Chaisson, Kowall, McClean, Stein, McKee.

Supervision: Mez, Daneshvar, Abdolmohammadi, Solomon, Cantu, Stern, McKee.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nowinski reported that he receives travel reimbursements for various unpaid advisory roles from the NFL Players’ Association, Major League Lacrosse, World Wrestling Entertainment (WWE), National Collegiate Athletic Association (NCAA), and the Ivy League; receives royalties from the publication of his book Head Games: The Global Concussion Crisis, published by Head Games The Film; served as a consultant for MC10 Inc as recently as 2013; serves as chief executive officer of the Concussion Legacy Foundation; and receives speaking honoraria and travel reimbursements for educational lectures. Ms Baugh reported that she receives research funding through the NCAA and the Harvard Football Players Health Study, which is funded by the NFL Players’ Association. Dr Cantu reported that he receives compensation from the NFL as senior advisor to its Head, Neck and Spine Committee, from the National Operating Committee on Standards for Athletic Equipment as chair of its Scientific Advisory Committee and from the Concussion Legacy Foundation as cofounder and medical director for some talks given and receives royalties from Houghton Mifflin Harcourt and compensation from expert legal opinion. Dr Stern reported that he has received research funding from the NFL, the NFL Players’ Association, and Avid Radiopharmaceuticals Inc; is a member of the Mackey-White Committee of the NFL Players’ Association; is a paid consultant to Amarantus BioScience Holdings Inc, Avanir Pharmaceuticals Inc, and Biogen; and receives royalties for published neuropsychological tests from Psychological Assessment Resources Inc and compensation from expert legal opinion. Dr McKee reported that she has received funding from the NFL and WWE and is a member of the Mackey-White Committee of the NFL Players’ Association.

Funding/Support: 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.

Role of the Funder/Sponsor: The funders of the study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit for publication.

Additional Contributions: We acknowledge the use of the resources and facilities at VA Boston Healthcare System and the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, Massachusetts). We also acknowledge the help of all members of the CTE Center at Boston University School of Medicine, Concussion Legacy Foundation, and the individuals and families whose participation and contributions made this work possible.</s>The neurodegenerative brain disease can be found in individuals who have been exposed to repeated head trauma. The disease is pathologically marked by a buildup of abnormal tau protein in the brain that can disable neuropathways and lead to a variety of clinical symptoms. These include memory loss, confusion, impaired judgment, aggression, depression, anxiety, impulse control issues and sometimes suicidal behavior.

It can only be formally diagnosed with an autopsy, and most cases, although not all, have been seen in either veterans or people who played contact sports, particularly American football.

"There's no question that there's a problem in football. That people who play football are at risk for this disease," said Dr. Ann McKee, director of Boston University's CTE Center and coauthor of the new study. "And we urgently need to find answers for not just football players, but veterans and other individuals exposed to head trauma."

The JAMA study is the largest of its kind and all of those studied were required to have football as their primary exposure to head trauma. The criteria for submitting a brain was based on exposure to repetitive head trauma, regardless of whether that individual exhibited symptoms during their lifetime.

The study points out potential bias because relatives of these players may have submitted their brains due to clinical symptoms they noticed while they were living. It also acknowledges the lack of a comparison group that represents all individuals exposed to college-level or professional football. Without that, the study lacks an overall estimate on the risk of participation in football and its effects on the brain.

Kevin Turner, Out of 202 deceased former football players total -- a combination of high school, college and professional players -- CTE was neuropathologically diagnosed in 177, the study said. The disease was identified in 110 out of 111 former NFL players. It was also found in three of the 14 high school players and 48 of the 53 college players. The study included brains of individuals who have been publicly confirmed to have had the disease, including Ken Stabler Bubba Smith and Dave Duerson

"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," the NFL told CNN in a statement, noting that "there are still many unanswered questions relating to the cause, incidence and prevalence of long-term effects of head trauma such as CTE."

In 2016, the NFL publicly acknowledged for the first time a connection between football and CTE . In June 2015, a federal judge approved a class-action lawsuit settlement between the NFL and thousands of former players, providing up to $5 million per retired player for serious medical conditions associated with repeated head trauma.

"The NFL is committed to supporting scientific research into CTE and advancing progress in the prevention and treatment of head injuries," the NFL statement on the study said. "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."

Questions raised

The study examined both the brain pathology -- which is the behavior of the disease in the brain -- and clinical history of every participant. It identified four stages of pathological CTE severity among the brains, based on amounts of tau buildup and distribution. Stages one and two are considered to be mild and stages three and four are considered severe.

Individuals who were reported to have experienced more behavioral mood symptoms during their lifetime were more likely to have findings indicative of mild disease as opposed to severe. These symptoms occurred in 96% of mild cases and 89% of severe cases. People with a mild build up and distribution of tau were also more likely to have died by suicide. Those with a more severe build up, on the other hand, were more likely to have experienced cognitive symptoms, such as memory loss.

The behavioral and mood symptoms in people with mild disease evidence may be the result of other influences, such as neuroinflammation or axonal injury, which is an injury to the brain cells, McKee said. The question of pathology's relationship to clinical symptoms is one they're hoping to answer in future studies, she said.

Dr. Jeffrey Kutcher, national director of the Sports Neurology Clinic at the Core Institute, who was not involved in the study, agreed with the need to further understand this relationship.

"Just because we are describing the same CTE pathology, the collection of tau and the distribution that's consistent with CTE, that doesn't mean it's the only pathological process," Kutcher said. "There could be others that we are yet to identify. So I think its important that we don't just focus on one pathology, and that we start looking for others."

Seeking help

Studies like this have the potential to create a powerful narrative for football players who read them, but may not have a full understanding of the science or the bias in the sample, Kutcher said. This could lead players to believe that they are damaged and that there is no use in seeking help, he said.

"To me, that is one of the biggest issues we have right now," Kutcher said. "Not emphasizing that people should seek treatment for their problems."

Although the disease cannot be formally diagnosed until after death, many of the symptoms of CTE that may be experienced during a lifetime, such as depression or anxiety, are treatable, Kutcher said. That is why its important for someone experiencing these symptoms to access a comprehensive evaluation by a neurologist, and work with them to figure out a treatment plan.

Kutcher said its also important to consider that the brains examined in the study came from players who played decades ago. Most of the participants with CTE played football during the 1950s, '60s, '70s, '80s and '90s, McKee said, with the rest having played in the 2000s and 2010s.

The experiences of the majority were different from those who play the sport today, Kutcher said, and there was not the same awareness, medical protocols or equipment to prevent brain injuries.

"My rule as a physician, as a neurologist, is to protect and promote the brain health of my patients over the course of a lifetime, no question about that. You have to look at the total person though," Kutcher said. "You have to understand why people play sports. It's an individual decision, everybody gets different things out of it. You also have to understand what the arc of their life is going to be, what their health is going to be at the end of their career."

Next steps

McKee and her colleagues are currently working to understand more about CTE and who is most susceptible to it. They are looking at the lengths of exposure to head trauma, the age of first exposure, the lengths of playing careers and how that relates to the risk of CTE and its pathological severity, she said.

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"It certainly can be prevented and that's why we really need to understand how much exposure to head trauma and what type of head trauma the body can sustain before it gets into this irreversible cascade of events," she said.

They are also using the 177 donated brains with CTE to try and see if there are any genetic risk factors of the disease.

"For the first time, we've established this really rich resource, not only of data, both the clinical symptoms and the pathological features, but also a tissue resource to enable future research in CTE," McKee said. "And we know that this study doesn't answer many of the very important questions in CTE, but the resource will help us understand the molecular underpinnings, will help us develop biomarkers and therapies by understanding the pathological features of the disease."</s>FILE PHOTO - New England Patriots linebacker Junior Seau celebrates sacking San Diego Chargers quarterback Philip Rivers in first quarter of the NFL's AFC championship football game in Foxborough, Massachusetts, U.S. on January 20, 2008.

BOSTON (Reuters) - The brains of 99 percent of former National Football League players showed signs of a disease linked to repeated hits to the head that can lead to aggression and dementia, according to research published in a leading medical journal on Tuesday.

The findings were based on the broadest review yet of the brains of former football players for signs of chronic traumatic encephalopathy. The condition, also known as CTE, is linked to the sort of head-to-head hits that were long a part of the sport, though the NFL and school leagues have been tweaking the game in recent years to limit blows to the head.

"The data suggest that there is very likely a relationship between exposure to football and risk of developing the disease," said Jesse Mez, a Boston University School of Medicine assistant professor of neurology, who was lead author of the study published in the Journal of the American Medical Association.

The researchers studied the brains of 202 former athletes who had played football in the NFL, the Canadian Football League or at the college or high school level and found signs of CTE in the brains of 110 of the former 111 NFL players.

The condition, which currently can be diagnosed only by taking brain tissue from a dead subject, has been diagnosed in former players including Hall of Fame linebacker Junior Seau and Pro Bowl safety Dave Duerson, who both committed suicide.

The researchers noted that the study had limitations including that the subjects' brains were donated by their families, and that families are more likely to opt into the study if the players had showed symptoms of CTE.

"We do not know what proportion of football players, or any group, for that matter, develop CTE," said Dr. Munro Cullum, a neuropsychologist with the O'Donnell Brain Institute at the University of Texas Southwestern Medical Center in Dallas.

The NFL, which last year pledged $100 million for neuromedical research, said the study would help the league and players to understand the condition.

"The NFL is committed to supporting scientific research into CTE and advancing progress in the prevention and treatment of head injuries," said NFL spokesman Brian McCarthy, in an e-mail.

The study found signs of CTE in the brains of 91 percent of the 53 former college players whose brains were studied and 21 percent of the former high school players.</s>Signs of a degenerative brain disease were widespread among a sample of donated brains of former football players, researchers reported Tuesday in the Journal of the American Medical Association.

The finding bolsters the connection between playing American football and developing Chronic traumatic encephalopathy (CTE), which is linked to repeated blows to the head and was first described in boxers. However, the large study provides little new information about the disease, its progression, or prevalence.

The bank of 202 former football players’ brains is a “convenience sample,” meaning it’s a biased sampling not representative of football players overall. Instead, players and their families donated the brains after players experienced symptoms connected with CTE during life or the players were suspected or considered at risk of developing CTE. The athletes represented in the sample reported much higher rates of CTE symptoms in life than those found in surveys of living, retired National Football League (NFL) players. Also, the study only had pathology data from one time point—after death—so progression of the disease couldn’t be examined. And, last, the study did not include a sampling of brains from people who were not exposed to football—a control group.

Overall, the study doesn’t tell us much about possible prevalence of CTE among football players, the absolute risk that people have of developing the disease, or the elevated relative risk that football players may have compared with non-football players.

Still, it adds to the growing evidence linking hard knocks in American football and other high-impact sports to the development of CTE. The devastating disease is associated with progressive memory problems, dementia, depression, and aggression.

CTE is diagnosed by post-mortem examination of the brain. Researchers look for abnormal clumps of protein that accumulate near small blood vessels. Mild cases of CTE show these defects in the brain’s outer layer, while those with severe cases have them in deeper regions of the brain.

For the study, researchers (led by Boston University neuropathologist Ann McKee) relied on a bank of brains from players who were considered at risk of CTE. The players had experienced repetitive head trauma during life by playing football. Their median age of death was 66. In the sample of 202 brains, 177 (87 percent) had signs of CTE.

That breaks down to: 110 of 111 (99 percent) NFL players diagnosed with CTE; seven of eight (88 percent) Canadian Football League players; 48 of 53 (91 percent) college football players; 9 of 14 (64 percent) semi-professional players; 3 of 14 (21 percent) high school players; and 0 of two pre-high school players. The three high school players with CTE all had mild cases. But the remaining player categories had a mix of mild and severe.

From extensive online and phone surveys of players’ family members, researchers collected clinical data about possible CTE symptoms and their progression of 111 players with CTE. The brain pathology data linked with the clinical data. For instance, among 84 participants with severe CTE signs in their brain, 75 (89 percent) had behavioral or mood symptoms or both, 80 (95 percent) had cognitive symptoms, and 71 (85 percent) had signs of dementia, the researchers reported. The finding offers a correlation that backs similar findings in earlier work, but it does not prove that the brain abnormalities caused the symptoms.

Previous surveys have found that about six percent of retired NFL players over the age of 56 reported memory problems and about 11 percent experienced depression.

In a statement, the NFL responded to the study saying:

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.</s>Chronic traumatic encephalopathy (CTE) has been diagnosed in 110 of 111 former NFL players whose brains were donated for research, according to a study published in The Journal of the American Medical Association.</s>The biggest ever study into football brain injuries has diagnosed CTE in 99 percent of former NFL players' brains in post-mortem examinations.

Boston University is leading the groundbreaking and ambitious research project to identify whether there is a direct link between concussions on the field and neurodegenerative diseases in players - including the late Aaron Hernandez.

They are focusing on chronic traumatic encephalopathy (CTE), a little-understood condition a progressive neurodegeneration associated with repetitive head trauma. It has been linked to ALS (also called 'locked-in syndrome') and Alzheimer's.

Now, the team has released their first major findings from post-mortem examinations on 202 deceased players' brains, which were donated to research.

Chronic traumatic encephalopathy (CTE) is a degenerative brain disease that is caused by repeated hits to the head. Over time, these hard impacts result in confusion, depression and eventually dementia. There has been several retired football players who have come forward with brain diseases. They are attributing their condition to playing football and the hits they took. More than 1,800 former athletes and military veterans have pledged to donate their brains to the Concussion Legacy Foundation for CTE research. CTE was usually associated with boxing before former NFL players began revealing their conditions.

They also interviewed next-of-kin to learn about each player's clinical symptoms, to compare with their findings.

The players, who lived to an average of 66 years old, had all played for a median of 15 years - from high school to professional leagues.

Overall, 177 of the brains they analyzed (87 percent) had CTE.

It was by far the most prevalent among NFL players: they found 110 of the 111 NFL players in the study (99 percent) had the hallmarks of CTE.

College players had the second-highest rate, with 48 out of 53 college players' brains (91 percent) diagnosed with CTE.

They also diagnosed CTE in seven out of eight Canadian Football League players (88 percent), nine out of 14 semi-professional players (64 percent), and three out of 14 high school players (21 percent).

All three of the high school players had mild CTE.

The majority of all the other players had severe pathology.

Among those with mild CTE pathology, 96 percent had behavioral and mood symptoms, 85 percent had cognitive symptoms, and 33 percent had signs of dementia.

Among those with severe CTE pathology, 89 percent had behavioral or mood symptoms or both, 95 percent had cognitive symptoms, and 85 percent had signs of dementia.

'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,' the article concludes.

Chronic traumatic encephalopathy (CTE) is a degenerative brain disease that is caused by repeated hits to the head.

Over time, these hard impacts result in confusion, depression and eventually dementia.

There has been several retired football players who have come forward with brain diseases.

They are attributing their condition to playing football and the hits they took.

More than 1,800 former athletes and military veterans have pledged to donate their brains to the Concussion Legacy Foundation for CTE research.

CTE was usually associated with boxing before former NFL players began revealing their conditions.

The authors admitted that several other football-related factors may influence CTE risk and disease severity. This could include their age at first exposure to football, duration of play, player position and cumulative hits.

The study has several limitations, including that it is a skewed sample based on a brain donation program because public awareness of a possible link between repetitive head trauma and CTE may have motivated players and their families with symptoms and signs of brain injury to participate in this research.

The authors urge caution in interpreting the high frequency of CTE in this study, stressing that estimates of how prevalent CTE may be cannot be concluded or implied.

Retired NFL stars Leonard Marshall and Matt Hasselbeck announced in May they would be donating their brains to CTE research.

Marshall, a two-time Super Bowl winner and defensive lineman for the New York Giants, said the sport has left him struggling with short-term memory loss and erratic behavior at age 55.

More than 1,800 former athletes and military veterans have pledged to donate their brains to the Concussion Legacy Foundation for CTE research.

Aaron Hernandez, a former Patriots player, committed suicide in his prison cell in April. His family has donated his brain to a team from the University of Boston to see whether he was suffering from CTE.

Nick Buoniconti said earlier in May he wouldn't have played football if he had known about the risks it posed to his brain health.

The 76-year-old former middle linebacker for the Patriots and Dolphins was diagnosed with dementia in October 2016.

Research published last week confirmed the strongest ever link between sports concussions and Alzheimer's disease. Until now, doctors only considered severe traumatic brain injury a key risk factor for developing neurodegenerative diseases. But the new study by Boston University School of Medicine (BUSM) has - for the first time - shown even low-impact injuries like concussion could have life-threatening consequences. They reached their conclusion by scanning the brains of 160 wounded war veterans after tours in Iraq and Afghanistan. Using MRI imaging, the researchers measured the thickness of their cerebral cortex in seven regions that have been pegged at the 'ground zero' for Alzheimer's disease. They also scanned seven control regions - regions that tend not to be affected. They found that having a concussion was associated with lower cortical thickness in brain regions that are the first to be affected in Alzheimer's disease. Lead author, Dr Jasmeet Hayes, said: 'Our results suggest that when combined with genetic factors, concussions may be associated with accelerated cortical thickness and memory decline in Alzheimer's disease relevant areas.' 2. BRAIN CHANGES IN HIGH SCHOOL PLAYERS AFTER JUST ONE SEASON A study at Wake Forest School of Medicine has been examining the brains of high school football players. One of the participants is the son of former Minnesota Vikings player Greg DeLong. The study published in the journal Radiology found measurable brain changes in teen players after a single season of ball - even without a concussion diagnosis. Now DeLong is speaking out to say he would have seriously reconsidered his football career if he had known the risks. 'Football's important to us, but there are other things out there that are more important,' DeLong told Good Morning America. The CDC has estimated that up to 3.8 million concussions occur in sports and recreational activities each year. But some experts wonder if those numbers underestimate total brain injuries, as some individuals may not seek treatment for mild or moderate symptoms. The agency has applied for federal funding to create a database in order to investigate sport injuries and brain diseases more in-depth. Meanwhile, the state of Texas has embarked on the largest ever study into concussions. State officials hope to track brain injuries among high school sports to discover whether more needs to be done to improve player safety and protect athletes. The University Interscholastic League, Texas' governing body for public high school sports, is partnering with the O'Donnell Brain Institute at UT Southwestern Medical Center for the project. A state as large as Texas, which has more than 800,000 public high school athletes, would be a key step in developing a national database of brain injuries in youths, officials say.</s>The latest study from an ongoing Boston University examination of the brains of former football players has yielded more ominous results.

In a study published July 25 in the Journal of the American Medical Medical Association, investigators reported that 177 out 202 brains of deceased American football players showed signs of chronic traumatic encephalopathy or CTE, the degenerative brain disease that's strongly linked to repeated blows to the head.

For former NFL players, the results were even more stark: 110 out 111 players' brains were diagnosed with the disease.

At varying levels of severity, CTE manifests with memory problems, mood disorders, depression, and dementia. There's still a lot we don't know about the disease and its causes, but this new data gives scientists even more reason to think professional football players may be at increased risk of suffering from CTE. It also suggests that these athletes are likely to have more severe forms of degenerative brain disease than the average patient.

That's a big deal when talking about America's favorite sport. The NFL has been accused of denying or concealing the risks of head injuries in the past, which led to a $1 billion lawsuit between the league and thousands of former players. Football players like Junior Seau and Dave Duerson, who both committed suicide, asked that their brains be examined for signs of the disorder and were diagnosed with CTE after their deaths.

Chris Nowinski, the executive director of the Concussion Legacy Foundation and author of "Head Games: The Global Concussion Crisis," previously told Business Insider that it's hard to understand just how bad this sort of disease can be "until you live this every day and really hear the horror stories of what happens to families when things go wrong."

What the new study tells us

The longer and more seriously someone played football, the study found, the more likely they were to have severe CTE. People who stopped playing after high school all had mild pathology, while those who played in college, semiprofessional, and professional leagues mostly had severe CTE.

Even the individuals posthumously diagnosed with "mild" CTE had showed signs of behavior problems, cognitive issues, and mood disorders when they were alive. Substance use disorders, a likelihood of committing suicide, and impulsivity were also common. In addition to those traits, those with severe CTE were frequently diagnosed with dementia.

"It is no longer debatable whether or not there is a problem in football — there is a problem," Dr. Ann McKee, who led the study, told The New York Times. Even if CTE was expected to be somewhat common, the fact that 99% of NFL players in the study showed signs of the disease indicates that it's prevalent among former players.

The brains that BU's CTE Center studied were all donated for research based on suspicions that the individuals they once belonged to might have developed the disorder. Unfortunately, CTE can only be diagnosed after death, but many of the players whose brains were examined displayed symptoms before death that are linked to the disorder.

So it's not a surprise that CTE was so common among this sample.

However, as the Times reports, approximately 1,300 former NFL players have died since the CTE Center began this research. Even if zero of the brains that were not examined in this study showed signs of CTE, that would still make the minimum CTE prevalence for former NFL players approximately 9%. That still seems high for a condition not frequently diagnosed in the general population. And it's likely the incidence is even higher than that.

What we still don't know

The NFL has already admitted that there's a link between playing football and developing CTE. But we still don't know what causes CTE in the first place.

It's possible that concussions, the bell-ringing hits that leave players confused and potentially knocked out, play a role. But it's perhaps even more likely that the degenerative condition is triggered by the hundreds or thousands of smaller hits to the head that players endure.

As the new study points out, the vast majority of football players aren't college or professional players. Most people who play football play at some point as kids or high school students but then stop. We don't yet know how risky that exposure is, but it could be dangerous.

"It's an ethical question, what is our culture comfortable with," Nowiski told Business Insider. "Is government underwriting brain damage for children through school sports?"

Oher sports may be risky as well. CTE was first identified as "dementia pugilistica" in former boxers, and at least one study found that 17% of former boxers' brains showed the disease. Concerns have also been raised about the consequences of heading the ball in soccer and about contact sports like hockey and rugby.

It's important to understand these overall risks and to compare them to the health and social problems associated with avoiding sports. Perhaps the games can be changed in ways that make them less dangerous — youth football leagues have already made an effort to do boost safety and have reduced concussion rates. But how do we decide when an activity is safe enough?

No one wants to suffer the effects of a degenerative brain disorder. If there's a way to help athletes avoid that, we need to figure out the best way to do so.</s>As a new American football season is set to begin, researchers examining the brains of deceased NFL players have found that 99 percent of them showed signs of degenerative disease -- believed to be caused by repeated blows to the head.

Researchers found striking evidence of chronic traumatic encephalopathy in 110 of the 111 donated brains of players who played in the National Football League, according to the study published Tuesday in the Journal of the American Medical Association.

CTE causes symptoms including memory loss, vertigo, depression and dementia. Problems can crop up years after a player's career has ended.

The NFL has faced growing scrutiny in recent years linked to the issue of concussions and head trauma, with the league agreeing in 2015 on a $1 billion settlement to resolve thousands of lawsuits by former players suffering from neurological problems.

Along with NFL players, researchers also examined the brains of those who had played in high school, college, semi-professionally and in the Canadian Football League.

Of the total 202 players examined, the authors of the study from Boston University found that 87 percent of the players -- whose median age at death was 66 years old -- showed signs of CTE.

The most acute evidence of the degenerative condition, which currently can only be diagnosed post-mortem, was found among those who played at the highest levels, with 86 percent of professional players having severe forms of CTE.

Though the research -- the largest CTE study published to date -- suggests the disease may be related to prior participation in football, researchers cautioned against extrapolating the results to the general population.

Because the brains studied were for the most part donated by concerned families, they do not necessarily represent all people who have played the rough contact sport.

Last year, an NFL official acknowledged for the first time a clear link between football and CTE.

In recent years, the league has donated money to concussion research and stepped up regulations in an attempt at minimizing the potentially traumatic physical impact of the game.</s>DALLAS (CBSDFW.COM) – Brain damage caused by concussions was found in 99 percent of the brains that were researched in a newly-released study by the Journal of the American Medical Association.

Chronic traumatic encephalopathy, or CTE, was found in 110 of 111 brains of deceased former NFL players.

The players of their families donated their brains to research after their death.

The same condition was found in 87 percent or the brains of players who played an average of 15 years, including high school and college.

Sometimes, all it takes one bad hit.

Benjamin Beggins suffered from a concussion while playing football in the 8th grade.

“How can one hit from football just after the rest of my life?” asked Beggins.

Now he’s graduated high school and traveled from Houston to Dallas to get treated at the Cerebrum Center in Dallas. The center has treated retired NFL players and even current players who don’t want anyone to know they’re being treated for brain injuries.

Dr. Brandon Brock said he isn’t surprised by new research. Brock said the risk may be even greater for high schools kids who don’t have the financial pay off NFL players do but are stuck with a concussion for years after. Dr. Brock says it’s time for parents to have an honest conversation with kids who play football.

“Do I want to put them in harm’s way where they have risk of an early onset neurodegenerative disease that can end their career or do we want to support them in their effort to become a professional football player which is probably less than one percent,” said Brock.

Beggins’ dad said if he knew then what he knows now, he wouldn’t have allowed his son to play football.
A study, published in the Journal of the American Medical Association, finds that 99 percent of the brains donated for scientific research by deceased National Football League players show signs of chronic traumatic encephalopathy (CTE), the disease identified in autopsies of numerous NFL players who have committed suicide, and the subject of the 2015 movie Concussion.