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      Duration of American Football Play and Chronic Traumatic Encephalopathy

      , MD, MS 1 , 2 , 3 , , MD, PhD 1 , 4 , , BA 1 , 2 , , MS 1 , 5 , , PhD 1 , 2 , , BA 1 , 2 , 6 , , BA 1 , 2 , , BA 1 , 2 , , MS 1 , 7 , , MS 1 , 7 , , PhD 1 , 8 , , PhD 1 , 2 , , PhD 1 , 9 , 10 , , MD 1 , 9 , 10 , , MD 2 , 11 , , MD, PhD 1 , 2 , 9 , 10 , , MD, PhD 1 , 3 , 9 , 10 , 12 , , MD, PhD 1 , 2 , 12 , 13 , 14 , , MD 2 , 11 , , MD 1 , 2 , 8 , 15 , 16 , , PhD 1 , 3 , 17 , 18 , , MD 1 , 2 , 9 , 12 , , PhD 1 , 2 , 15 , 17 , , MS, ScD 19 , , MPH, ScD 18 , , PhD 1 , 5 , , MD , 1 , 2 , 3 , 9 , 10 , 12

      Annals of Neurology

      John Wiley & Sons, Inc.

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          Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose–response relationship between duration of football played and CTE risk and severity.


          In a convenience sample of 266 deceased American football players from the Veterans Affairs–Boston University–Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias.


          In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19–1.41; p = 3.8 × 10 −9) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07–1.22; p = 3.1 × 10 −4). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100–0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8–10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios.


          The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116–131

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          Most cited references 24

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          Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury.

          Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.
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            A structural approach to selection bias.

            The term "selection bias" encompasses various biases in epidemiology. We describe examples of selection bias in case-control studies (eg, inappropriate selection of controls) and cohort studies (eg, informative censoring). We argue that the causal structure underlying the bias in each example is essentially the same: conditioning on a common effect of 2 variables, one of which is either exposure or a cause of exposure and the other is either the outcome or a cause of the outcome. This structure is shared by other biases (eg, adjustment for variables affected by prior exposure). A structural classification of bias distinguishes between biases resulting from conditioning on common effects ("selection bias") and those resulting from the existence of common causes of exposure and outcome ("confounding"). This classification also leads to a unified approach to adjust for selection bias.
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              Chronic traumatic encephalopathy in a National Football League player.

              We present the results of the autopsy of a retired professional football player that revealed neuropathological changes consistent with long-term repetitive concussive brain injury. This case draws attention to the need for further studies in the cohort of retired National Football League players to elucidate the neuropathological sequelae of repeated mild traumatic brain injury in professional football. The patient's premortem medical history included symptoms of cognitive impairment, a mood disorder, and parkinsonian symptoms. There was no family history of Alzheimer's disease or any other head trauma outside football. A complete autopsy with a comprehensive neuropathological examination was performed on the retired National Football League player approximately 12 years after retirement. He died suddenly as a result of coronary atherosclerotic disease. Studies included determination of apolipoprotein E genotype. Autopsy confirmed the presence of coronary atherosclerotic disease with dilated cardiomyopathy. The brain demonstrated no cortical atrophy, cortical contusion, hemorrhage, or infarcts. The substantia nigra revealed mild pallor with mild dropout of pigmented neurons. There was mild neuronal dropout in the frontal, parietal, and temporal neocortex. Chronic traumatic encephalopathy was evident with many diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas. There were no neurofibrillary tangles or neuropil threads in the hippocampus or entorhinal cortex. Lewy bodies were absent. The apolipoprotein E genotype was E3/E3. This case highlights potential long-term neurodegenerative outcomes in retired professional National Football League players subjected to repeated mild traumatic brain injury. The prevalence and pathoetiological mechanisms of these possible adverse long-term outcomes and their relation to duration of years of playing football have not been sufficiently studied. We recommend comprehensive clinical and forensic approaches to understand and further elucidate this emergent professional sport hazard.

                Author and article information

                Ann Neurol
                Ann. Neurol
                Annals of Neurology
                John Wiley & Sons, Inc. (Hoboken, USA )
                23 November 2019
                January 2020
                : 87
                : 1 ( doiID: 10.1002/ana.v87.1 )
                : 116-131
                [ 1 ] Boston University Alzheimer's Disease and Chronic Traumatic Encephalopathy Center Boston University School of Medicine Boston MA
                [ 2 ] Department of Neurology Boston University School of Medicine Boston MA
                [ 3 ] Framingham Heart Study Boston University School of Medicine Boston MA
                [ 4 ] Department of Rehabilitation Medicine Stanford University School of Medicine Stanford CA
                [ 5 ] Department of Biostatistics Boston University School of Public Health Boston MA
                [ 6 ] Midwestern University Arizona College of Osteopathic Medicine Glendale AZ
                [ 7 ] Data Coordinating Center Boston University School of Public Health Boston MA
                [ 8 ] Concussion Legacy Foundation Boston MA
                [ 9 ] VA Boston Healthcare System, US Department of Veteran Affairs Boston MA
                [ 10 ] Department of Veterans Affairs Medical Center Bedford MA
                [ 11 ] Braintree Rehabilitation Hospital Braintree MA
                [ 12 ] Department of Pathology and Laboratory Medicine Boston University School of Medicine Boston MA
                [ 13 ] Department of Psychiatry Boston University School of Medicine Boston MA
                [ 14 ] Department of Biomedical Engineering Boston University College of Engineering Boston MA
                [ 15 ] Department of Neurosurgery Boston University School of Medicine Boston MA
                [ 16 ] Department of Neurosurgery Emerson Hospital Concord MA
                [ 17 ] Department of Anatomy & Neurobiology Boston University School of Medicine Boston MA
                [ 18 ] Department of Epidemiology Boston University School of Public Health Boston MA
                [ 19 ] Department of Environmental Health Boston University School of Public Health Boston MA
                Author notes
                [* ] Address correspondence to

                Dr McKee, Boston University AD and CTE Center, 72 E Concord Street, Robinson Suite 7800, Boston, MA 02118.

                E‐mail: amckee@ 123456bu.edu

                © 2019 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 http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 5, Tables: 5, Pages: 16, Words: 9843
                Funded by: Alzheimer's Association , open-funder-registry 10.13039/100000957;
                Award ID: NIRG‐15‐362697
                Award ID: NIRG‐305779
                Funded by: Andlinger Foundation
                Funded by: Concussion Legacy Foundation
                Funded by: National Football League , open-funder-registry 10.13039/100006425;
                Funded by: National Institute of Neurological Disorders and Stroke , open-funder-registry 10.13039/100000065;
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                Funded by: National Institute on Aging , open-funder-registry 10.13039/100000049;
                Award ID: F32NS096803
                Award ID: K23AG046377
                Award ID: P30AG13846
                Award ID: R01AG057902
                Award ID: R01AG061028
                Award ID: R01AG1649
                Award ID: R21HD089088
                Award ID: supplement 0572063345
                Funded by: Nick and Lynn Buoniconti Foundation
                Funded by: the National Operating Committee on Standards for Athletic Equipment (NOCSAE) , open-funder-registry 10.13039/100005636;
                Funded by: U.S. Department of Defense , open-funder-registry 10.13039/100000005;
                Award ID: PRARP‐13267017
                Award ID: W81XWH‐13‐2‐0064
                Award ID: W81XWH‐13‐2‐0095
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                Funded by: U.S. Department of Veterans Affairs , open-funder-registry 10.13039/100000738;
                Award ID: B6796‐C
                Award ID: CSP 501
                Award ID: I01 CX001135
                Funded by: World Wrestling Entertainment (WWE)
                Research Article
                Research Articles
                Custom metadata
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:21.01.2020



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