Athletic exposure to repetitive brain trauma and its effect on the development of chronic traumatic encephalopathy

Thesis (Ph.D.)--Boston UniversityChronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease marked by widespread accumulation of hyperphosphorylated tau (ptau). CTE is associated with a constellation of symptoms, including impairments in cognition, behavior, and mood. Although initially described in boxers as dementia pugilistrca, CTE has been diagnosed in athletes from a variety of backgrounds, as well as military veterans and other individuals exposed to traumatic brain injury (TBI). To date, the only shared risk factor for CTE is a history of single or multiple TBI. This work aimed to better elucidate the relationship between exposure to head impacts and the development and progression of CTE. Although the link between brain injury and CTE has been well described, the magnitude of this relationship has never been studied epidemiologically. The minimum prevalence of CTE was determined in a cohort at high risk of exposure to head impacts, specifically National Football League (NFL) athletes. All former NFL athletes who passed away in 2011 were identified; a subset of these athletes were studied and diagnosed with CTE to establish a minimum prevalence of CTE. The characteristics of those examined and diagnosed with CTE and those undiagnosed were explored. These analyses represent the first epidemiologic study of CTE; the high prevalence highlights the relationship between exposure to head impacts and the diagnosis of CTE. Next, the relationship between the nature of athletic exposure and CTE was quantified. An athletic history questionnaire was developed and integrated into a mathematical model, incorporating data from sensors placed in football players' helmets, to identify the theoretical frequency and magnitude of an athlete's head impact exposure. This model was adapted for use postmortem, and it was found that the duration of athletic exposure, total theoretical collisions experienced; and the sum of the 95th percentiles of the rotational acceleration endured, were all significantly associated with extent of CTE pathology. The relationships between the type of athletic exposure and the clinical presentation of disease and the specific neuroanatomic distribution of p-tau were also explored. These findings indicate the significant role of athletic exposure to head impacts on the diagnosis and progression of CTE, clinically and pathologically

Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football

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.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

TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy

Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43–positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease

An apolipoprotein-E mediated relationship between smoking and risk of mild cognitive impairment and Alzheimer's disease

Thesis (M.A.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [email protected]. Thank you.Increasing evidence indicates that the sooner treatment begins for patients with Alzheimer's Disease (AD), the better the chance of delaying progression of the disease. As a result, studies have begun focusing on risk factors for AD with the goal of identifying individuals with AD at the earliest possible stage. Such studies have found that individuals with Mild Cognitive Impairment (MCI) are at increased risk for AD and other forms of dementia. This study examines the potential mediating effect of a set of prospective risk factors, smoking and ApolipoproteinE (ApoE) genotype, on the incidence of MCI and AD. Although results of this study provide some preliminary evidence of an interaction, the study models presented here fail to reach significance. Additional studies are needed to confirm the hypothesis of an ApoE mediated relationship of smoking on MCI and AD.2031-01-0