The spectrum of disease in chronic traumatic encephalopathy

McKee, Ann C.; Stein, Thor D.; Nowinski, Christopher J.; Stern, Robert A.; Daneshvar, Daniel H.; Alvarez, Victor E.; Lee, Hyo-Soon; Hall, Garth F.; Wojtowicz, S; Baugh, Christine M.; Riley, Donald E.; Kubilus, Caroline A.; Cormier, Kerry; Jacobs, Matthew A.; Martin, Brett; Abraham, Carmela R.; Ikezu, Tsuneya; Reichard, R. Ross; Wolozin, Benjamin; Budson, Andrew E.; Goldstein, Lee E.; Kowall, Neil W.; Cantu, Robert C.

doi:10.1093/brain/aws307

Cited by 1,799 publications

(2,511 citation statements)

References 75 publications

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“…In the past decade, there have been several reports on the effects of r‐mTBI on amyloid β deposition6 and the accumulation of the tau protein in very specific and recognizable patterns following human brain trauma 4. In our rodent mTBI model, we found no association between r‐mTBI and abnormal tau or A β accumulation at 24 months post injury, mirroring our observations in earlier timepoints.…”

Section: Discussionsupporting

confidence: 85%

“…In addition to learning and executive function impairment, patients sustaining mTBI can develop behavioral disinhibition or exhibit increased risk taking behavior 6, 31. The mice sustaining repetitive mTBI in this model demonstrated behavioral disinhibition, as manifested in the elevated plus maze at 24 months post injury.…”

Section: Discussionmentioning

confidence: 89%

“…Depending on the part of the brain affected, the result can vary greatly across individuals. Repetitive mTBI is clinically associated with symptoms of irritability, impulsivity, aggression, depression, short‐term memory loss, heightened suicidality, concentration difficulties, and sleep disturbance 6. A recent series of studies have demonstrated that cognitive deficits are more common in former athletes who sustained sport concussions when compared with age‐matched control patients 26, 27, 28, 29, 30.…”

Section: Discussionmentioning

confidence: 99%

“…However, a subset of this population demonstrates persisting neurocognitive dysfunction and non‐neurological disorders that cannot be considered mild 3. Notably, it is now well documented that the adverse effects of r‐mTBI in participants of contact sports and in former military personnel may continue for many years after the original event,4, 5, 6, 7, 8 with brain trauma being a risk factor for the development of neurodegenerative disease,9 in particular chronic traumatic encephalopathy (CTE); for review see Smith et al 10…”

Section: Introductionmentioning

confidence: 99%

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Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Mouzon

Bachmeier

Ojo

et al. 2017

Ann Clin Transl Neurol

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ObjectiveExposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long‐term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival.MethodsMale C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety‐like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies.ResultsAt 24 months survival animals exposed to r‐mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule‐motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI.InterpretationIn this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Mouzon

Bachmeier

Ojo

et al. 2017

Ann Clin Transl Neurol

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“…An mTBI is induced by biomechanical forces, and a single mTBI typically results in transient neurological impairment 5. Sustaining repeated mTBI, however, may result in cumulative and persisting neurological deficits,6, 7, 8, 9, 10 and has been associated with increased risk of developing neurodegenerative disease such as chronic traumatic encephalopathy (CTE) 11, 12. Considering the difficulty of mTBI diagnosis and prognosis, and the potential for long‐term sequalae after repeated mTBI, there have been increased research efforts to develop sensitive and objective biomarkers to help guide the clinical management of these injuries 10, 13, 14…”

Section: Introductionmentioning

confidence: 99%

Diffusion MRI abnormalities in adolescent rats given repeated mild traumatic brain injury

Wortman

Meconi

Neale

et al. 2018

Ann Clin Transl Neurol

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ObjectiveMild traumatic brain injury (mTBI) is a serious health concern in the adolescent population. Repeated mTBI may result in more pronounced deficits, and has been associated with long‐term neurological consequences including neurodegeneration. As such, there is a critical need for the development of objective mTBI biomarkers to help guide medical management. Diffusion‐weighted imaging (DWI) is an advanced magnetic resonance imaging (MRI) technique that may detect brain abnormalities after mTBI. Diffusion tensor imaging (DTI) is the most commonly applied DWI method, and initial studies have reported DTI changes in mTBI patients. Furthermore, new DWI methods (e.g., track‐weighted imaging; TWI) are being developed that may also be sensitive to mTBIs, but remain to be comprehensively studied.MethodsThis study utilized the Awake Closed Head Injury (ACHI) model of mTBI to investigate changes in DTI and TWI following repeated mTBI in adolescent male and female rats. A total of four ACHI impacts, two/day over two consecutive days, were delivered beginning on postnatal day 25. At 1 day and 7 days postinjury, rats were euthanized and brains were collected for DWI analyses.ResultsRats given repeated mTBI displayed changes in fractional anisotropy and radial diffusivity (i.e., DTI measures), as well as track density (i.e., TWI).InterpretationThese findings are consistent with initial DTI findings in mTBI patients, suggest that TWI may complement DTI, support the utility of DWI measures as biomarkers in mTBI, and further validate the ACHI rat model of mTBI.

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Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football

Mez

Daneshvar

Kiernan

et al. 2017

JAMA

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888

778

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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.

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The spectrum of disease in chronic traumatic encephalopathy

Cited by 1,799 publications

References 75 publications

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Diffusion MRI abnormalities in adolescent rats given repeated mild traumatic brain injury

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football

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