Publications by authors named "Christopher J Nowinski"

34 Publications

Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology.

Alzheimers Dement 2021 Apr 7. Epub 2021 Apr 7.

Boston University Alzheimer's Disease and CTE Centers, Boston University School of Medicine, Boston, Massachusetts, USA.

Introduction: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed.

Methods: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses.

Results: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2-5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12-0.59).

Discussion: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction.
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http://dx.doi.org/10.1002/alz.12338DOI Listing
April 2021

Who Will Protect the Brains of College Football Players?

JAMA Neurol 2021 Mar;78(3):273-274

Concussion Legacy Foundation, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaneurol.2020.4740DOI Listing
March 2021

Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy.

Acta Neuropathol 2020 12 17;140(6):851-862. Epub 2020 Sep 17.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.
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http://dx.doi.org/10.1007/s00401-020-02206-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669574PMC
December 2020

Chronic Traumatic Encephalopathy: Advocacy and Communicating with the Public.

Semin Neurol 2020 08 26;40(4):461-468. Epub 2020 Jul 26.

Boston University Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA.

Over the past 40 years, advocacy groups have been instrumental in raising awareness for neurodegenerative diseases such as Alzheimer's disease. More recently, advocates have emerged to educate about sports concussions and chronic traumatic encephalopathy (CTE), including the Concussion Legacy Foundation (CLF). CTE is a neurodegenerative disease caused in part by repetitive head impacts (RHI). While the majority of CTE research has focused on studying former American football players, CTE has also been found in military personnel, victims of domestic violence, and contact sport athletes from high school to professional levels of play. Advocates' many goals include creating a culture of brain donation and modifying youth contact sports to decrease RHI. Here, we provide the first review of CTE advocacy, summarize the accomplishments of the CLF, and consider the connections between CTE advocacy, research, and legislation over the last decade.
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http://dx.doi.org/10.1055/s-0040-1713621DOI Listing
August 2020

Duration of American Football Play and Chronic Traumatic Encephalopathy.

Ann Neurol 2020 01 23;87(1):116-131. Epub 2019 Nov 23.

Boston University Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA.

Objective: 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.

Methods: 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.

Results: 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 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10 ). 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.

Interpretation: 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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http://dx.doi.org/10.1002/ana.25611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973077PMC
January 2020

Variation in TMEM106B in chronic traumatic encephalopathy.

Acta Neuropathol Commun 2018 11 4;6(1):115. Epub 2018 Nov 4.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, 72 E Concord Street, B7800, Boston, MA, 02118, USA.

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22-0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29-0.98, p = 0.043), and increased synaptic protein density (β = 0.306, 95% CI 0.065-0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16-0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.
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http://dx.doi.org/10.1186/s40478-018-0619-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215686PMC
November 2018

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports.

J Neuropathol Exp Neurol 2018 09;77(9):757-768

Department of Neurology.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.
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http://dx.doi.org/10.1093/jnen/nly065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097837PMC
September 2018

Age of first exposure to tackle football and chronic traumatic encephalopathy.

Ann Neurol 2018 05;83(5):886-901

Boston University Alzheimer's Disease and CTE Center, Department of Neurology, Boston University School of Medicine, Boston, MA.

Objective: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE.

Methods: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset.

Results: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE.

Interpretation: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.
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http://dx.doi.org/10.1002/ana.25245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367933PMC
May 2018

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

Brain 2018 02;141(2):422-458

Alzheimer's Disease Center, CTE Program, Boston University School of Medicine, Boston, MA 02118, USA.

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.
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http://dx.doi.org/10.1093/brain/awx350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837414PMC
February 2018

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

JAMA 2017 07;318(4):360-370

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, Massachusetts2Department of Neurology, Boston University School of Medicine, Boston, Massachusetts4VA Boston Healthcare System, US Department of Veteran Affairs, Boston, Massachusetts5Department of Veterans Affairs Medical Center, Bedford, Massachusetts12Department of Pathology, Boston University School of Medicine, Boston, Massachusetts23Boston University School of Medicine, Boston, Massachusetts.

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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http://dx.doi.org/10.1001/jama.2017.8334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807097PMC
July 2017

Utility of providing a concussion definition in the assessment of concussion history in former NFL players.

Brain Inj 2017 4;31(8):1116-1123. Epub 2017 May 4.

a Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine , Boston , MA , USA.

Objective: Former National Football League (NFL) players' working knowledge of concussion has not yet been evaluated, despite this population being a major clinical research target due to the association between repetitive head impacts (RHI) and long-term clinical impairments. This study examined former NFL players' understanding of the current concussion definition, and the association between number of concussions with clinical function.

Methods: 95 former NFL players (mean age = 55.29; mean NFL year = 8.10) self-reported number of concussions before being provided with a concussion definition and after being read a modern definition of concussion. Subjects reported number of concussions with loss of consciousness (LOC). Principal Component Analysis of a battery of tests generated behaviour/mood, psychomotor speed/executive function, and verbal and visual memory factor scores.

Results: Post-definition number of concussions (median = 50) was five times the pre-definition (median = 10; p < 0.001). Greater pre- (p = 0.019) and post-definition concussions (p = 0.036) correlated with worse behaviour/mood scores, after controlling for years of football played, with specific effects for depressive symptoms and impulsivity. LOC did not account for variance beyond number of concussions.

Conclusions: Practitioners and clinical researchers should provide a definition of concussion in the assessment of concussion history in former football players to facilitate accuracy and standardization.
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http://dx.doi.org/10.1080/02699052.2017.1294709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157273PMC
April 2018

Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players.

JAMA Neurol 2017 Jan;74(1):67-74

Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Importance: Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury.

Objective: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity.

Design, Setting, And Participants: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level-, and body mass index-matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016.

Main Outcomes And Measures: Positron emission tomography-based regional measures of TSPO using [11C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance.

Results: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [11C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P < .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance.

Conclusions And Relevance: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.
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http://dx.doi.org/10.1001/jamaneurol.2016.3764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504689PMC
January 2017

Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination.

J Neuropsychiatry Clin Neurosci 2017 19;29(1):6-12. Epub 2016 Aug 19.

From Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston (MLA, JM, NWK, TDS, LEG, RCC, TMS, PTK, LM, BA, DD, PHM, CJN, RAS, ACM); the Department of Neurology, Boston University School of Medicine, Boston (MLA, JM, NWK, TDS, LEG, DIK, TMS, PTK, LM, BA, DD, PHM, RAS, ACM); Internal Medicine Department, North Shore Medical Center (DD); the VA Boston Healthcare System, U.S. Department of Veteran Affairs, Boston (NWK, TDS, ACM); the Departments of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston (NWK, TDS, ACM); the Department of Veterans Affairs Medical Center, Bedford, Mass. (TDS, ACM); the Departments of Psychiatry and Ophthalmology, Boston University School of Medicine, Boston (LEG); the Departments of Biomedical, Electrical & Computer Engineering, Boston University College of Engineering, Boston (LEG); the Concussion Legacy Foundation (RCC, CJN); the Department of Neurosurgery, Boston University School of Medicine, Boston (RAS); the Department of Neurosurgery, Emerson Hospital, Concord, Mass. (RCC); Braintree Rehabilitation Hospital, Braintree, Mass. (DIK); and the Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston (PHM, RAS).

This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age at cognitive and behavioral/mood symptom onset and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age at cognitive (p=0.02) and behavioral/mood (p=0.02) onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE.
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http://dx.doi.org/10.1176/appi.neuropsych.16030043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288278PMC
April 2017

Cumulative Head Impact Exposure Predicts Later-Life Depression, Apathy, Executive Dysfunction, and Cognitive Impairment in Former High School and College Football Players.

J Neurotrauma 2017 01 15;34(2):328-340. Epub 2016 Jun 15.

1 Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine , Boston, Massachusetts.

The term "repetitive head impacts" (RHI) refers to the cumulative exposure to concussive and subconcussive events. Although RHI are believed to increase risk for later-life neurological consequences (including chronic traumatic encephalopathy), quantitative analysis of this relationship has not yet been examined because of the lack of validated tools to quantify lifetime RHI exposure. The objectives of this study were: 1) to develop a metric to quantify cumulative RHI exposure from football, which we term the "cumulative head impact index" (CHII); 2) to use the CHII to examine the association between RHI exposure and long-term clinical outcomes; and 3) to evaluate its predictive properties relative to other exposure metrics (i.e., duration of play, age of first exposure, concussion history). Participants included 93 former high school and collegiate football players who completed objective cognitive and self-reported behavioral/mood tests as part of a larger ongoing longitudinal study. Using established cutoff scores, we transformed continuous outcomes into dichotomous variables (normal vs. impaired). The CHII was computed for each participant and derived from a combination of self-reported athletic history (i.e., number of seasons, position[s], levels played), and impact frequencies reported in helmet accelerometer studies. A bivariate probit, instrumental variable model revealed a threshold dose-response relationship between the CHII and risk for later-life cognitive impairment (p < 0.0001), self-reported executive dysfunction (p < 0.0001), depression (p < 0.0001), apathy (p = 0.0161), and behavioral dysregulation (p < 0.0001). Ultimately, the CHII demonstrated greater predictive validity than other individual exposure metrics.
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http://dx.doi.org/10.1089/neu.2016.4413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220530PMC
January 2017

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study.

Alzheimers Res Ther 2015 Oct 12;7(1):62. Epub 2015 Oct 12.

Alzheimer's Disease Center, Boston University School of Medicine, 72 East Concord Street, B-7800, Boston, MA, 02118, USA.

Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE.

Methods: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE.

Results: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology.

Conclusions: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.
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http://dx.doi.org/10.1186/s13195-015-0148-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601147PMC
October 2015

Beta-amyloid deposition in chronic traumatic encephalopathy.

Acta Neuropathol 2015 Jul 6;130(1):21-34. Epub 2015 May 6.

VA Boston Healthcare System, Boston, MA, 02130, USA,

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid β peptide (Aβ) levels, the extent of Aβ deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Aβ deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Aβ deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Aβ deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Aβ plaques and those without. Aβ deposition was significantly associated with the presence of the APOE ε4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (β = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both Aβ plaques and total levels of Aβ1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that Aβ deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that Aβ is associated with both pathological and clinical progression of CTE independent of age.
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http://dx.doi.org/10.1007/s00401-015-1435-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529056PMC
July 2015

Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy.

Alzheimers Res Ther 2015 15;7(1):13. Epub 2015 Mar 15.

Center for Clinical Spectroscopy, Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, 4 Blackfan Street HIM-820, Boston, MA 02115 USA ; Centre for MR in Health, School of Health Sciences, University of Newcastle, Newcastle, NSW 2308 Australia.

Introduction: The goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY).

Methods: To achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil.

Results: The variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P ≤0.05), between healthy controls and those athletes with RBT. Men with RBT showed higher levels of glutamine/glutamate (31%), choline (65%), fucosylated molecules (60%) and phenylalanine (46%). The results were evaluated and the sample size of five found to achieve a significance level P = 0.05 and a power of 90%. Differences in N-acetyl aspartate and myo-inositol between RBT and controls were small and were not statistically significance.

Conclusions: A study of a small cohort of professional athletes, with a history of RBT and symptoms of chronic traumatic encephalopathy when compared with healthy controls using 2D L-COSY, showed elevations in brain glutamate/glutamine and choline as recorded previously for early traumatic brain injury. For the first time increases in phenylalanine and fucose are recorded in the brains of athletes with RBT. Larger studies utilizing the L-COSY method may offer an in-life method of diagnosis and personalized approach for monitoring the acute effects of mild traumatic brain injury and the chronic effects of RBT.
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http://dx.doi.org/10.1186/s13195-015-0094-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361214PMC
March 2015

Concussion reporting intention: a valuable metric for predicting reporting behavior and evaluating concussion education.

Clin J Sport Med 2015 May;25(3):243-7

*Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, Massachusetts; †Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, Massachusetts; ‡Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; §Sports Legacy Institute, Boston University School of Medicine, Boston, Massachusetts; ¶Department of Neurosurgery, Boston University School of Medicine, Boston, Massachusetts; and ‖Department of Neurosurgery, Emerson Hospital, Concord, Massachusetts.

Objective: This study aimed to evaluate whether preseason concussion knowledge and reporting intention predicted in-season concussion reporting behavior.

Design: Prospective cohort study.

Setting: Collegiate athletic facility of each participating team.

Participants: National Collegiate Athletic Association Division I men's ice hockey players in 1 conference of competition (n = 116).

Independent Variables: Intention to report symptoms of a "minor" concussion and concussion knowledge were assessed at preseason.

Main Outcome Measures: Postseason recall of non-report of postimpact symptoms.

Results: Preseason concussion knowledge was not significantly associated with in-season reporting behavior. Intention to report concussion symptoms was significantly related to in-season reporting behavior. There was a significant interaction between the number of different symptoms experienced and both preseason reporting intention and in-season reporting behavior.

Conclusions: Evaluations of concussion education programs tend to measure concussion knowledge. The present findings suggest that reporting intention may be more strongly predictive of reporting behavior than concussion knowledge and should be included in evaluations of concussion effectiveness. New concussion education initiatives should consider targeting psychosocial constructs that increase reporting intention.

Clinical Relevance: Sports medicine clinicians who are involved in evaluating concussion education programs should measure constructs other than just concussion knowledge. Intention, to report symptoms or to continue play while experiencing symptoms of a concussion, seems to be an important and feasible construct to include as part of proximal evaluations of education effectiveness.
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http://dx.doi.org/10.1097/JSM.0000000000000137DOI Listing
May 2015

Self-reported concussion history: impact of providing a definition of concussion.

Open Access J Sports Med 2014 7;5:99-103. Epub 2014 May 7.

Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA ; Department of Neurology, Boston University School of Medicine, Boston, MA, USA ; Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA ; Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA.

Background: In recent years, the understanding of concussion has evolved in the research and medical communities to include more subtle and transient symptoms. The accepted definition of concussion in these communities has reflected this change. However, it is unclear whether this shift is also reflected in the understanding of the athletic community.

What Is Known About The Subject: Self-reported concussion history is an inaccurate assessment of someone's lifetime exposure to concussive brain trauma. However, unfortunately, in many cases it is the only available tool.

Hypothesis/purpose: We hypothesize that athletes' self-reported concussion histories will be significantly greater after reading them the current definition of concussion, relative to the reporting when no definition was provided. An increase from baseline to post-definition response will suggest that athletes are unaware of the currently accepted medical definition.

Study Design: Cross-sectional study of 472 current and former athletes.

Methods: Investigators conducted structured telephone interviews with current and former athletes between January 2010 and January 2013, asking participants to report how many concussions they had received in their lives. Interviewers then read participants a current definition of concussion, and asked them to re-estimate based on that definition.

Results: THE TWO ESTIMATES WERE SIGNIFICANTLY DIFFERENT (WILCOXON SIGNED RANK TEST: z=15.636, P<0.001). Comparison of the baseline and post-definition medians (7 and 15, respectively) indicated that the post-definition estimate was approximately twice the baseline. Follow-up analyses indicated that this effect was consistent across all levels of competition examined and across type of sport (contact versus non-contact).

Conclusion: Our results indicate that athletes' current understandings of concussions are not consistent with a currently accepted medical definition. We strongly recommend that clinicians and researchers preface requests for self-reported concussion history with a definition. In addition, it is extremely important that researchers report the definition they used in published manuscripts of their work.

What This Study Adds To Existing Knowledge: Our study shows that unprompted reporting of concussion history produces results that are significantly different from those provided after a definition has been given, suggesting one possible mechanism to improve the reliability of self-reported concussion history across multiple individuals.
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http://dx.doi.org/10.2147/OAJSM.S58005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019619PMC
June 2014

Clinical presentation of chronic traumatic encephalopathy.

Neurology 2013 Sep 21;81(13):1122-9. Epub 2013 Aug 21.

From the Center for the Study of Traumatic Encephalopathy (R.A.S., D.H.D., C.M.B., D.R.S., P.H.M., D.O.R., N.G.F., J.M.S., C.A.R., T.D.S., V.E.A., C.J.N., R.C.C., A.C.M.), BU Alzheimer's Disease Center (R.A.S., T.D.S., L.E.G., A.E.B., N.W.K., A.C.M.), Departments of Neurology (R.A.S., C.M.B., D.R.S., V.E.A., A.E.B., N.W.K., A.C.M.), Neurosurgery (R.A.S., R.C.C.), and Pathology (T.D.S., N.W.K., A.C.M.), Molecular Genetics Core Facility (I.S.), Boston University School of Medicine; Sports Legacy Institute (L.M., C.J.N., R.C.C.), Waltham; VA Boston Healthcare System (T.D.S., V.E.A., A.E.B., N.W.K., A.C.M.); Departments of Psychiatry, Neurology, Pathology & Laboratory Medicine, Ophthalmology, Biomedical Engineering, and Electrical & Computer Engineering (L.E.G.), Boston University School of Medicine and College of Engineering; and Department of Neurosurgery (R.C.C.), Emerson Hospital, Concord, MA.

Objective: The goal of this study was to examine the clinical presentation of chronic traumatic encephalopathy (CTE) in neuropathologically confirmed cases.

Methods: Thirty-six adult male subjects were selected from all cases of neuropathologically confirmed CTE at the Boston University Center for the Study of Traumatic Encephalopathy brain bank. Subjects were all athletes, had no comorbid neurodegenerative or motor neuron disease, and had next-of-kin informants to provide retrospective reports of the subjects' histories and clinical presentations. These interviews were conducted blind to the subjects' neuropathologic findings.

Results: A triad of cognitive, behavioral, and mood impairments was common overall, with cognitive deficits reported for almost all subjects. Three subjects were asymptomatic at the time of death. Consistent with earlier case reports of boxers, 2 relatively distinct clinical presentations emerged, with one group whose initial features developed at a younger age and involved behavioral and/or mood disturbance (n = 22), and another group whose initial presentation developed at an older age and involved cognitive impairment (n = 11).

Conclusions: This suggests there are 2 major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.
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http://dx.doi.org/10.1212/WNL.0b013e3182a55f7fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795597PMC
September 2013

NCAA concussion education in ice hockey: an ineffective mandate.

Br J Sports Med 2014 Jan 16;48(2):135-40. Epub 2013 Aug 16.

Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston Massachusetts, USA.

Background/aim: Despite concussion education being increasingly mandated by states and sports leagues, there has been limited evaluation of what education is in fact effective. The National Collegiate Athletic Association (NCAA) currently mandates that institutions provide concussion education, without specifying content or delivery. The present study evaluated the effectiveness of this general mandate, as enacted for male collegiate ice hockey teams within one conference of competition.

Methods: In a prospective cohort design, 146 players from 6 male collegiate ice hockey teams in one Division 1 conference completed written surveys before and after receiving their institution-determined concussion education. Knowledge, attitudes, perceived norms and behavioural intention were assessed using validated measures. Education content and delivery was assessed by open-ended responses and consultation with team athletic trainers.

Results: All teams received concussion education material; however, content and delivery varied. Rates of material recall differed by delivery format. Considering all teams together, there were no significant improvements in knowledge and only a very small decrease in intention to continue playing while experiencing symptoms of a concussion. Pre-education and post-education, there were significant between-team differences in attitudes towards concussion reporting and behavioural intention.

Conclusions: The NCAA's general education mandate was divergently enacted; it did not significantly change the constructs of interest nor did it mitigate the pre-education team differences in these constructs. Existing educational materials should be evaluated, theory and evidence-driven materials developed, and mandates extended to, at a minimum, recommend materials found to be effective in changing concussion-reporting behaviour.
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http://dx.doi.org/10.1136/bjsports-2013-092498DOI Listing
January 2014

Profile of self-reported problems with executive functioning in college and professional football players.

J Neurotrauma 2013 Jul 11;30(14):1299-304. Epub 2013 Jul 11.

Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston University, Boston, Massachusetts, USA.

Repetitive mild traumatic brain injury (mTBI), such as that experienced by contact-sport athletes, has been associated with the development of chronic traumatic encephalopathy (CTE). Executive dysfunction is believed to be among the earliest symptoms of CTE, with these symptoms presenting in the fourth or fifth decade of life. The present study used a well-validated self-report measure to study executive functioning in football players, compared to healthy adults. Sixty-four college and professional football players were administered the Behavior Rating Inventory of Executive Function, adult version (BRIEF-A) to evaluate nine areas of executive functioning. Scores on the BRIEF-A were compared to published age-corrected normative scores for healthy adults Relative to healthy adults, the football players indicated significantly more problems overall and on seven of the nine clinical scales, including Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, and Task Monitor. These symptoms were greater in athletes 40 and older, relative to younger players. In sum, football players reported more-frequent problems with executive functioning and these symptoms may develop or worsen in the fifth decade of life. The findings are in accord with a growing body of evidence that participation in football is associated with the development of cognitive changes and dementia as observed in CTE.
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http://dx.doi.org/10.1089/neu.2012.2690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713446PMC
July 2013

The spectrum of disease in chronic traumatic encephalopathy.

Brain 2013 Jan 2;136(Pt 1):43-64. Epub 2012 Dec 2.

United States Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA.

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.
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http://dx.doi.org/10.1093/brain/aws307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624697PMC
January 2013

Effectiveness of the SLICE program for youth concussion education.

Clin J Sport Med 2012 Sep;22(5):385-9

MD-PhD Program, Harvard Medical School, Boston, Massachusetts 02138, USA.

Objective: To analyze the effectiveness of the Sports Legacy Institute Community Educators (SLICE) curriculum for student-athletes on recognition and appropriate responses to concussions.

Design: Prospective cohort study, level II.

Setting: The SLICE concussion workshop.

Participants: All students ranging from 9 to 18 years (n = 636) taking the SLICE concussion education program.

Intervention: The SLICE concussion education program featuring interactive demonstrations, discussion, and case studies of athletes delivered by medical students and others in health-related fields.

Main Outcome Measures: Evaluations assessing knowledge of concussion recognition and appropriate response were administered before and after participating in the SLICE concussion education program.

Results: Students displayed significant improvements in absolute mean score on the concussion knowledge quiz between prepresentation and postpresentation (P < 0.0001). Significant improvements in mean score were observed among both male and female students within each age group. The proportion of students who passed the quiz increased from 34% prepresentation to 80% postpresentation (P < 0.0001). However, the percentage who passed the quiz postpresentation was significantly higher among female students compared with male students (P < 0.0001) and among students 13 years of age or older compared with students less than 13 years (P < 0.0001). Using multivariable logistic regression, we identified age group and gender as the most significant factors associated with passing the quiz postpresentation.

Conclusion: The SLICE program promotes effective learning and knowledge about concussion recognition and response among students ranging from 9 to 18 years. Lessons from the SLICE program may be broadly applicable to youth concussion education.
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http://dx.doi.org/10.1097/JSM.0b013e3182639bb4DOI Listing
September 2012

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.

Sci Transl Med 2012 May;4(134):134ra60

Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
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http://dx.doi.org/10.1126/scitranslmed.3003716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739428PMC
May 2012

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.

Sci Transl Med 2012 May;4(134):134ra60

Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
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http://dx.doi.org/10.1126/scitranslmed.3003716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739428PMC
May 2012

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.

Sci Transl Med 2012 May;4(134):134ra60

Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
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http://dx.doi.org/10.1126/scitranslmed.3003716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739428PMC
May 2012

Long-term consequences: effects on normal development profile after concussion.

Phys Med Rehabil Clin N Am 2011 Nov 23;22(4):683-700, ix. Epub 2011 Sep 23.

Department of Neurology, Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston 02118, MA, USA.

Each year in the United States, approximately 1.7 million people are diagnosed with a traumatic brain injury (TBI), about 75% of which are classified as mild TBIs or concussions. Although symptoms typically resolve in a matter of weeks, both children and adults may suffer from postconcussion syndrome for months or longer. A progressive tauopathy, chronic traumatic encephalopathy, is believed to stem from repeated brain trauma. Alzheimer-like dementia, Parkinsonism, and motor neuron disease are also associated with repetitive brain trauma. Effective diagnoses, treatments, and education plans are required to reduce the future burden and incidence of long-term effects of head injuries.
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http://dx.doi.org/10.1016/j.pmr.2011.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208826PMC
November 2011

Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions.

Curr Opin Neurol 2011 Dec;24(6):525-31

Center for the Study of Traumatic Encephalopathy, Boston University, and Brigham and Women's Hospital, Boston, Massachusetts 02118, USA.

Purpose Of Review: There are currently no consensus-based clinical diagnostic criteria for chronic traumatic encephalopathy (CTE). This review provides an update on recent literature pertaining to clinically relevant procedures that--presently or in the future--may be useful for the in-vivo detection, characterization, and/or prediction of CTE.

Recent Findings: Preliminary evidence about the clinical manifestations of CTE has been accumulating via post-mortem medical record review and interviews of friends or family members of individuals with neuropathologically documented CTE. This evidence suggests that CTE is manifested clinically by changes in cognition (especially memory and executive functioning, with dementia later in the disease course), mood (especially, depression, apathy, and suicidality), personality and behavior (especially poor impulse control and behavioral disinhibition), and movement (including parkinsonism and signs of motor neuron disease). At the present time, evidence regarding CTE has not been confirmed in a prospective study of a cohort at risk for CTE.

Summary: On the basis of recent research in the fields of dementia and traumatic brain injury, several in-vivo procedures (including neurological examination, neuropsychological assessment, neuroimaging techniques, and blood and cerebrospinal fluid biomarkers) each have the potential to contribute unique information about the manifestations of CTE, including clinical and preclinical stages. More research is needed to develop a set of consensus diagnostic criteria that provide a reliable and valid indicator of neuropathologically verified CTE. Until such criteria are developed, the clinical assessment of CTE should be informed by modern research that is of relevance to traumatic brain injury and neurodegenerative diseases.
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http://dx.doi.org/10.1097/WCO.0b013e32834cd477DOI Listing
December 2011

Helmets and mouth guards: the role of personal equipment in preventing sport-related concussions.

Clin Sports Med 2011 Jan;30(1):145-63, x

Department of Neurology, Boston University School of Medicine, Center for the Study of Traumatic Encephalopathy, 72 East Concord Street, B7800, Boston, MA 02118, USA.

Millions of athletes in the United States experience concussions annually. Although helmets and mouth guards have decreased the risk of catastrophic head injuries, their protective effects on concussions are less clear. This article evaluates the current literature on the effect of equipment on concussions. Understanding the role that these equipment play in preventing concussions is complicated by many factors, such as selection bias in nonrandomized studies, variations in playing style, and risk compensation in sports with mandatory protective equipment. Improving coach and player education about proper concussion management, encouraging neck-strengthening exercises, and minimizing high-risk impacts may reduce concussions in sports.
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http://dx.doi.org/10.1016/j.csm.2010.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987604PMC
January 2011