Tau Positron-Emission Tomography in Former National Football League Players.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied. METHODS: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group. RESULTS: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease. CONCLUSIONS: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).

Limbic system structure volumes and associated neurocognitive functioning in former NFL players.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.

Cerebrospinal fluid tau, Aß, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration.

INTRODUCTION: Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid ß1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy. METHODS: Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau181, amyloid ß1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI. RESULTS: No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P = .041), and higher sTREM2 levels were associated with higher t-tau concentrations (P = .009). DISCUSSION: In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.

Age at First Exposure to Repetitive Head Impacts Is Associated with Smaller Thalamic Volumes in Former Professional American Football Players.

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.

Concussion Care Practices and Utilization of Evidence-Based Guidelines in the Evaluation and Management of Concussion: A Survey of New England Emergency Departments.

Evidence-based clinical practice guidelines can facilitate proper evaluation and management of concussions in the emergency department (ED), often the initial and primary point of contact for concussion care. There is no universally adopted set of guidelines for concussion management, and extant evidence suggests that there may be variability in concussion care practices and limited application of clinical practice guidelines in the ED. This study surveyed EDs throughout New England to examine current practices of concussion care and utilization of evidence-based clinical practice guidelines in the evaluation and management of concussions. In 2013, a 32-item online survey was e-mailed to 149/168 EDs throughout New England (Connecticut, Rhode Island, Massachusetts, Vermont, New Hampshire, Maine). Respondents included senior administrators asked to report on their EDs use of clinical practice guidelines, neuroimaging decision-making, and discharge instructions for concussion management. Of the 72/78 respondents included, 35% reported absence of clinical practice guidelines, and 57% reported inconsistency in the type of guidelines used. Practitioner preference guided neuroimaging decision-making for 57%. Although 94% provided written discharge instructions, there was inconsistency in the recommended time frame for follow-up care (13% provided no specific time frame), the referral specialist to be seen (25% did not recommend any specialist), and return to activity instructions were inconsistent. There is much variability in concussion care practices and application of evidence-based clinical practice guidelines in the evaluation and management of concussions in New England EDs. Knowledge translational efforts will be critical to improve concussion management in the ED setting.

Olfactory Function and Associated Clinical Correlates in Former National Football League Players.

Professional American football players incur thousands of repetitive head impacts (RHIs) throughout their lifetime. The long-term consequences of RHI are not well characterized, but may include olfactory dysfunction. RHI has been associated with changes to brain regions involved in olfaction, and olfactory impairment is common after traumatic brain injury. Olfactory dysfunction is a frequent early sequelae of neurodegenerative diseases (e.g., Alzheimer's disease), and RHI is associated with the neurodegenerative disease, chronic traumatic encephalopathy (CTE). We examined olfaction, and its association with clinical measures, in former National Football League (NFL) players. Ninety-five former NFL players (ages 40-69) and 28 same-age controls completed a neuropsychological and neuropsychiatric evaluation as part of a National Institutes of Health-funded study. The Brief Smell Identification Test (B-SIT) assessed olfaction. Principal component analysis generated a four-factor structure of the clinical measures: behavioral/mood, psychomotor speed/executive function, and verbal and visual memory. Former NFL players had worse B-SIT scores relative to controls (p = 0.0096). A B-SIT cutoff of 11 had the greatest accuracy (c-statistic = 0.61) and specificity (79%) for discriminating former NFL players from controls. In the former NFL players, lower B-SIT scores correlated with greater behavioral/mood impairment (p = 0.0254) and worse psychomotor speed/executive functioning (p = 0.0464) after controlling for age and education. Former NFL players exhibited lower olfactory test scores relative to controls, and poorer olfactory test performance was associated with worse neuropsychological and neuropsychiatric functioning. Future work that uses more-comprehensive tests of olfaction and structural and functioning neuroimaging may improve understanding on the association between RHI and olfaction.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

Cavum Septi Pellucidi in Symptomatic Former Professional Football Players.

Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho = 0.98; Intraclass Correlation Coefficient [ICC] 0.99; p < 0.0001; septum length: rho = 0.93; ICC 0.96; p < 0.0001). For presence versus absence of CSP, there was high agreement (Cohen kappa = 0.83, p < 0.0001). A higher rate of CSP, a greater length of CSP, as well as a greater ratio of CSP length to septum length was found in symptomatic former professional football players compared with athlete controls. In addition, a greater length of CSP was associated with decreased performance on a list learning task (Neuropsychological Assessment Battery List A Immediate Recall, p = 0.04) and decreased test scores on a measure of estimate verbal intelligence (Wide Range Achievement Test Fourth Edition Reading Test, p = 0.02). Given the high prevalence of CSP in neuropathologically confirmed CTE in addition to the results of this study, CSP may serve as a potential early in vivo imaging marker to identify those at high risk for CTE. Future research is needed to investigate the pathomechanism underlying the development of CSP after repetitive head impacts, and its potential association with neuropathologically confirmed CTE.

Age at First Exposure to Football Is Associated with Altered Corpus Callosum White Matter Microstructure in Former Professional Football Players.

Youth football players may incur hundreds of repetitive head impacts (RHI) in one season. Our recent research suggests that exposure to RHI during a critical neurodevelopmental period prior to age 12 may lead to greater later-life mood, behavioral, and cognitive impairments. Here, we examine the relationship between age of first exposure (AFE) to RHI through tackle football and later-life corpus callosum (CC) microstructure using magnetic resonance diffusion tensor imaging (DTI). Forty retired National Football League (NFL) players, ages 40-65, were matched by age and divided into two groups based on their AFE to tackle football: before age 12 or at age 12 or older. Participants underwent DTI on a 3 Tesla Siemens (TIM-Verio) magnet. The whole CC and five subregions were defined and seeded using deterministic tractography. Dependent measures were fractional anisotropy (FA), trace, axial diffusivity, and radial diffusivity. Results showed that former NFL players in the AFE <12 group had significantly lower FA in anterior three CC regions and higher radial diffusivity in the most anterior CC region than those in the AFE ≥12 group. This is the first study to find a relationship between AFE to RHI and later-life CC microstructure. These results suggest that incurring RHI during critical periods of CC development may disrupt neurodevelopmental processes, including myelination, resulting in altered CC microstructure.

Age of first exposure to football and later-life cognitive impairment in former NFL players.

OBJECTIVE: To determine the relationship between exposure to repeated head impacts through tackle football prior to age 12, during a key period of brain development, and later-life executive function, memory, and estimated verbal IQ. METHODS: Forty-two former National Football League (NFL) players ages 40-69 from the Diagnosing and Evaluating Traumatic Encephalopathy using Clinical Tests (DETECT) study were matched by age and divided into 2 groups based on their age of first exposure (AFE) to tackle football: AFE <12 and AFE ≥12. Participants completed the Wisconsin Card Sort Test (WCST), Neuropsychological Assessment Battery List Learning test (NAB-LL), and Wide Range Achievement Test, 4th edition (WRAT-4) Reading subtest as part of a larger neuropsychological testing battery. RESULTS: Former NFL players in the AFE <12 group performed significantly worse than the AFE ≥12 group on all measures of the WCST, NAB-LL, and WRAT-4 Reading tests after controlling for total number of years of football played and age at the time of evaluation, indicating executive dysfunction, memory impairment, and lower estimated verbal IQ. CONCLUSIONS: There is an association between participation in tackle football prior to age 12 and greater later-life cognitive impairment measured using objective neuropsychological tests. These findings suggest that incurring repeated head impacts during a critical neurodevelopmental period may increase the risk of later-life cognitive impairment. If replicated with larger samples and longitudinal designs, these findings may have implications for safety recommendations for youth sports.

Clinical presentation of chronic traumatic encephalopathy.

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.