Julie M. Stamm

Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.

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.

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

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.

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.

Clinical Practices in Collegiate Concussion Management

Background: In recent years, sports leagues and sports medicine experts have developed guidelines for concussion management. The extent to which current clinical practice is consistent with guideline recommendations is unclear. At the collegiate level, there have been few examinations of concussion management practices and the extent to which meaningful differences across divisions of competition exist. Purpose: The purposes of this study were to (1) examine current practices in concussion diagnosis and management at National Collegiate Athletic Association (NCAA) member colleges, (2) explore the extent to which current practices reflect current recommendations for concussion diagnosis and management, and (3) determine whether there are differences in management patterns across divisions of competition. Design: Descriptive epidemiology study. Methods: An electronic questionnaire was sent to sports medicine clinicians at all NCAA member colleges during September and October 2013. Clinicians were asked about baseline assessments, diagnosis and management practices, return-to-play protocols, the perceived prevalence of underdiagnosis, and basic demographic information. Results: Approximately 30% (n = 866) of contacted clinicians, representing nearly 50% (n = 527) of NCAA member colleges, responded to the questionnaire. Preparticipation baseline examinations were administered at the majority of schools (95%), but most (87.5%) administered baseline assessments only to selected high-risk athletes. Computerized neurocognitive testing and balance assessments were most commonly used as preseason baseline and postinjury assessments. Multimodal examination in line with NCAA and other guidance was used only at a minority of institutions. Athletic trainers most commonly administered and interpreted the preseason baseline examination. Most clinicians reported that their institutions’ practices were in line with NCAA guidelines during the first 24 hours of an athlete’s concussion diagnosis, with exact percentages varying across measures. Differences across divisions of competition included shorter return-to-play time at Division I schools than Division III schools (9.13 vs 10.31 days, respectively) and more frequently referring concussed athletes to a physician within 24 hours of diagnosis at Division I schools. Conclusion: Concussion management at many colleges in the United States incorporates elements recommended by current guidelines; however, there is room to improve. Increasing the use of a multimodal baseline and postinjury examination will elevate the concussion care provided to college athletes and better align with best practice guidance.

Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes

Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19–3.91; MI, 2.10,1.17–3.76; CES-D, 3.08,1.65–5.76; AES, 2.39,1.32–4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76–0.97) and CES-D (OR, 95% CI: 0.85, 0.74–0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.

Differing Patterns of Altered Slow-5 Oscillations in Healthy Aging and Ischemic Stroke

The ‘default-mode’ network (DMN) has been investigated in the presence of various disorders, such as Alzheimer’s disease and Autism spectrum disorders. More recently, this investigation has expanded to include patients with ischemic injury. Here, we characterized the effects of ischemic injury in terms of its spectral distribution of resting-state low-frequency oscillations and further investigated whether those specific disruptions were unique to the DMN, or rather more general, affecting the global cortical system. With 43 young healthy adults, 42 older healthy adults, 14 stroke patients in their early stage (<7 days after stroke onset), and 16 stroke patients in their later stage (between 1 to 6 months after stroke onset), this study showed that patterns of cortical system disruption may differ between healthy aging and following the event of an ischemic stroke. The stroke group in the later stage demonstrated a global reduction in the amplitude of the slow-5 oscillations (0.01–0.027 Hz) in the DMN as well as in the primary visual and sensorimotor networks, two ‘task-positive’ networks. In comparison to the young healthy group, the older healthy subjects presented a decrease in the amplitude of the slow-5 oscillations specific to the components of the DMN, while exhibiting an increase in oscillation power in the task-positive networks. These two processes of a decrease DMN and an increase in ‘task-positive’ slow-5 oscillations may potentially be related, with a deficit in DMN inhibition, leading to an elevation of oscillations in non-DMN systems. These findings also suggest that disruptions of the slow-5 oscillations in healthy aging may be more specific to the DMN while the disruptions of those oscillations following a stroke through remote (diaschisis) effects may be more widespread, highlighting a non-specificity of disruption on the DMN in stroke population. The mechanisms underlying those differing modes of network disruption need to be further explored to better inform our understanding of brain function in healthy individuals and following injury.

Age of first exposure to football and later-life cognitive impairment in former NFL playersAuthor Response

Editors’ Note: The study “Age of first exposure to football and later-life cognitive impairment in former NFL players” raised several concerns among Neurology® readers. Maroon et al. pointed out methodologic limitations, Andrikopoulos raised questions about inaccuracies in definitions and references cited, and Larrabee et al. suggested that premorbid impairments may have been misinterpreted as brain injury effects. The authors of the study answer those inquiries in detail, acknowledging some of the limitations while rebutting others. They also point out that this is a preliminary study and encourage future research on this important issue. —Chafic Karam, MD, and Robert C. Griggs, MD

Brain-Computer Interface Training after Stroke Affects Patterns of Brain-Behavior Relationships in Corticospinal Motor Fibers

Background: Brain–computer interface (BCI) devices are being investigated for their application in stroke rehabilitation, but little is known about how structural changes in the motor system relate to behavioral measures with the use of these systems. Objective: This study examined relationships among diffusion tensor imaging (DTI)-derived metrics and with behavioral changes in stroke patients with and without BCI training. Methods: Stroke patients (n = 19) with upper extremity motor impairment were assessed using Stroke Impact Scale (SIS), Action Research Arm Test (ARAT), Nine-Hole Peg Test (9-HPT), and DTI scans. Ten subjects completed four assessments over a control period during which no training was administered. Seventeen subjects, including eight who completed the control period, completed four assessments over an experimental period during which subjects received interventional BCI training. Fractional anisotropy (FA) values were extracted from each corticospinal tract (CST) and transcallosal motor fibers for each scan. Results: No significant group by time interactions were identified at the group level in DTI or behavioral measures. During the control period, increases in contralesional CST FA and in asymmetric FA (aFA) correlated with poorer scores on SIS and 9-HPT. During the experimental period (with BCI training), increases in contralesional CST FA were correlated with improvements in 9-HPT while increases in aFA correlated with improvements in ARAT but with worsening 9-HPT performance; changes in transcallosal motor fibers positively correlated with those in the contralesional CST. All correlations p < 0.05 corrected. Conclusion: These findings suggest that the integrity of the contralesional CST may be used to track individual behavioral changes observed with BCI training after stroke.

Recovery of slow-5 oscillations in a longitudinal study of ischemic stroke patients

Functional networks in resting-state fMRI are identified by characteristics of their intrinsic low-frequency oscillations, more specifically in terms of their synchronicity. With advanced aging and in clinical populations, this synchronicity among functionally linked regions is known to decrease and become disrupted, which may be associated with observed cognitive and behavioral changes. Previous work from our group has revealed that oscillations within the slow-5 frequency range (0.01–0.027 Hz) are particularly susceptible to disruptions in aging and following a stroke. In this study, we characterized longitudinally the changes in the slow-5 oscillations in stroke patients across two different time-points. We followed a group of ischemic stroke patients (n = 20) and another group of healthy older adults (n = 14) over two visits separated by a minimum of three months (average of 9 months). For the stroke patients, one visit occurred in their subacute window (10 days to 6 months after stroke onset), the other took place in their chronic window (> 6 months after stroke). Using a mid-order group ICA method on 10-minutes eyes-closed resting-state fMRI data, we assessed the frequency distributions of a components representative time-courses for differences in regards to slow-5 spectral power. First, our stroke patients, in their subacute stage, exhibited lower amplitude slow-5 oscillations in comparison to their healthy counterparts. Second, over time in their chronic stage, those same patients showed a recovery of those oscillations, reaching near equivalence to the healthy older adult group. Our results indicate the possibility of an eventual recovery of those initially disrupted network oscillations to a near-normal level, providing potentially a biomarker for stroke recovery of the cortical system. This finding opens new avenues in infra-slow oscillation research and could serve as a useful biomarker in future treatments aimed at recovery.