Significant Research Findings
|Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury
Dr. Ann McKee reviewed 48 cases of neuropathologically-verified CTE recorded in the literature and documented the findings of CTE in three professional athletes. This was the first paper ever published by the Boston University CTE Center.
Prior to 2009, the precise immunohistochemical and pathological characterization of CTE had never been described and there was no rigorous compilation of the clinical and demographic findings. This manuscript was the first to report that the pathology of CTE was distinctive and consisted of an irregular accumulation of phosphorylated tau pathology in a perivascular and irregular pattern at the depths of the cortical sulci. Dr. Ann McKee and the CTE Center team also described the involvement of the medial temporal lobe in later stages of the disease with prominent involvement of the brainstem and deep cholinergic nuclei. The neurodegeneration was latent; occurring 8-10 years after the last trauma, was very typically slowly progressive (as long as 40 years), with prominent behavioral and personality changes in addition to cognitive changes and memory loss.
This paper marked the beginning of a worldwide upsurge of interest in the chronic effects of repetitive head impacts. Although there had been several previous case reports of CTE in the literature, this was the first major academic publication that established CTE as a distinct tauopathy. The manuscript has been cited more than 1,700 times and is the most cited and the most viewed manuscript at J Neuropath Exp Neurol.
|TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy
Dr. Ann McKee led a study that examined 12 cases of CTE. They found widespread TAR DNA-binding protein of approximately 43kd (TDP-43) affecting various brain regions in 10 of the 12 brains examined. This paper was the first to suggest that repetitive head trauma experienced through contact and collision sports may be associated with motor neuron disease (MND) development.
|Chronic Traumatic Encephalopathy in blast exposed military veterans and blast neurotrauma mouse model
Dr. Lee E. Goldstein examined a case series of postmortem brains from US military veterans exposed to blast and/or concussive injuries, finding evidence of CTE similar to that found in American football players and a former professional wrestler. Dr. Goldstein and his team developed a blast neurotrauma mouse model recapitulating CTE neuropathology in mice, further highlighting the determinants of CTE and providing evidence linking blast exposure to neurophysiological impairment.
|The Spectrum of Disease in Chronic Traumatic Encephalopathy
Led by Dr. Ann McKee, this paper described the McKee staging scheme for CTE pathology. Analyzing a cohort of 85 brain donors exposed to repetitive head impacts (RHI), Dr. McKee and researchers developed a progressive staging scheme for CTE on a I-IV scale, with each increasing stage corresponding to more severe and widespread pathology. The paper also described clinical symptoms commonly observed in brain donors exposed to RHI.
|Clinical Subtypes of Chronic Traumatic Encephalopathy: Literature Review and Proposed Research Diagnostic Criteria for Traumatic Encephalopathy Syndrome
Led by Drs. Philip Montenigro and Robert Stern, this paper proposed research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE. Reviewing the literature of clinical symptomatology in 202 published cases of clinically-suggestive CTE, the authors proposed four variants of TES, as well as classifications of “possible” or “probable” CTE. These criteria were not intended to be used for clinical diagnosis, rather as fluid research criteria meant to be modified in conjunction with new research.
|Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study
Dr. Mez and colleagues described the methodology for the UNITE study, a U01 project funded by the NINDS. The researchers aimed to examine the brains and spinal cords of 300 RHI-exposed subjects over a four-year period. Ultimately, the authors’ goal was to investigate the validity of clinical criteria for CTE using validated neuropathological criteria, and to use statistical modeling to identify features predicting CTE pathology.
|The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy
Dr. McKee and a panel of neuropathologists convened to blindly review 25 cases of various tauopathies, using preliminary neuropathological criteria. They found that there was good agreement between reviewers who diagnosed the cases, and very good agreement between reviewers and the diagnosis of CTE. The panel of neuropathologists defined the primary and supportive features of CTE neuropathologically, and developed recommendations for the future development of validated neuropathological criteria for CTE.
|Clinicopathological Evaluation of Chronic Traumatic Encephalopathy In Players of American Football
Led by Drs. Jesse Mez and Dan Daneshvar, the authors examined a case series of 202 former American football players, finding CTE in 99% of the NFL players studied, 91% of the college football players, and 21% of the high school players. This paper received widespread global attention as it put a spotlight on the burgeoning research into the issue of CTE in football players.
|Age of first exposure to tackle football and chronic traumatic encephalopathy
Dr. Michael Alosco and colleagues studied a sample of 246 former American football players, examining the relationship between the age at which brain donors started playing football, with CTE severity and age of symptom onset. The authors found that a younger age of first exposure to football play was not associated with CTE severity, but it did predict earlier neurobehavioral symptom onset, suggesting that earlier exposure to football play may reduce resiliency to pathology later in life.
|Duration of American Football Play and Chronic Traumatic Encephalopathy
Led by Dr. Jesse Mez, this study found associations between years of American football play and CTE. Mez and colleagues concluded that the odds of developing CTE double for every 2.6 years of football played. These findings held even after accounting for any possible brain bank selection bias.
|Validity of the 2014 Traumatic Encephalopathy Syndrome Criteria for CTE Pathology
Drs. Ann McKee, Jesse Mez, and colleagues described the application of TES criteria in 336 brain donors to the UNITE Brain Bank. The 2014 TES criteria proved to be highly sensitive to CTE pathology, with relatively low specificity. Presence of cognitive symptoms was associated with CTE pathology, making the inclusion of cognitive symptoms in revised TES criteria a possible means to improve CTE pathology prediction.
|Characterizing Tau Deposition in Chronic Traumatic Encephalopathy (CTE): Utility of the McKee CTE Staging Scheme
Drs. Ann McKee, Michael Alosco, Jonathan Cherry, and colleagues published this paper which outlined and validated the 2013 McKee staging scheme for CTE pathology in 366 male brain donors exposed to RHI from the UNITE Brain Bank. The findings lent additional support to the application of the McKee staging scheme for CTE and highlighted the regional distribution of phosphorylated tau in CTE.
|National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome
A panel of 20 clinician-scientists across diverse medical specialties participated in a consensus meeting to review the predictive validity data on clinical features of traumatic encephalopathy syndrome in a study of 298 brain donors. The panel ultimately developed new consensus diagnostic criteria for TES for use in future CTE research.
|The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy
A consensus panel reconvened a year after the initial 2015 meeting to review and refine the preliminary criteria for the neuropathological diagnosis of CTE. Eight neuropathologists reviewed 27 tauopathy cases, leading to a significant association between the raters and CTE diagnosis for both blinded and unblinded rounds of scoring. The panel proposed a protocol for a minimum threshold for diagnosis of CTE, and an algorithm assessing CTE severity as either “low” or “high”.
|Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts
The authors investigated neuropathologic correlates of antemortem white matter hyperintensities (WMH) in brain donors exposed to repetitive head impacts (RHI), visualized on routine MRI scans. They found an association between years of American football play and greater volume of WMH independent of p-tau severity and vascular risk factors such as smoking, hypertension, diabetes, and sleep apnea. The authors concluded that WMH may be capturing long-term white matter pathologies caused by RHI exposure, necessitating future imaging studies to better understand this relationship.
Alyssa Phelps and colleagues surveyed a cohort of 447 former Notre Dame football players in an effort to estimate the prevalence of self-reported health conditions among former college football players as compared with a sample of men in the general population. Former players were found to have a higher prevalence of cognitive impairment, cardiovascular disease, and other outcomes, but a lower prevalence of diabetes and all-cause mortality. Given the findings of both positive and negative health outcomes, the authors concluded that additional research is necessary to better maximize factors improving health outcomes and minimize factors increasing risk for worse long-term outcomes.
|Association of APOE Genotypes and Chronic Traumatic Encephalopathy
This cross-sectional genetic association study examined a cohort of brain donors in the UNITE Brain Bank. The authors tested associations of at least one APOEε4 or APOEε2 allele with several outcomes of interest. They found that amongst older donors, the presence of at least one APOEε4 allele was associated with CTE severity and tau burden across several primary brain regions of interest. These findings suggest that APOEε4 may confer greater risk for worse outcomes clinically and neuropathologically among older brain donors exposed to RHI.
|White matter hyperintensities in former American football players
The authors examined white matter hyperintensities (WMH) in a cohort of football players and asymptomatic, unexposed, living male participants as part of the DIAGNOSE CTE Research Project. Using MRI and neuropsychological testing scores, they found that older male football players had higher levels of WMH across the frontal, temporal, and parietal lobes, as compared to the unexposed asymptomatic men; higher WMH burden was associated with poorer executive functioning and verbal memory.
|Associations between near end-of-life flortaucipir PET and post-mortem CTE-related tau neuropathology in six former American Football Players
Researchers studied three former National Football League (NFL) players and three collegiate football players who had flortaucipir and florbetapir PET prior to death. They were then evaluated postmortem for the presence of CTE. They found four of the six were autopsy confirmed CTE and three of these four had met the criteria for traumatic encephalopathy syndrome (TES). One of the players without autopsy confirmed CTE also met the criteria for TES. Researchers concluded that flortaucipir–PET could be useful in detecting high-stage CTE in living persons, although off–target flortaucipir binding in the hippocampus and thalamus can affect the interpretation of testing.
|Tau Pathology in Chronic Traumatic Encephalopathy is Primarily Neuronal
Researchers studied 150 individuals with autopsy confirmed CTE and no comorbid pathologies. Significantly more neuronal p-tau than astrocytic p-tau was found across all cortical regions tested. These findings support the hypothesis that neuronal degeneration is a driving feature of CTE and will help inform future research and the development of fluid biomarkers for the detection of neuronal degeneration in CTE.
Dr. Daniel Daneshvar and colleagues created a positional exposure matrix (PEM) utilizing football helmet sensor data to estimate lifetime repetitive head impact exposure (RHI). They found that along with duration of play, PEM-derived measures such as lifetime exposure to linear (CHII-G) and rotational (CHII-R) acceleration classified CTE status and severity. In fact, the authors found that these PEM-derived measures proved to be better classifiers of CTE status and severity than duration of play.