ARTICLE IN BRIEF
An independent postmortem analysis of the brain of NFL linebacker Junior Seau by NIH neuropathologists found signs of chronic traumatic encephalopathy — with clusters of NFTs and scattered glial tangles in the neocortex, primarily involving the sulcal depths. Some clusters in the frontal, superior temporal cortex had an angiocentric pattern, while a superficial cortical layer predominance of NFTs was found in some neocortical sections.
JUNIOR SEAU, who pla...Image Tools
The brain of a professional football player who committed suicide last year had signs of multifocal tauopathy consistent with chronic traumatic encephalopathy, or CTE, according to the National Institutes of Health (NIH).
The NIH invited an independent group of outside experts to examine tissue samples from three unidentified brains, including that of former National Football League player Junior Seau, who killed himself with a gunshot wound to the chest in May, 2012. In the blinded review, the panel confirmed a diagnosis of CTE earlier made by two neuropathologists at the National Institute of Neurological Disorders and Stroke (NINDS).
The 43-year-old linebacker, who retired in 2010 after playing 20 professional seasons, had reportedly exhibited marked personality changes for months prior to his suicide, including depression, irritability, and attention problems.
CTE is characterized by the accumulation of tau protein deposits in the form of neurofibrillary tangles (NFTs), glial tangles, and neuropil threads in the brain, which eventually kill brain cells. In later stages, CTE can result in atrophy and loss of brain weight. Tau NFTs also occur in patients with Alzheimer's disease and other neurodegenerative disorders, including Parkinson disease (PD).
According to the NIH report, Seau's brain showed clusters of NFTs and scattered glial tangles in the neocortex, primarily involving the sulcal depths. Some clusters in the frontal, superior temporal cortex had an angiocentric pattern, while a superficial cortical layer predominance of NFTs was found in some neocortical sections. (For additional findings see “Junior Seau: Brain Autopsy Results.”)
This regional brain distribution of NFTs is unique to CTE, and distinguishes it from other brain disorders.
Russell Lonser, MD, chair of neurological surgery at Ohio State University in Columbus, and immediate past chief of surgical neurology at NINDS, coordinated the independent review. He told Neurology Today in a telephone interview that it marks the first time NINDS has specifically examined CTE in an athlete's brain tissue and had the results corroborated in a blinded fashion by outside neuropathologists.
“We were surprised by the results, but I can say they were not unexpected. There is a lot more we need to know. Now NINDS will compare imaging results with the histological findings to see if there is any correlation.”
In recent years, CTE has been diagnosed in a number of deceased professional football players and other athletes in high-contact sports, as well as combat veterans exposed to repeated blasts in Iraq and Afghanistan.
CTE has been also been found in individuals who experienced only subconcussive blows, suggesting that prolonged and repeated exposure to mild forms of brain trauma may be sufficient to trigger CTE in some individuals, according to Ann McKee, MD, professor of neurology and pathology and co-director of Boston University School of Medicine's Center for the Study of Traumatic Encephalopathy (CSTE) at Bedford Veterans Administration Medical Center, in Boston.
The CTSE maintains the largest repository of brains for CTE, with some 100 donated brains and tissue samples, including several dozen from deceased athletes.
In a December study published online ahead of print in the journal Brain, Dr. McKee and her colleagues reported the largest case series of CTE to date, with results from 68 athletes and blast-exposed military veterans, including 50 professional, college, and high school football players.
Dr. McKee, who also directs the neuropathology service at the New England VA Medical Centers, told Neurology Today in an telephone interview that signs of CTE have been identified in 80 percent of athletes' brains, and that 89 percent of individuals had clinical symptoms involving cognition, behavior, or mood before their death.
Several other professional football players who committed suicide were later found to have had CTE, including NFL players Dave Duerson in 2011, Andre Waters in 2006, and Owen Thomas, a 21-year-old University of Pennsylvania player who killed himself in 2010.
Based on neuropathological findings, medical records, and information provided by families, Dr. McKee and colleagues have developed a CTE rating scale, dividing the disease into four pathological stages: stage I) headaches and issues related to attention and concentration are common; stage 2) depression, explosivity and short-term memory impairment; stage 3) cognitive impairment and problems with executive functions, specifically planning, organization, multitasking and judgment; stage 4) full-blown dementia.
According to Dr. McKee's interpretation of the autopsy report, Junior Seau had “at least” stage 2 disease.
“We do not know how early in a player's life the first changes start taking place with CTE, but the earliest we have seen is in one player who was 17 years old, and another who was 18,” she said.
While CTE appears to slowly progress in most persons, it may not progress or may not progress at the same rate in everyone, she said. And whether or not CTE might be halted and/or reversed if caught in its early stages remains one of the biggest questions facing researchers.
“Giving the central nervous system time to recover might help early on because tau phosphorylation is a dynamic process that can be reversed, but once a patient reaches a certain threshold it most likely cannot be undone,” she said.
LITTLE KNOWN ABOUT CAUSE
Perhaps the most important aspect of the NIH report is that it confirms CSTE's work, commented Patrick Lyden, MD, Carmen and Louis Warschaw chair in neurology and director of the stroke program at Cedars-Sinai Medical Center in Los Angeles.
“Most of the CTE work has been done at this one center, so it is reassuring now to have independent confirmation, but we still know very little about the cause or prevention of CTE, or even if it is an actual risk in football,” he told Neurology Today in a telephone interview.
CTE research is in a very early stage, and the relationship between the multifocal tauopathy form of CTE and cognitive symptoms, or whether and how the disorder progresses to more extensive brain degeneration, remains unclear, he noted. Although CTE has been found in brains of athletes who had no history of concussion, it is not known if they, like Seau, simply continued playing after milder head injuries.
One thing most had in common, however, were signs of cognitive impairment and personality changes, especially symptoms of depression, he said.
“I don't think you can escape the fact that there is a disorder — it's real and can occur after multiple concussions, blast injuries, and other brain trauma over time. But we still don't have a common denominator, or know how many people will develop it. Whether or not there is a genetic susceptibility component is a big question that needs exploration.”
The increasing body of CTE evidence in high-profile athletes will hopefully result in more funding for research, commented Jeffrey Cummings, MD, the Andrea and Joseph Hahn chair of neurotherapeutics at the Neurological Institute of Cleveland Clinic, and director of Cleveland Clinic's Lou Ruvo Center for Brain Health, in Las Vegas, NV.
“We need to look for predictive strategies — how much head trauma might be acceptable in professional athletics, what are the early signs of CTE and when to recommend interruption of players' careers,” he said. “Also, whether there are any strategies or therapeutics that might help prevent or reduce risk and progression of damage.”
That signs of CTE have been found in much younger players suggests that the disorder may begin much earlier than previously thought, he also told Neurology Today.
“What we have is essentially an evolving series of observations, with a higher rate of early onset dementia in CTE cases and development of cognitive symptoms in the mid-50s, earlier than typically is seen in Alzheimer disease. CTE can also lead to symptoms of ALS and Parkinson disease.”
New data suggest that tauopathies, like prion disorders, involves specific cell-to-cell interplay in order to spread through the brain, he noted.
“Finding ways to prevent this spread may be one therapeutic approach. Cell-to-cell transfer offers an opportunity to find disease vulnerability, and there are a number of drugs under development targeting tau because of its role in Alzheimer disease.”
JUNIOR SEAU: BRAIN AUTOPSY RESULTS
DR. JEFFREY CUMMINGS...Image Tools
DR. RUSSELL LONSER s...Image Tools
* Adult six layer cytoarchitectonics in the neocortex.
* A region in left frontal lobe with focal rarefaction (pallor) of white matter with a few foci of hemosiderin around blood vessels, with a mild accompanying gliosis.
* No appreciable neuronal loss seen.
* No Lewy bodies or amyloid deposits.
* Sections from the cerebellum and medulla were unremarkable.
* The subcortical white matter showed mild generalized pallor.
* Pigmented neurons in the substantia nigra and locus cerulei did not show depopulation, but several globoid neurofibrillary tangles in intact neurons were identified.
* Occasional NFTs were identified in the CA4 sector of the hippocampus, pyriform and insular cortex, nucleus accumbens, basal forebrain, hypothalamus, midbrain and pons.
* No neuritic (senile) plaques were observed in the neocortex.
FOR FURTHER READING:
• McKee AC, Stein TD, Cantu RC. The spectrum of disease in chronic traumatic encephalopathy. Brain 2012; E-pub 2012 Dec. 2.
• Stern RA, Riley DO, Daneshvar DH, et al. Long-term consequences of repetitive brain trauma: Chronic traumatic encephalopathy. PMR 2011;3:S460–467.
• Omalu B, Hammers JL, Bailes J, et al. Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg Focus
• Daneshvar DH, Nowinski CJ, Cantu RC, et al. The epidemiology of sport-related concussion. Clin Sports Med 2011;30:1-17.
• Omalu B, Bailes J, Fitzsimmons RP, et al. Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: the role of the forensic pathologist. Am J Forensic Med Pathol 2010;2:130–132.
• McKee AC, Cantu RC, Nowinski CJ. Chronic traumatic encephalopathy in athletes: Progressive tauopathy following repetitive head injury. J Neuropath Exp Neurol
2009; 68(7): 709–735.
• Cantu RC. Chronic traumatic encephalopathy in the National Football League. Neurosurgery 2007;2:223–225.