AANS Neurosurgeon : Features

Volume 20, Number 1, 2011

Inside Sports-Related Head Injuries

Tau Inclusion Bodies and Proteins in a Tangle

Lawrence S. Chin, MD, Mayur Jayarao, MD, and Robert C. Cantu, MD

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Memory loss. Moodiness. Increasingly erratic and sometimes overly aggressive behavior. Speech difficulties. Movement disorders like tremors and gait disturbances. Eventually,  dementia. These symptoms could describe Alzheimer’s disease, an illness that is becoming increasingly well-known to the public as a disease of older adults. But when the symptomatic person is younger and an athlete, the illness could be chronic traumatic encephalopathy, CTE.

CTE apparently is what 1987 NFL Man of the Year Award-winner Dave Duerson feared before his suicide early this year. The 50-year-old former Chicago Bears safety who died of a self-inflicted gunshot wound to the chest left a note asking that his brain be “given to the NFL’s brain bank.” The reference is to the brain bank registry at Boston University Center for the Study of Traumatic Encephalopathy, CSTE.

Stained whole brain section with immuno- staining for tau protein. Note the preferred deposition in the mesial temporal lobe structures.
Through his work with the football players union, Duerson probably had become aware of CTE and other cases of retired players who had suffered from CTE-like symptoms. For example, Michael Lewis Webster, Justin Strzelczyk, and Terry Long, all of the Pittsburgh Steelers, Andre Waters of the Philadelphia Eagles, Chris Henry of the Cincinnati Bengals, and Tom McHale of the Tampa Bay Buccaneers all died after years of strange, erratic and sometimes overly aggressive behavior.

In 2008 John Grimsley, a former NFL linebacker for the Houston Oilers and Miami Dolphins, died at age 45 from a gunshot wound to the chest. He was thought to have been cleaning his rifle and the authorities ruled his death an accident, despite the fact that he was an excellent marksman. Subsequent microscopic analysis of his cerebral cortex by McKee and colleagues at Boston University CSTE demonstrated evidence of tau-positive inclusion bodies and neurofibrillary tangles. In conjunction with clinicopathological features of several other cases, tau-positive inclusion bodies and neurofibrillary tangles have become established as the hallmarks of chronic CTE.

Chronic Traumatic Encephalopathy: Symptoms and Pathophysiology
CTE, originally described by Martland in 1928, is believed to result from repetitive, often minor head trauma. It manifests initially with affective disturbances and short-term memory loss followed by increasingly erratic behavior, speech and gait difficulties, and finally dementia.

Although in CTE tau protein is diffusely distributed throughout the brain, the regions that tau protein most affects are the mesial temporal lobe, entorhinal cortex, amygdala and hippocampus. Areas less involved include the frontal, subfrontal, subcallosal, olfactory bulb, hypothalamus, mamillary bodies, substantia nigra and other brainstem nuclei. This tau distribution, which shows preference for the limbic system, provides an anatomical basis for some of the striking psychological changes seen in CTE sufferers. The tau deposition is typically perivascular in pattern and seen most densely in the superficial cortical laminae I–III. Interestingly, although the tau protein in CTE is histologically identical to that found in Alzheimer’s disease, the two diseases differ in that β-amyloid is not a consistent and never a prominent feature in CTE. Also, the tau in Alzheimer’s disease is most dense in the deeper cortical laminae IV–V. A point of convergence among Alzheimer’s disease, traumatic brain injury and CTE is the increased prevalence of ApoE ε4 allele carriers in each of these diseases, although its prevalence is less well-established in CTE.

Recent findings indicate that the brain may not be the only site of injury in CTE. A study by McKee and colleagues of Boston University CSTE suggests that tau protein deposition may provide a link between CTE and some cases of sporadic amyotrophic lateral sclerosis, which has been associated with previous head injuries. Three athletes with CTE and motor neuron disease characterized by weakness, atrophy, spasticity and fasciculations were found to have tau protein deposits, TDP-43, in the brain and spinal cord with axonal loss in the corticospinal tracts and medullary pyramids as well as loss of anterior horn cells. While the exact function of TDP-43 is unknown, it is widely expressed and likely is involved in multiple biological processes by binding with DNA, RNA and other proteins. TDP-43 overexpression has been demonstrated to cause neurodegeneration and cell death, both in vitro and in vivo. One hypothesis suggests that mild traumatic brain injury causes an axonal shear injury and cytoskeletal disruption leading to reorganization of neurofilament proteins. TDP-43 is upregulated and binds to neurofilament mRNA in order to stabilize the transcript and mediate the injury response. This upregulation of tau causes protein aggregation, however, and then inclusion body formation, neurofibrillary tangles and, ultimately, neuronal death.

Younger Athletes and Others at Risk
CTE at first was considered a disease of older athletes, but recent studies also have identified it in younger athletes. In 2009 a study commissioned by the NFL and conducted by the University of Michigan Institute for Social Research on 1,063 retired NFL athletes found that 6.1 percent of athletes 50 and older reported that they had received a dementia-related diagnosis; this rate is five times higher than the national average of 1.2 percent. Importantly, those age 30 through 49 showed a rate of 1.9 percent, or 19 times that of the national average (0.1 percent).

In 2010 Owen Thomas, a 21-year-old football player at the University of Pennsylvania, committed suicide by hanging. He subsequently was diagnosed with CTE. Pathological evidence of CTE also has been found in an 18-year-old high school football athlete who had sustained multiple concussions. With more than a million teenagers competing in football every year, the risk of CTE looms as a potential public health disaster.

However, CTE is not unique to football. More than 30 cases of CTE in athletes competing in other sports such as boxing, ice hockey, soccer, and wrestling have been identified. This group notably includes former professional wrestlers Chris Benoit and Andrew Martin as well as ice hockey professional Reg Fleming. Boxers may have a higher risk of developing CTE due to sustained, repetitive head blows. Suspected but not proven cases include Muhammad Ali, Jimmy Ellis, Floyd Patterson, Bobby Chacon, Wilfred Benitez, Emile Griffith, Freddie Roach and Sugar Ray Robinson. CTE also has been documented in nonathletes with repetitive head trauma including those who have suffered physical abuse, autism with head-banging behavior, or epileptic seizures, and those engaged in dangerous occupations such as a man who made his living as a clown shot from a cannon.

Taking Action
For the $8 billion-a-year NFL industry the ramifications of CTE have become obvious and urgent. During the 2009–2010 season the NFL publicly acknowledged a link between football and CTE and instituted specific return-to-play guidelines that required a concussed player to be immediately benched from any game or practice and additionally to obtain independent clearance from a neurological expert before returning to the field. Additionally, the NFL has increased public safety awareness, warning young athletes of the dangers of head trauma while simultaneously donating unrestricted funds to independent research groups for further research in CTE. One such entity is the brain bank registry created by the Boston University CSTE and the Sports Legacy Institute. The institute was founded by Robert Cantu, MD, and Chris Nowinski, a former collegiate football player and professional wrestler who retired because of postconcussive symptoms. More than 300 athletes from a variety of different sports have committed to donating their brains after death to the brain bank registry for CTE study.

While there are philosophical questions concerning head injury regulations for professional athletes, it is clear that the athletes whose interests are least protected and who are most at risk for injury are the young male and female athletes who, by virtue of their less developed physique and developing brains, are more prone to concussions and potentially to CTE. Adding to the concern are surveys that indicate a surprisingly high percentage of these young people are willing to risk permanent brain injury in exchange for a shot at athletic glory.

As neurosurgeons, we must take the lead in enforcing prudent return-to-play guidelines for athletes and continue our studies into the long-term effects of head injuries in sports. Sports-related head injuries will never be eradicated given the popularity of sports in our culture, but improved understanding of the pathophysiology of CTE may lead to preventive measures.

Lawrence S. Chin, MD, FAANS, FACS, Mayur Jayarao, MD, and Robert C. Cantu, MD, FAANS, FACS, are members of the Department of Neurosurgery, Boston University School of Medicine and Boston Medical Center, Boston, Mass. Dr. Chin is a member of the AANS Neurosurgeon Editorial Board. The authors reported no conflicts for disclosure.

For Further Information

Incidence of Catastrophic Injuries in Sports

Catastrophic injuries in sports, although rare, are tragic events. The National Center for Catastrophic Sports Injury Research defines such injuries as sport injuries that result in brain or spinal cord injury, or skull or spinal fractures.

The NCCSI subclassifies catastrophic injuries as nonfatal (permanent functional disability) or serious (transient with no functional disability). These injuries can be fatal either directly during participation in sport or indirectly due to systemic exertion while participating in sport.

During the 25-year period from 1982 to 2007, the NCCSI identified 1,068 direct catastrophic injuries in high school and college sports. Approximately 150 million high school athletes participated in sports within that 25-year period with a combined (direct and indirect) catastrophic injury rate of 0.89 per 100,000. The rate is slightly higher in college athletes, 3.81 catastrophic injuries per 100,000. For all sports, traumatic brain injury that causes intracranial hemorrhage is the leading cause of death.

While there has been a great deal of attention placed on preventing these catastrophic injuries, a silent epidemic has been growing in patients who suffer mild TBI or concussions. The CDC estimates that over 200,000 ER visits per year are for nonfatal sports-related head injuries. Other studies indicate that of high school and college football players, 5.1 percent have suffered at least one concussion each year with 14.7 percent having suffered more than one concussion during the same season. It is well recognized that these figures are underreported by a factor of five or more in football and hockey.

The true incidence of catastrophic injuries in sports is difficult to document, as are the long-term effects of mild TBI.