CTE and the NFL

Lately, professional sports leagues (mainly the NFL, but also the NHL and FIFA) have been under incredible scrutiny to protect players from concussions. The idea being that repetitive brain trauma, or concussions, could lead to Chronic Traumatic Encephalopathy (CTE). Clinically, CTE is associated with memory disturbances, behavioral and personality changes, Parkinsonism, as well as speech and gait abnormalities (McKee et al, 2010). CTE gained immense popularity when NFL Legend, Junior Seau, devastatingly committed suicide in 2012 due to cognitive changes which have been post-humously linked to CTE (Samson 2013). Sports fan may feel like every couple of months a story is released of a former athlete who recently committed suicide, with his complicated mental status being linked to the head trauma he received from his years of competing in professional sports. However, maybe these suicides aren't as common as they may seem.

In 2005, Dr. Bennet Omalu, a pathologist at the University of Pittsburgh, performed an autopsy on a deceased NFL player, Mike Webster, and described the finding of CTE (Omalu, 2005). Dr. Omalu's work would eventually be popularized in the major motion picture "Concussion". Dr. Omalu has since analyzed the brains of four other former NFL players who committed suicide (Terry Long, Justin Sterzelczyk, Andre Waters, and Tom McHale), and found a common neuropathological link between them, characterized as Chronic Traumatic Encephalopathy (Omalu, 2006). The neurodegeneration, and subsequent cognitive disturbances, in these players has been linked to their careers as professional football players, which has cast a large shadow of blame on the NFL to protect its players. 

Between 2006 and 2015, it was reported that 12 players from the NFL committed suicide. Surely, there are many people who can recall some of these incidents in the news. However, there were more confirmed suicides of NFL players in that decade than between 1946 and 2005 combined (10) (Riley, 2016). This could be attributed to several factors, one of which being that it was harder to keep track of these incidents in the past. A second being that players are bigger, faster, stronger, and can hit each other harder, resulting in more significant brain trauma. A third being the idea of an availability heuristic, which essentially says that an action becomes more common when you hear about something similar happening. This factor would place a large portion of responsibility on the media's shoulders. In all reality, it is more than likely a culmination of several factors that account for this discrepancy.

If Chronic Traumatic Encephalopathy is the result of repetitive head trauma, and CTE often leads to suicide, it would be expected that the suicide rate in NFL players would be incredibly high. However, a study looking at the cause of death for athletes with at least 5 years of experience in the NFL found the suicide rate to be two-thirds lower than the suicide rate in the general population (Baron 2012). This doesn't necessarily discredit the link between head trauma and CTE, but it begs the question: is the recent increase in suicide amongst NFL players related to CTE, or could the increase simply be the result of the Werther Effect?

The Werther Effect, is similar to the idea of an availability heuristic, but applies specifically to suicides. The term, "Werther Effect" comes from the book The Sorrow of Young Werther, in which the main character commits suicide. The publication of this book resulted in a local spike in suicides (Niederkrotenthaler, 2007). Applying this idea to the recent increase in suicide among NFL players, the publicity of CTE in NFL players, and their suicides, could subconsciously, persuade other players to follow that path. 

These suicides should serve as a reminder that, although these elite athletes are idolized and immortalized by the media and many Americans, they are subject to the same downfalls as everyone else. The cause of suicide among NFL players may be from CTE, a result of the media and the Werther Effect, or a variety of other factors and/or their combinations. Regardless, it is very clear that suicide is increasing among NFL players and is a pressing issue that needs to be addressed.

Sources:
McKee A.C., et al,: Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy following Repetitive Head Injury. J Neuropathol Exp Neurol 2010; 68(7): 709-735
Samson, K.: NFL's Junior Seau had Chronic Traumatic Encephalopathy. Neurology Today 2013; 13(4): 12-15
Omalu B.I., DeKosky S.T., Minster R.L., Kamboh M.I., Hamilton R.L., and Wecht C.H.: Chronic Traumatic Encephalopathy in a National Football League player. Neurosurgery 2005; 57: 128-134
Omalu B.I., Hamilton R.L., Kamboh M.I., DeKosky S.T., Bailes J.: Chronic Traumatic Encephalopathy (CTE) in a National Football League Player: case report and emerging medicolegal practice questions. J. Forensic Nurs 2010; 6: 40-46
Riley E.T.: Chronic Traumatic Encephalopathy and Professional Athletes: Suicides are Contagious. Neurosurgery 2016; 94: 576-577
Baron S.L., Hein M.J., Lehman E. Gersic C.M.: Body mass index, playing position, race, and cardiovascular mortality of retired professional football players. Am J Cardiol 2012; 109: 889-896
Niederkrotenthaler T., Herberth A., Sonneck G.: The Werther Effect: Legend or Reality. Neuropsychiatry 2007; 21(4): 284-290

CTE in Professional Soccer Players

A recent study has determined that former professional soccer players had pathologically confirmed CTE at death. As a former collegiate soccer player, I understand the huge amount of head impacts that may occur over a soccer player's career.  It also causes this subject to be closer to my heart, and something I will tend to follow as future research continues.

The studied looked at 14 retired soccer players with progressive cognitive impairment at an average age of 63.6 years and an average disease duration of 10 years. 12 cases died from neurodegenerative disease and  6 participants consented to have post-mortem brain examination, of which all six were determined to have septal abnormalities consistent of chronic repetitive head impacts.  Four of the 6 were confirmed pathologically to have CTE.  This finding is probably related to the numerous head impacts that soccer players can accumulate. Trauma can occur from head-to-head contact or even simply heading the ball.  An average player can head the ball 6-12 times per game and may perform more than 2000 headers during a 20-year career, in addition to heading drills in training (Spiotta, AM. et al., 2012).  Even so, the majority of head injuries in soccer are caused by head-player contact (40%) compared to head-ball (12.6%) (Boden, BP. et al., 1998).  Cognitive and brain structural changes have been reported in soccer players that have been exposed to repetitive subconcussive head impacts (Koerte, IK et al., 2012; Koerte, IK et al., 2015)

The cases in this report all played soccer in the 1980's.  These players would have been exposed to heavier balls, and a corresponding increased impact from headers.  However,  the balls played with today are lighter and move at a greater velocity.  Recent studies have found radiological findings of abnormal white matter microstructure in frequent headers of the ball (Lipton, Ml. et al., 2013) as well as in postmortem findings of CTE in a 29-year-old player with ALS (McKee AC. et al., 2014).  These results may support the idea that these lighter balls may result in the same net force on head impact

Sources
Boden BP, Kirkendall DT, Garrett WE Jr (1998) Concussion incidence in elite college soccer players. Am J Sports Med 26:238–241
Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME (2012) White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA 308:1859– 1861.
Koerte IK, Lin AP, Muehlmann M, Merugumala S, Liao H, Starr T, Kaufmann D, Mayinger M, Steffinger D, Fisch B et al (2015) Altered Neurochemistry in Former Professional Soccer Players without a History of Concussion. J Neurotrauma 32:1287–1293.
Lipton ML, Kim N, Zimmerman ME, Kim M, Stewart WF, Branch CA, Lipton RB (2013) Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology 268:850–857
McKee AC, Daneshvar DH, Alvarez VE, Stein TD (2014) The neuropathology of sport. Acta Neuropathol 127:29–51.
Spiotta AM, Bartsch AJ, Benzel EC (2012) Heading in soccer: dangerous play? Neurosurgery 70:1–11.

Neuropathological Criteria Creation (NINDS/NIBIB)

Given the controversy surrounding Chronic Traumatic Encephalopathy (CTE) and its presence (or lack thereof) of distinct neuropathologic manifestations as well as the ever increasing media attention it garners, it is unsurprising that both the National Institutes of Health and the National Football League supported a 2013 investigation to determine what, if any, unique neuropathologic criteria distinguish and define CTE as distinct from other neurodegenerative tauopathies. As mentioned in the McKee et al., 2016 article, NINDS/NIBIB called for a series of consensus panels to better define the neuropathological criteria of CTE. Assembling a team of 7 neuropathologists well versed in neurodegenerative diseases, particularly tauopathies, the consensus panel examined 25 cases of various tauopathies that included presumed diagnoses of CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The panel was blinded to any clinical or demographic information, gross neuropathological features of the brain, and the total number of each type of cases within the set of cases (McKee et al. 2016).

The objective of the study was to utilize previously established preliminary criteria for the neuropathologic diagnosis of CTE in order to determine what components would be most useful as part of a well defined system of criteria. The preliminary criteria is elucidated as follows (McKee et al., 2013):

"1. Perivascular foci of p-tau immunoreactive NFTs and ATs in the neocortex 
2. Irregular distribution of p-tau immunoreactive NFTs and ATs at the depths of cerebral sulci 
3. NFTs in the cerebral cortex located preferentially in the superficial layers (often most pronounced in temporal cortex)
4. Supportive, non-diagnostic features: Clusters of subpial ATs in the cerebral cortex, most pronounced at the sulcal depths"

In addition to these CTE preliminary criteria, neuropathologists were provided with additional well-known and supported criteria for other tauopathies to assist in making their presumptive diagnoses. Utilizing a certainty scale (1, unsure; 2, possible; 3, probable; 4, definite), neuropathologists rated their certainty for each presumptive diagnosis of the individual 25 cases. Cohen's Kappa was used as the statistical measure to analyze agreement among the neuropathologists for all of the cases both CTE and non-CTE as well as agreement between the neuropathologists in regards to those cases solely identified as having CTE. Interestingly, there was greatest agreement between neuropathologists for cases having been identified as CTE with a Cohen's kappa value of 0.78 (at the high end of good agreement). Furthermore, a second interesting result was the increase in the level of certainty after clinical features of the cases were made known to investigators (McKee et al. 2016).

Demonstrating the utility of McKee's previous preliminary criteria and the high level of agreement to which a series of neuropathologists were able to identify CTE, the consensus panel recognized a what they consider to be a pathognomonic lesion of CTE distinguishing it from other neurodegenerative disorders. "The pathognomonic lesion of CTE consists of p-tau aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at the depths of the cortical sulci (McKee et al. 2016)." The group was able to identify other supportive neuropathological features of CTE, but these features are neither necessary nor sufficient in isolation for the diagnosis of CTE.

As noted by the McKee et al., 2016, the study was limited by its relatively small sample size and use of presumptive CTE cases in later stages of disease. Future research should most certainly investigate the manner which the conclusions of this consensus study can be applied to a larger sample size and cases in which CTE is less readibly identified or at an earlier stage of progression. Given the previous inconsistency of methodological diagnostic criteria for CTE, this study should serve as a crucial cornerstone for developing a standardized methodology for identifying CTE in post-mortem cases. By effectively identifying post-mortem CTE cases with both greater precision and accuracy, researchers will be able to more effectively direct their research in to the specific pathogenic mechanisms underlying CTE development and progression. 

McKee, A.C., Cairns, N.J., Dickson, D.W. et al. Acta Neuropathol (2016) 131: 75. doi:10.1007/s00401-015-1515-z

McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. doi:10.1093/brain/ aws307

Neuropathologic “predecessors” to Chronic Traumatic Encephalopathy (CTE) ie. dementia pugilistica/punch drunk syndrome.

The first article with the term "Chronic Traumatic Encephalopathy" was a 1949 publication by Macdonald Critchley titled Punch Drunk syndromes: The Chronic Traumatic Encephalopathy of Boxers. Prior to the use of the term, which today has become fairly well known, repetitive brain injury was studied primarily in boxers and termed dementia pugilistica and punch drunk syndrome. This blog post will delve into dementia pugilistica/punch drunk syndrome to provide background information on the conditions such as those at risk, and clinical manifestations.

Dementia pugilistica/punch drunk was first introduced in medical literature by Dr. Harrison Martland in 1928. It is unknown who truly first coined the term "punch drunk", but it is suspected to be a layman (Critchley, 1956). As with every subject we have learned about in medical school, history of present illness is important in evaluating the extent of the disease. Punch drunk is more often found in fighters of what would be considered brawling type today, those who take a substantial amount of abuse in hopes of landing a haymaker that ends the fight (Martland, 1928). This is a fighting characteristic of lower caliber boxers as compared to the champion boxers who incorporate an intelligent component to their fights. A couple select populations at risk for punch drunkenness piqued my interest; boxers traveling with fairs who worked the boxing booth, taking on anyone, at any weight and boxers who resigned themselves to be sparring partners for championship heavyweights and would be knocked out several times a day (Critchley, 1956. Martland, 1928). Another interesting component, is the amount of matches that boxers had at this time in the early 20th century as well. One case study remarked on the 21 year career of an Algerian boxer who had competed in 310 bouts, winning 285 and never being knocked out (Lepreux, S. et al, 2015). For comparison, boxing legend Muhammad Ali participated in 61 bouts throughout his 21 year career.

Clinical manifestations varied widely. As a rule, gradual evolution of mental and physical anomalies marks the insidious onset of the encephalopathy (Critchley, 1956). Early symptoms present in the extremities with very slight flopping in the foot/leg with walking or a slight unsteadiness (Martland, 1928). Speech and thought slow with memory deterioration as well (Critchley, 1956). For example, the aforementioned Algerian boxer initially presented with memory issues and his wife noting loss of leisure and household chores that he once managed (Lepreux, S. et al, 2015). This boxer eventually disoriented at home, developed aggressiveness and was placed in a psychiatric hospital then institutionalized prior to his death.

Sources
Martland, Harrison S. "Punch Drunk."  Journal of the American Medical Association. 91.15 (1928): 1103. Web.
Critchley, Macdonald. "Medical Aspects of Boxing, Particularly from a Neurological Standpoint." Bmj 1.5015 (1957): 357-62. Web.
Lepreux, Sébastien, Sophie Auriacombe, Claude Vital, Bruno Dubois and Anne Vital. "Dementia Pugilistica: A Severe Tribute to a Career." Clinical Neuropathology 34.07 (2015): 193-98. Web.

Is "If you don't use it you lose it" applicable to the brain and CTE?

In order to get a better idea of who is more susceptible for the clinical implications of CTE, researchers have begun to identify risk factors and factors that can delay progression of cognitive symptoms. One of the most recent papers has begun a preliminary discussion on Cognitive Reserve and its impact on delay of cognitive and behavioral symptoms. The theory is that a person with a higher cognitive reserve will be able to use pre-existing cognitive processes to deal with the neuropathological insult. This research was spurred on by other papers that showed that higher education can decrease cognitive dysfunction and improves recovery in traumatic brain injury (TBI) (Kesler et al 2003, Schneider et al 2014). The researchers used these studies to start their own study on cognitive reserves effect on CTE.

In this study, the researchers used brains with confirmed stage III or IV neuropathological criteria for CTE. They then reached out to the next of kin of these individuals and conducted structured and unstructured interviews as well as online surveys in order to get a better idea of the person's educational attainment, occupation and onset of symptoms (both behavioral/mood and cognitive). The educational attainment and occupation were used as proxies for cognitive reserve. The occupation for each individual was rated as low or high attainment based on the DOT guidelines. 

The results of this preliminary study showed that while educational attainment did not predict the onset of symptoms, occupational attainment had a very significant impact on both behavioral and cognitive onset of symptoms. In fact after controlling for duration of football play, cognitive symptoms appeared 10 years earlier in the individuals with low cognitive impairment (Alosco et al 2016). Below is a table of the study results:

Alosco ML, Mez, J, Kowall, NK et al: Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination. J Neuropsychiatry Clin Neurosci 2017, 29:6-12.

The results of this data was very similar to the data found in Alzheimer's disease, another similar tauopathy (Stern et al 1994). Even though this data shows a difference between cognitive reserve and onset of symptoms, it appears that there is a generalized improvement in cognition with increased cognitive reserve, and it is not solely protective in CTE (Wilson et al 2013). Furthermore, we need more information as to the relationship between cognitive reserve and symptom onset, by using larger study groups and by performing longitudinal studies with living athletes at risk of CTE. Using a longitudinal study will help to move away from retroactive interviews with next of kin, which has the potential to be less reliable than more rigorous longitudinal observation. Nevertheless, this data provides some clues that professions that engage the mind can be beneficial in delaying the symptoms that can occur in CTE. Therefore it is recommended that retired athletes continue to challenge their brains and remain engaged in higher attainment occupations. 

Kesler SR, Adams HF, Blasey CM, et al: Premorbid intellectual functioning, education, and brain size in traumatic brain injury: an investigation of the cognitive reserve hypothesis. Appl Neuropsychol 2003; 10:153–162

Schneider EB, Sur S, Raymont V, et al: Functional recovery after moderate/severe traumatic brain injury: a role for cognitive reserve? Neurology 2014; 82:1636–1642

Alosco ML, Mez, J, Kowall, NK et al: Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination. J Neuropsychiatry Clin Neurosci 2017, 29:6-12.

Stern Y, Gurland B, Tatemichi TK, et al: Influence of education and occupation on the incidence of Alzheimer’s disease. JAMA 1994; 271:1004–1010

Wilson RS, Nag S, Boyle PA, et al: Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology 2013; 80: 1202–1208

Traumatic Encephalopathic Syndrome and CTE

The current definition for diagnosis of Chronic Traumatic Encephalopathy outlines a series of clinical symptoms that must be correlated with postmortem findings for a definitive diagnosis. The clinical symptoms are often gathered from family members and friends of the patient following his or her death, and must be matched with gross and microscopic changes to the brain at autopsy. The clinical presentation includes a wide range of symptoms in areas of mood, behavior, cognition, and movement.

Behavioral: explosivity, verbal and physical violence, loss of control, impulsivity, paranoia, and rage

Cognitive: deficits in memory, executive function, impaired attention

Motor: dysarthria, dysphagia, parkinsonism, coordination problems

These symptoms are then correlated with the pathological findings, that include deposition of hyperphosphorylated tau protein as neurofibrillary tangles, thorned astrocytes, and neurites in a unique pattern. The tau is characteristically found in a perivascular distribution, more often deep in cerebral sulci.

Because the definition of CTE is currently only applicable postmortem, it is important to establish a definition for the disease in living individuals in order to better classify the disease and identify patients in need of care. To distinguish a description of the clinical syndrome from that of the pathology-confirmed disease, the name “Traumatic Encephalopathy Syndrome” has been used. These criteria are meant to describe a clinical syndrome associated with a history of repeated brain trauma, and are not meant to predict neuropathological changes. A set of criteria proposed by Montenigro et al., 2014 outlines five general criteria, three clinical features, and nine supportive features for TES.

            The five general criteria for TES include a history of multiple impacts to the head, which can be defined as mild TBI or concussion, moderate/severe TBI (GCS score of less than 13), or subconcussive trauma. There must also be no other diagnosed neurological disorder in the individual. Clinical features must have been present for at least 12 months, with one of the “core” clinical features being present, and at least two of the supportive features.

            The clinical features of TES are the same as those described above for the clinical presentation of CTE and include changes in cognition, behavior, or mood, with a change in at least one of these areas being required for TES diagnosis.

 Finally, at least two supportive features must be present for a diagnosis of TES. These features are: impulsivity, anxiety, apathy, paranoia, suicidality, headache, motor signs, documented decline, and delayed onset.

            While there is significant overlap between portions of the diagnostic criteria for CTE and the definition of TES, these guidelines help to better elucidate a specific constellation of symptoms involved in TES and to define clinical findings of degenerative neuropathy prior to death and autopsy.

Antemortem diagnostic techniques

Antemortem diagnosis of CTE

Because the first description of CTE and subsequent studies depended upon autopsied brain sections, and microscopic pathologic findings, developing methods for antemortem diagnosis of CTE has proven elusive. Recent studies have attempted to use brain imaging modalities and plasma biomarkers to correlate symptoms of the disease in living persons with brain pathology. A recent study used PET scan imaging in combination with Florbetapir, a tracer that binds to aggregated tau in neurofibrillary tangles. The study examined a 39-year-old retired NFL football bplayer who had experienced 22 concussions throughout his playing career, and who was exhibiting neuropsychiatric symptoms associated with CTE. Logitunally acquired MRIs revealed cortical thinging in frontal and lateral temporal lobes, and volume loss in the basal ganglia. Florbetapir PET imaging revealed tau accumulations at the depths of corical sulci, which is the defining lesion of CTE in autopsied brains¹.

            This study established the possibility of using imaging modalities in antemortem diagnosis of CTE, but does not define a radiologic signature of CTE. Furthermore, this modality needs to be confirmed by postmortem examination of the brains of people imaged during life, to correlate these findings with confirmed cases of CTE.

            Efforts to develop more rapid tests that do not require expensive imaging modalities and radiation exposure have also expanded greatly in recent years. Tau levels in cerebrospinal fluid have been proposed as an appropriate biomarker for CTE, but the lumbar puncture required to retrieve CSF is viewed as invasive, and is often feared by patients. The search for blood-based markers of the disease is the newest frontier for diagnostic techniques.

            Direct measurement of tau, while possible, may not be representative of tau tangles within neurons as it is often released from damaged neurons. Nanovesicles, which are vesicles exocytosed by cells of the body, reflect the contents of their cell of origin. They are released into CSF, blood, and urine, are very stable, and are capable of crossing the blood-brain barrier, making them an ideal marker of disease. The technique of nanovesicle or exosome isolation has been used to successfully detect Alzheimer Disease pathology ten years prior to the onset of symptoms². Furthermore, Stern et al. recently applied this technique in measuring tau exosomes in symptomatic former NFL players, compared with non-contact athletes and raised levels of tau-positive plasma exosomes was significantly correlated with worse neuropsychological test performance³. This may represent a significant step forward in antemortem diagnosis of CTE, but further study correlating plasma levels with postmortem disease confirmation is required.

Sources

1)    Pullman MY, Dickstein DL, DeKoscky ST, Gandy S. Antemortem biomarker support for a diagnosis of clinically probable chronic traumatic encephalopathy. Mol Psychiatry 2017, Advance online publication.

2)    Goetzl et al., Altered Lysosomal Proteins in Neural-Derived Plasma Exosomes in Preclinical Alzheimer Disease. Neurology. 2015 July 7; 85(1):40-47

3)    Stern et al., Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. J Alzheimers Dis. 2016; 51(4):1099-1109