It has been well established that repetitive concussive or subconcussive blows to the head place individuals at risk for CTE [5
]. CTE has been associated with athletes who participate in contact sports like American football, boxing, hockey, soccer, and professional wrestling. Other sports that are not directly associated with CTE, but have well-documented cases of concussion, include mixed martial arts, rugby, and horseback riding. Other groups at risk for repetitive head trauma and CTE are military veterans, epileptics, and victims of domestic abuse [5
]. It has been reported that approximately 17% of professional retired boxers will exhibit CTE [3
]. Although each group listed has a unifying factor of head trauma, they differ in particular aspects that may influence the severity or chronicity of their injury (see for a summary of risk factors).
Risk factors associated with chronic traumatic encephalopathy.
A recent study by Crisco et al. examined head impact exposure in collegiate football players and found that the average number of impacts received by an individual player during a single season was 420 with a maximum of
]. These impacts vary in severity based on their position. Offensive linemen, defensive linemen, and linebackers had the most frequent impacts while quarterbacks and running backs received the greatest magnitude of head impacts [9
]. In the literature McKee and colleagues reported that in five football players with diagnosed CTE all played similar positions: 3 were offensive linemen, 1 defensive linemen, and one linebacker [5
]. However, according to Boston University's Center for the Study of Chronic Traumatic Encephalopathy, CTE has also been found in other position players like safety and wide receiver dismissing the idea that only certain positions are at risk for developing CTE.
While it is clear that anyone who suffers repeated head trauma, regardless of the mechanism, may carry the risk of developing CTE, there is no clear consensus on how much or how little trauma is needed to cause CTE. While most feel CTE is a manifestation of repetitive trauma, the question still stands if it can be caused by a single TBI [10
]. In a study by Johnson et al., widespread tau and beta-amyloid deposition was found in the brains of individuals who suffered a single traumatic brain injury. The study included the examination of postmortem brains from long-term survivors (1–47 years) of a single TBI (N
= 39) versus uninjured age-matched controls (N
= 47). Results showed NFTs to be exceptionally rare in young uninjured controls, yet were abundant and diffuse in one-third of TBI cases. This was also true of beta-amyloid deposition, which was found in greater density following TBI than controls [11
]. While these brains showed classic changes associated with CTE, they did not have the symptomatic profile to accompany their neuropathologic findings [11
]. If these subjects went on to have repeated brain injury, it would be reasonable to expect more extensive damage with more pronounced clinical symptoms.
In a study of repeated head trauma in mice, Kane et al. created an animal model where mice did not suffer severe TBI but rather mTBI to look for CTE-like changes. They reported that exposure to head trauma for 5 consecutive days showed increased expression of glial fibrillary acidic protein and phospho-tau 30 days (~160% increase) after the last injury when compared to controls. They also reported that with their mTBI model they did not find edema, cortical contusions, obvious loss of neuronal matter beneath the skull, disruption of the blood brain barrier, or microglial activation. However, they compared this to mice that were subject to a single traumatic injury and found substantial microglial activation in the hippocampus and overlying cortex 30 days after the initial impact [12
Another high-risk group that has recently been studied are individuals in the military [12
]. Operations in Iraq and Afghanistan are reporting that TBI accounts for roughly 28% of all combat casualties and approximately 88% of these are closed-head injuries [12
]. While these numbers are significant, the US Defense and Veterans Brain Injury Center has estimated that approximately 180,000 soldiers have been diagnosed with mTBI between 2001 and 2010 while others estimate the number to be more than 300,000. Additionally, soldiers may also be exposed to toxins like organophosphates, chemical nerve agents, and heavy metals like uranium increasing their risk for brain injury [13
Age is another possible risk factor for the development of CTE. At younger ages, while the brain is developing traumatic injury may begin the cascade of destructive events and compounded through the years of continued play. Conversely, at younger ages the brain has more plasticity allowing greater ability to manage injury than that in the mature brain [8
]. Length of play is another risk factor where longer careers with prolonged exposures to injury may cause more severe CTE. Of the 51 cases reviewed by Dr. McKee, 39 boxers had an average career of 14.4 years (range 4–25) while the 5 football players averaged careers of 18.4 years (range 14–23 years). These athletes began their respective sports between 11 and 19 years of age [5
Genetic factors have also been thought to play a role in the development of CTE specifically the apolipoprotein E gene (ApoE). The ApoE4 allele has been well described in its association with Alzheimer's disease (AD) where individuals with homozygous ApoE4/E4 genotype have a 19-fold increased risk of developing AD [14
]. This same gene is now thought to possibly have a role in the development of CTE [5
]. Studies have shown that ApoE4-positive individuals had poorer outcomes with head trauma. Teasdale et al. reported that that patients with ApoE4 allele are more than twice as likely than those without ApoE4 to have unfavorable outcomes 6 months after head injury [15
]. Kutner et al. examined 53 professional American football players to see if their cognitive functioning differed based on age and ApoE4 genotype. They reported that older age and presence of ApoE4 scored lower on cognitive tests than did those without the allele or with less playing experience [16
]. Jordan et al. looked at ApoE4 genotype in boxers in relation to chronic TBI. They found that all boxers with severe impairment, based on the chronic brain injury scale, had at least 1 ApoE4 allele. Therefore, they reported that ApoE4 may be associated with increased severity of chronic neurologic deficits in high-exposure boxers [17
In McKee and colleagues' review of the 51 CTE cases, ApoE genotyping was reported in 10 cases where 50% carried at least one ApoE4 allele and one was homozygous for E4. While they did not report what the other 4 genotypes were, it raised their suspicions to believe that ApoE4 was the gene of interest. In animal studies ApoE4 transgenic mice had greater mortality from TBI than those with ApoE3 allele. Another study showed that transgenic mice that overexpress ApoE4 allele showed increased deposition of beta-amyloid after experimental TBI [5
However, a study by Omalu et al. reported that 70% of their CTE cohort had the ApoE3 genotype. Of the 17 athletes they used in their study they were able to determine the ApoE genotype in 10 of 14 professional athletes and in 2 of 3 high school athletes. Of the 10 professional athletes 90% had at least one ApoE3 allele, and 7 of the 10 with confirmed ApoE genotype also had CTE. Of these 7 athletes with CTE 100% had at least one ApoE3 allele (5 E3/E3, 2 E3/E4). It should also be noted that the only professional athlete in their study that did not have the E3 allele (E2/E4) was negative for CTE. Additionally, the two other professional athletes that had the ApoE allele but did not have CTE were E2/E3 (24 years old) and E3/E3. The authors note that the one case of E3/E3 that did not have tauopathy was assessed from only select sections of the brain as they did not have access to the full brain. Of the two high school athletes both were E3/E3 genotypes and did not show any histological signs of CTE [18