Omalu et al. (2011) observed in an 18-year-old former high school football player "none to sparse" neurofibullary tangles in the cerebral cortex, subcortical nuclei, and brain stem. However he did conclude there was sufficient evidence of CTE but described these pathological findings as "incipient CTE", and suggested such findings potentially represented an initial stage of CTE development. McKee et al. have described a CTE pathology staging system to standardize CTE findings. Stage I lists the earliest abnormalities observed for CTE as focal epicenters of pathological tau located in the frontal cortex. By contrast, in more advanced CTE Stages III-IV the neuropathology is characterized by less focal and more widespread distribution of pathological tau throughout the cerebrum, subcortical nuclei, brainstem, and spinal cord. These neuropathologies are typically observed in older CTE subjects. McKee et al. has also reported a correlation of greater neuropathologic changes with greater number of years played, thus suggesting more advanced CTE pathology is linked to increased exposure to head trauma, and exclusive to older age of death. Due to limited available data the natural progression of CTE is still unknown. Whether less-advanced cases of CTE reported in generally younger subjects would eventually progress to advanced neuropathologic findings associated with advanced CTE has not been documented. There are early reports that PET scanning for tau protein may be useful to determine premorbid CTE and could possibly be used to follow changes over time.
 Apolipoprotein E. Apolipoprotein E (ApoE) allele is a well-known genetic risk factor for Alzheimer disease. Kutner et al. and Jordan et al. have also reported that the presence of ApoE4 allele is associated with worse cognitive deficits in patients following severe head injury. Data on ApoE genotype was available for 80 CTE cases, which represents the largest compilation of CTE ApoE genotype to date. A Chi-square goodness of fit test was used to compare ApoE genotype of this CTE population to the ApoE genotype of the general population (data adapted from Beydoun et al.). This analysis revealed no significant group difference between ApoE4 carriers in the CTE population and the general population (p = .26), suggesting that ApoE may not be a significant risk factor for the development of CTE. The result of this analysis is similar to findings by McKee et al. (2012) who also reported non-significant difference between ApoE genotype of the general population and the 68 cases of CTE in presented in their cohort. The non-random selection and incomplete data of all CTE subjects limits speculation as to the significance of these findings. Further comparisons are needed to investigate the differences between post-mortem ApoE genotype of CTE, mTBI survivors and the general population.
 Substance abuse. Thirty cases (20%) out of 153 CTE cases reported a positive history of substance abuse, which is greater than the 7.7% reported by Comptom et al. for substance abuse in US adults over their lifetime. Cottler et al. (2011) reported that 52% of retired football players used opioids during their NFL career, of which 71% reported misuse. CTE researchers have noted that the clinical presentation of CTE may be distorted due to history of substance abuse. Research investigating neurodegenerative effects of substance abuse has shown that several commonly abused substances may potentiate the development of other neurodegenerative conditions. These changes can include tau pathology, activated microglia, neuronal loss, and white matter rarefaction. In fact, in addition to these non-specific neurodegenerative changes, abuse of some substances such as opiates and opioids may elicit pathology very similar to those observed in CTE. In their research detailing the postmortem findings of opiate and opioid abusers, Anthony et al. (2010) observed enhanced NFT and NT deposition in their drug user subjects when compared to normal age-matched controls. Notably, histopathological analysis revealed the enhanced tau pathologies observed in the drug users were analogous to the pathological tau found in AD and CTE, but as in the case of CTE, the distribution was determined to be distinct from classical AD progression. How substance abuse may influence, co-present, or alter the pathologies observed in CTE is unknown. Due to the limited number of CTE cases that include information about history of substance use/abuse as well as limited reporting on the extent of use/abuse, no conclusion can be made as to the presence and nature of an association between substance abuse and CTE.
 CTE related clinical signs and symptoms. Due to a lack of consistent clinical data in the CTE case reports, this review did not specifically discuss the various premorbid clinical signs and symptoms reported with CTE. Reported CTE-related sign and symptoms include headache, difficulties with attention and memory, mood disorders, motor dysfunction and dementia. McKee et al. have proposed a classification system (Stage I-IV) correlating advanced clinical findings to the degree of expected post mortem neuropathologic changes found with CTE. (Table 5) For comparison, Table 5 includes the clinical symptoms of CTE as well as clinical symptoms of other common neurodegenerative conditions. This comparison demonstrates a significant overlap between signs and symptoms of CTE and other common neurodegenerative conditions. Based on this proposed classification it is difficult to distinguish symptomatic CTE from other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and FTLD. Postmortem neuropathological assessment remains the standard for definitive diagnosis.
 Table 5 also compares clinical findings currently attributed to CTE to common signs and symptoms seen with post-concussion syndrome (PCS). In most cases, signs and symptoms associated with a concussion resolve within 1-4 weeks. PCS is characterized by a protracted course following the incident of mTBI that may last months to years following injury. Reynolds et al. and others have demonstrated that over time therapeutic interventions, such as cognitive, visual and balance therapies can improve recovery rates in patients with persistent PCS. Based on McKee's proposed clinical classification, symptoms of PCS substantially overlap with incipient symptoms of CTE. But unlike PCS where symptoms continue well after an mTBI, CTE attributed clinical findings are generally recognized as having a latent asymptomatic period of years to decades between exposure to mTBI and CTE symptom onset. Additionally, CTE, once symptomatic, is generally thought to be progressive and does not resolve over time. Despite the differences in the general onset of these conditions, some researchers have reported PCS proceeding directly to pathologically diagnosed CTE, further skewing the clinical diagnosis of CTE.
Most cases of neuropathologically confirmed CTE have reported signs and symptoms of neurological decline prior to death. However, McKee et al. (2012) reported 11% of their CTE-positive cohort (n = 5) were asymptomatic for any neurological conditions. Asymptomatic presentation was reported as advanced as CTE Stage III where there is widespread NFT pathology and neurodegeneration. Although asymptomatic presentation of neuropathology such as in AD is common, it remains unclear why some pathologically diagnosed CTE subjects experience symptoms while others do not.
 American football players. Of the 153 CTE cases, 63 had a history of participation in football, and the majority of football subjects played at the professional level. It is important to separate out this subgroup since former football players have dominated CTE in the modern era of CTE research. In the 2012 review of 68 cases of CTE, McKee et al. observed that pathological findings of CTE were significantly correlated to the number of years a subject participated in football. However, despite the professional levels making up the majority of CTE cases, high school football players have also been reported to have CTE in spite of their limited mTBI exposure period. Although several of the high school football players were found to have CTE decades after their participation in high school football, three of the seven high school football players found to have CTE died prior to the age of 20. Despite this, the average age at death for football players is similar to the overall CTE cohort: 69% of CTE football cases compared to 75% of the remaining cases died prior to age 70. There was, however, a substantially higher prevalence of suicide in football players compared to the rest of the CTE cohort (17.5% (n = 11) vs. 5.26% (n = 3)). Football players account for 79% of all suicides case reports.
It is unknown whether this finding indicates that suicide is an at-risk behavior specifically related to former football players or if it is due to the bias associated with case reporting. Iverson et al. (2014) has noted that between the years 1960 and 2007 there were only nine cases of suicide of all former NFL players, again providing evidence that recent selective case reporting limits assertions as to risk factors associated with CTE.
Prevalence of substance abuse in American football players (n = 9; 14%) was lower compared to the rest of CTE cohort (n = 21; 23%). The limited data collected on substance abuse in the CTE literature prevents us to draw any firm conclusion about the association between CTE and substance abuse. However, it is of interest that the reported prevalence of substance abuse in former professional football players with CTE is substantially less than the prevalence suggested by other studies exploring substance abuse in former football players. For example, in a study by Cottler et al. (2011), 52% of retired football players used opioids during their NFL career with 71% reporting misuse. What, if any, effect substance abuse contributes to CTE in football players remains unknown and requires further exploration.
Data on ApoE genotype was available for 53 out of the 63 football players (84.1%). A chi-square goodness of fit test was conducted to compare the prevalence of ApoE4 carriers in football mTBI subgroup with the general populations. The analysis revealed that the difference in frequency between the ApoE4 allele carriers in former football players with CTE and the general population was also non-significant (p = .56).
The data compiled in this review is considerably limited due to the inherent limitations associated with retrospective case reports used to study CTE for the last 80 years. Case reporting lacks consistency in the types of data reported in CTE cases, such as incomplete pre-morbid data and furthermore, CTE case reports are inherently subject to selection bias. Despite the many millions who have participated in contact sports and potentially suffered an mTBI, there are currently only 40 modern era CTE articles with 153 pathologically confirmed CTE cases reported.
Although CTE research is still in its early stages, especially with American football players, researchers are encouraged to move beyond case reporting. These pioneering reports suggest an association between chronic neurodegeneration changes and head trauma, but without prospective controlled studies definitive conclusions about the incidence, prevalence and associated risk factors cannot be drawn.
Based on this review, beyond a history of prior head trauma, no other evidence was found to be associated with CTE related brain changes. Other previously suggested risk factors for CTE, such as severity and frequency of pre-morbid mTBI, history of substance abuse, duration of play in a contact sport, underlying genetic factors or uniqueness of pre-morbid symptoms, cannot be meaningfully associated with CTE at this time.
Although prior head trauma has been considered a consistent risk factor for CTE, Hazrati et al. (2013) demonstrated not all of those with prior sports related head trauma will have later onset of neurological deficits or develop neuropathology associated with CTE. They observed that 3 out of 6 (50%) brains of former CFL athletes displayed CTE neuropathological abnormalities, although all 6 players had extensive histories of head injury. Both Omalu et al. (2011) and McKee et al. (2012) observed similar findings in their cases where 6 out of 17 (35.3%) and 17 out of 85 (20%) subjects, respectively, were found negative for CTE neuropathologies, despite histories of multiple mTBI.