Chronic traumatic encephalopathy: clinical‐biomarker correlations and current concepts in pathogenesis
- Sam Gandy1, 2, 3, 4Email author,
- Milos D Ikonomovic5,
- Effie Mitsis^2, 3,
- Gregory Elder1, 2, 3, 4,
- Stephen T Ahlers6,
- Jeffrey Barth7,
- James R Stone8 and
- Steven T DeKosky9
© Gandy et al.; licensee BioMed Central Ltd. 2014
Received: 10 December 2013
Accepted: 13 May 2014
Published: 17 September 2014
Chronic traumatic encephalopathy (CTE) is a recently revived term used to describe a neurodegenerative process that occurs as a long term complication of repetitive mild traumatic brain injury (TBI). Corsellis provided one of the classic descriptions of CTE in boxers under the name “dementia pugilistica” (DP). Much recent attention has been drawn to the apparent association of CTE with contact sports (football, soccer, hockey) and with frequent battlefield exposure to blast waves generated by improvised explosive devices (IEDs). Recently, a promising serum biomarker has been identified by measurement of serum levels of the neuronal microtubule associated protein tau. New positron emission tomography (PET) ligands (e.g., [18 F] T807) that identify brain tauopathy have been successfully deployed for the in vitro and in vivo detection of presumptive tauopathy in the brains of subjects with clinically probable CTE.
Major academic and lay publications on DP/CTE were reviewed beginning with the 1928 paper describing the initial use of the term CTE by Martland.
The major current concepts in the neurological, psychiatric, neuropsychological, neuroimaging, and body fluid biomarker science of DP/CTE have been summarized. Newer achievements, such as serum tau and [18 F] T807 tauopathy imaging, are also introduced and their significance has been explained.
Recent advances in the science of DP/CTE hold promise for elucidating a long sought accurate determination of the true prevalence of CTE. This information holds potentially important public health implications for estimating the risk of contact sports in inflicting permanent and/or progressive brain damage on children, adolescents, and adults.
Despite condemnation of boxing by the American Medical Association  and by the American Pediatrics Association  in 1997 and predictions of the rapid demise of boxing, the sport continues today, and multimillion dollar purses still await the winners. In turn, the chance to compete for these purses continues to attract new boxers into professional associations, fueling the sport. Other sports associated with repetitive head trauma (e.g., ultimate fighting and mixed martial arts) have expanded and found larger participant groups and fans. Despite much social opposition to these sports, all efforts at boxing bans have so far been stymied by the influence of pro-boxing lobbyists on state and federal legislatures . While over 50 sports-associated cases of CTE have been reported , efforts at educating the public regarding the risks of repetitive head injury are hindered by some retired boxing champions who refuse to recognize that their own brain disease is due to their chronic exposure to boxing. Newer “sports” involving various forms of fighting provide further encouragement.
On the occasion of the first promising blood biomarker for TBI that correlates with outcome and the presentation of the first tauopathy PET images that support a diagnosis of CTE during life, we take this opportunity to review the existing knowledge about CTE up to now.
Neuropsychology of CTE
The recommended assessment in CTE includes neuropsychological evaluation, neurological examination, brain imaging, and blood and CSF biomarkers. Particular attention should be paid to cognitive function, mood, personality, behavior, and olfaction . Most of what is known about neuropsychological function in CTE comes from the study of boxers and, more recently, football players, athletes from other contact sports, as well as those exposed to domestic violence, and military personnel exposed to battlefield blast injuries [20, 21]. However, there have been no prospective studies linking clinical phenotypes during life (including neuropsychological function and outcome) with autopsy-confirmed CTE. Thus, the clinical and neuropsychological characterization of CTE is yet to be properly developed. The development of biomarkers for CTE (reviewed in detail below) should greatly facilitate the fulfillment of this goal.
In their review of 48 cases of neuropathologically confirmed CTE, McKee et al. found that memory loss was reported in over half of the individuals. As in AD, loss of insight often precluded patients from recognizing their deficits, and this important piece of the presentation was derived from friends or family. Other studies have reported that impairment in executive function is common in neuropathologically confirmed CTE . Executive functions are a collective set of higher order abilities (judgment, self-inhibitory behaviors, decision-making, planning and organization) considered to be primarily dependent upon adequate functioning of the frontal lobes of the brain. Damage to various regions of the frontal cortex can disrupt these higher order abilities, leading to poor impulse control, and socially inappropriate, avolitional, and apathetic behaviors. For example, damage to the orbitofrontal regions can result in significant changes in personality. Thus, changes in personality, apathy, impulsivity, aggression, and “short fuse” behaviors typical of CTE  are consistent with the atrophy and other neuropathological changes of the frontal lobes that have been described in nearly all reported cases of CTE [16, 21–24].
Neuropsychological, mood, and neurobehavioral dysfunction in CTE typically presents in midlife after a latency period, usually years or decades after exposure to the repetitive trauma. The cognitive and behavioral symptoms of CTE begin insidiously, followed by progressive and gradual deterioration. Mood symptoms are typically depression, apathy, irritability, and suicidality. Behavior symptoms are impulse control, disinhibition, and aggression as well as comorbid substance abuse . The continued degeneration of brain regions most severely affected in CTE (cerebral cortices, hippocampi, amygdalae, basal forebrain, mammillary bodies) results in the worsening of behavioral and mood symptoms, and the further deterioration of cognitive abilities subserved by these regions. Baugh et al. organized the neuropsychological and neuropsychiatric symptoms of CTE into the categories of cognition, mood, and behavior. As mentioned, the early cognitive symptoms of CTE involve memory impairment and executive dysfunction. The early involvement of hippocampal-entorhinal cortices and medial thalamic circuits may explain the memory impairment and its similarity to the memory loss associated with AD. As in AD, the genetic risk posed by apolipoprotein E ε4 (APOE ε4) may play a role in the dementia associated with CTE [25–27]. The dysexecutive syndrome in CTE may result from the early neurofibrillary degeneration of the frontal cortex [10, 21, 22]. As the disease progresses, there is worsening memory impairment and executive dysfunction, language problems, motor dysfunction, aggression (physical as well as verbal), and apathy . Dementia is evident in most CTE individuals who live to be over the age of 65 years . However, the high rates of suicides, accidents, and drug overdoses often lead to death prior to this age [10, 28]. As a result, most persons with neuropathologically confirmed CTE were not demented at the time of death. In view of the young age of onset as compared with AD, CTE may be misdiagnosed as the behavioral variant of FTD. However, CTE has a more gradual and prolonged progression than does FTD, and CTE is associated with a repetitive TBI history but with no family history .
Neuropsychological testing may be valuable in scientific studies on TBI in both the acute and chronic phases. Athletes and military combatants exposed to multiple blast events are at highest risk for sustaining multiple mild TBI or concussions and potentially developing CTE. In order to appreciate fully the effects of single and multiple concussive and sub-concussive brain injuries and to enable tracking of recovery in individual cases, brief baseline and serial post-concussion neurocognitive assessments, based upon the Sports as a Laboratory Assessment Model (SLAM) methodology, are the recommended standard of practice . Key neurocognitive elements of these abbreviated assessments include attention, processing speed, reaction time, and learning and memory.
Once CTE is suspected, based upon a history of repeated trauma and presence of cognitive and/or behavioral impairment, scientific studies are needed to evaluate the value of comprehensive neuropsychological testing; e.g., assessment of general verbal and visuospatial problem solving, language fluency, attention, learning and memory, speed of mental processing, abstract reasoning, judgment, new problem solving, planning and organization, mental flexibility, sensory and motor intactness, and emotional/psychological and behavioral functioning. A recent cross-sectional study assessed cognitive impairment and depression, as well as the neuroimaging correlates of these dysfunctions, in former NFL players . Former NFL players with cognitive impairment and depression were compared to cognitively normal retired players who were not depressed, and a group of matched, healthy control subjects. The cognitive deficits found were primarily in naming, word-finding, and memory (verbal and visual) and were associated with disrupted white matter integrity on DTI and changes in regional cerebral blood flow. Although none of the players fit the clinical profile of CTE per se, the sample size was very small. Nevertheless, this is one of the first studies examining the neural correlates of cognitive dysfunction and depression in players with a history of concussions (range 1–13 concussions in this sample).
Neuropathological changes in boxers (dementia pugilistica, punch-drunk syndrome)
For this section, the combined term DP/CTE is employed, since the term DP appears in this original literature. However, the revival of the term CTE was intended to include DP and to supplant the use of the term DP. In 1934, Parker described three cases of boxers affected with the illness  and drew attention to the risk of developing DP/CTE in professional boxing. Neuropathological examination of these retired professional boxers’ brains demonstrated that the primary DP/CTE lesion involved multifocal intracellular aggregates of hyperphosphorylated tau, which resembled the neurofibrillary tangles (NFT) found in AD brains . Using Congo red and silver staining, Corsellis and colleagues studied 15 cases of DP/CTE and confirmed the abundance of NFT. Like the NFT of AD, the NFT of DP/CTE is also reactive to antibodies to other AD-related proteins such as ubiquitin  and Aβ . The anatomical patterns of NFT distribution are different in DP/CTE and AD: there is greater involvement of superficial layers of the associational neocortex in cases with DP/CTE and notably in the depths of cortical sulci . This difference may reflect a unique way in which NFT are formed and propagated in DP/CTE.
In clear distinction to neuropathologically confirmed AD, no congophilic or argyrophilic plaques were observed in the Corsellis study . In 1991, other investigators re-examined 14 out of the original 15 DP/CTE cases from the Corsellis study as well as additional brains of professional and amateur boxers, using Aβ immunohistochemistry and formic acid pre-treatment of tissue sections [34, 36–38]. Re-examination revealed that these 14 brains with NFT pathology (and even two amateur fighters’ brains that lacked NFT) also had Aβ-immunoreactive plaques [34, 36–38]. These DP/CTE plaques were described as diffuse in most cases; they lacked both Congo red positivity and the silver-positive dystrophic neurites that are typical of mature AD plaques. Some cases also displayed cerebrovascular deposits of Aβ. These data demonstrated that DP/CTE is associated with both the NFT and Aβ-related AD-like pathology. The antigenic similarities of neurofibrillary lesions in DP and AD led Roberts to suggest that the two conditions likely share the same pathogenesis and that TBI may be a risk factor for developing AD .
More recent studies reconfirmed that DP/CTE includes both NFT and Aβ pathology. Tokuda et al. and Nowak et al. examined the brains of boxers who suffered a progressive cognitive decline before death, and reported NFT as well as infrequent neuritic Aβ plaques. McKee and colleagues  studied two aged (80 and 73 years) professional boxers and presented them along with 37 previously published cases of boxers with neuropathologically verified DP/CTE. Similar to earlier reports, the most striking pathological feature in these two cases involved multifocal patches of neuronal and astrocytic NFT in superficial cortical layers, most frequently at the depths of the sulci and around large blood vessels . In one of the two boxers, there were moderate diffuse Aβ plaques and sparse neuritic plaques in several neocortical regions. Collectively, these reports indicate that the neuropathology of DP/CTE was heterogeneous and involves both NFT and diffuse Aβ deposits, although the extent and proportions of these lesions vary from case to case and may be influenced by other factors such as number of years since TBI, age at the time of the TBI, and genetic predisposition. In a study by Geddes and colleagues, the brain of a 23-year-old boxer was found to have all neocortical areas affected with NFT; however no other changes (including Aβ deposits) were reported . APOE ε4 alleles have been associated with more severe cognitive deficits in boxers  and could contribute to more severe Aβ pathology, as has been demonstrated in AD. In an APOE ε4 heterozygous retired boxer with DP/CTE, death was caused by hemorrhage due to amyloid angiopathy . Clinical misdiagnosis of DP/CTE as AD is not unusual; interestingly, both boxers in the McKee report were diagnosed with AD during life. Differential diagnosis is likely to be clarified with amyloid imaging. We reported a case report illustrating this wherein the clinical diagnosis of retired NFL player could not be resolved until florbetapir imaging excluded the diagnosis of AD .
Other common findings in DP/CTE include cerebral infarcts and fenestrated cavum septum pellucidum (CSP) as well as substantia nigra degeneration . Changes in substantia nigra could explain the increased incidence of Parkinsonism in retired boxers. It had been proposed that identification of CSP on CT scans could be of a diagnostic value for DP/CTE . However this pathological feature is not consistently present , possibly because of the high prevalence of CSP in both boxers and non-boxers . Because of the rigid enclosure of the brain inside the calvarium, acceleration-deceleration injuries associated with boxing often involve cerebral and meningeal vascular damage, the most common of which is subdural hematoma and to a lesser extent epidural, subarachnoid, and/or intraparenchymal hemorrhages . Neuropathological sequelae of boxing appear to be less severe in amateur boxers, likely due to better-implemented regulations, fewer total bouts, and other measures of protection. In retired professional boxers, however, the risk of developing DP/CTE is greater: the extent of neurological abnormalities defined by CT and EEG, and severity of DP/CTE symptoms, correlated with numbers of fights and overall duration of boxers’ career [25, 47, 48].
Not shown here are some other CTE-associated structures described by McKee  including astrocytic tangles, perivascular tau pathology, or patchy tau pathology. An important significance for these structures is that McKee uses their presence to differentiate CTE from AD. The reader is referred to  for typical images of those structures.
Neuropathological changes associated with American football
In contrast to the neurodegenerative changes associated with professional boxing, the chronic neuropathological sequelae of repetitive hits to the head in American football and other contact sports (hockey, rugby, etc.) have only been recognized more recently. Impacts to the head in American football cause less rotational acceleration than those suffered in boxing ; football-related injuries are of a translational acceleration-deceleration type, and despite the use of helmets, they can result in concussions or unconsciousness. In 2005, Omalu and colleagues reported the first neuropathology finding of CTE in a 50-year old retired NFL player . In this case, they described AD-like changes that consisted of neocortical Aβ-immunoreactive plaques and sparse tau-immunoreactive neuronal and axonal aggregates resembling NFT and neuropil threads. While coexistence of Aβ plaques and NFT might have suggested an ongoing AD process, several observations argued against this idea: 1) there was no family history of AD; 2) at autopsy, the brain had no signs of cortical atrophy or overt neuronal loss; 3) the neocortical Aβ-immunoreactive plaques were numerous, but were diffuse (non-neuritic); and 4) NFT were scarce in the neocortex and absent in the entorhinal cortex and hippocampus which is the initial focus of NFT development in AD, prior to any cortical NFT . The neuropathological pattern consisting of diffuse neocortical Aβ plaques and scarce NFT was similar to changes described in subjects with acute severe TBI  or in cases with preclinical AD, suggesting that both mild repetitive and severe brain injuries may initiate early AD-like changes. The second case reported by Omalu and colleagues  was a 45-year old retired NFL player who had numerous cortical and subcortical tau-immunoreactive NFT and neuropil threads, but no Aβ-immunoreactive plaques. In a more recent study, McKee and colleagues  described CTE in a 45-year old retired football player and compared their findings to previous neuropathology reports in four players who had played similar positions during their career. Tau-immunoreactive NFT-like neuronal and glial (fibrillar astrocytic) profiles and thread-like neuropil neurites were frequent in multiple cortical regions, predominantly occupying deep sulcal and perivascular locations . NFT were also abundant in the entorhinal cortex, hippocampus, amygdala, nucleus basalis and septal nuclei, hypothalamus, thalamus, striatum, and olfactory bulb. Diffuse Aβ plaques were reported in 3 of the 5 cases . As in CTE due to boxing (i.e., DP), there are similarities of the effects of football injuries to AD and other neurodegenerative disorders, notably involving NFT and diffuse Aβ deposition, and these findings require further investigation.
Neuropathological changes associated with battlefield blast exposure
Studies of military servicemen who participated in recent wars indicate that repetitive mild head injury and concussions due to blast (explosive) injury might also result in CTE. This literature is the least mature since the index case of military CTE was only reported by Omalu a few years ago . Brody and colleagues used diffusion tensor imaging (DTI) to evaluate the extent of axonal injury in 63 U.S. military personnel diagnosed with mild TBI after blast exposure with secondary mechanical injuries . They found that, in these subjects, TBI was associated with significant axonal injury, which was still present 6–12 months later at follow up evaluation with DTI. Diffuse loss of white matter integrity was also detected using high angular resolution diffusion imaging (HARDI) in military veterans from Iraq and Afghanistan who had been diagnosed with mild TBI and comorbid PTSD . Collectively, these findings indicate that TBI associated with blast or chronic mild injury produces chronic neuronal damage. Blast injuries and closed head injuries have similar clinical features , however, the extent of neurological damage in blast injured veterans is likely influenced by injuries of other systems, since air-filled organs (including lungs) are often severely affected [56, 57].
Goldstein  and colleagues performed postmortem analyses of brain tissues from four military veterans who were exposed to blast or concussive injury and compared them to four professional athletes who suffered repetitive concussions. In the neocortex from military veterans, there were frequent perivascular and deep sulcal accumulations of NFT-like tau-positive neurons and glial cells as well as dystrophic axons were reported . Subcortical white matter in close proximity to these lesions had dystrophic axonal changes and clusters of activated microglia were described. These pathological changes were similar to those observed in sports CTE. The findings in this study have been challenged because all military CTE subjects had histories of both civilian and military TBI, making it impossible to distinguish which lesions arose from which injuries. Similar tau-immunoreactive neuropathological features were described in an Iraqi war veteran with PTSD who had been exposed to multiple blast explosions during his deployments . These autopsy studies of brains from blast-injured veterans are not in agreement with recent body fluid biomarker analyses in soldiers exposed to blast , emphasizing both the variability of such injuries and the variability in the accuracy of the historical details surrounding the injuries. In this study of Army officers exposed to different levels of blast overpressure by firing heavy weapons, Blennow and colleagues  measured CSF biomarkers of neuronal injury (tau and neurofilament protein) or glial injury (GFAP and S-100β) as well as CSF/serum albumin ratio, hemoglobin, and bilirubin content in CSF. GFAP and S-100β were also analyzed in serum samples. All analyses indicated normal levels of examined markers, leading the authors to conclude that high-impact blast was not associated with biomarker evidence of brain damage . The discrepancy between this report and published evidence of neuropathology in blast injured servicemen warrants further investigation, and the issue of whether the blast wave itself causes injury remains open. Another possible explanation is the lag time between injury and serum sampling. Both  and  illustrate the discrepancy between neuropathology that can be static and long-lasting vs serum biomarkers that will rise acutely and then fall as the marker molecule is cleared. Recent studies of serum tau as a marker of acute TBI in hockey players showed surprisingly good correlation with outcome .
Molecular pathogenesis of CTE
As noted above, CTE is considered to be primarily a tauopathy with frequent coexistence of Aβ pathology. Notably acute severe TBI is associated with diffuse Aβ plaques and minimal tau pathology . Other types of abnormal protein aggregates are less common in CTE; for example, alpha-synuclein immunoreactive inclusions were not reported in any of 51 CTE cases reported by McKee and colleagues ; however, they were detected only following acute severe TBI . Multiple cases of Parkinsonism have been reported in professional boxers, and there is increased prevalence of ALS in professional football  and soccer players .
The detailed molecular pathogenesis of CTE is unknown. As observed in cases with single severe head trauma, axonal injury occurs in CTE, and this may be responsible for accumulation of phosphorylated tau. Tau is a microtubule-associate protein which can undergo excessive phosphorylation in the pathological milieu of brain injury associated with ischemic foci that increase the risk of damage from oxidative stress. The idea of ischemic changes as a contributing factor to tau hyperphosphorylation and formation of NFT-like changes in CTE is consistent with their preferential deep sulcal and perivascular localization. Because both neuronal and astrocytic NFT are observed in these areas, it is possible that changes in tau are related to a more general injury response mechanism that is not injury-specific or cell-specific (e.g., brain ischemia, inflammatory reaction).
Diffuse axonal injury (DAI) is the most consistently reported neuropathological feature following acute head trauma . DAI is associated with intra-axonal accumulation of tau, Aβ-precursor protein (APP), ubiquitin, and α-synuclein [64, 65]. As an acute reaction to TBI, there is an upregulation of APP and/or a switch in its metabolic processing resulting in increased concentrations of Aβ, which can deposit in diffuse, predominantly Aβ42, plaques both acutely after severe TBI  and chronically in boxers with DP/CTE. In studies of both autopsy cases and in surgical biopsy tissue from subjects with TBI , about 30% of acute severe TBI patients are reported to show evidence of Aβ plaques. Aβ deposits in CTE have received less attention in the literature than has the tauopathy; however these changes may have a significant role. The development of Aβ lesions may depend on age of the subject, time interval since the head injury, and genetic factors. More extensive and mature Aβ pathology (i.e., neuritic plaques) may be absent, or may recede over years, in subjects with protective genetic factors that can result in better degradation/clearance of Aβ from the brain [66, 67], while tau-related pathology may develop more slowly, may be more resistant to degradation and therefore observed at late stages of disease. Other genetic factors (APOE4) may influence Aβ pathology. The link of APOE ε4 to dementia in CTE is unexpected on the basis of tauopathy, since APOE ε4 modulates Aβ pathology in AD but not tauopathy. Perhaps APOE ε4 modulates the severity of the acute Aβ deposition which, in turn, affects clinical severity. This is a key point in determining which types of interventions will be most promising and at what point in pathogenesis each is most likely to be successful. Recent evidence that chronic action of interleukin-1β can reduce amyloidosis while exacerbating tauopathy raises the possibility that this neurodegeneration-associated cytokine may drive the conversion of acute post-traumatic Aβ deposition to chronic tauopathy with only minimal or inconsistent Aβ residua .
Alternatively, the extent and type of neuropathology changes in CTE resulting from different contact sports may reflect differences in the biomechanics associated with head injury, including impact level (force) and type of head movement (rotation, acceleration, deceleration). Novel genetic, biomarker, and neuroimaging analyses should be developed and employed for early detection of neuropathology, to provide a window of opportunity for preventing or at least delaying the clinical manifestations of neurodegenerative disease after TBI. Furthermore, timely identification of people at risk (e.g., APOE ε4 carriers) , and regular testing (imaging, CSF analyses, and detailed neuropsychological evaluation) should be considered essential.
Modeling CTE in laboratory animals
Relevance of existing animal models of TBI to human CTE
Because of its potential clinical importance, animal modeling of TBI has been vigorously pursued and a number of methods have been developed that can induce focal, diffuse or mixed brain injury . Most studies of TBI use rodents, but rabbits, pigs, cats, dogs, and nonhuman primates have all been studied as well . The choice of species has practical as well as theoretical implications. While rodents are less expensive than larger animals, their lissencephalic brains lack the structure of gyri and sulci found in humans. The white/grey matter ratio is also less in rodents compared to human brain; these anatomical factors may affect the biophysical properties of the brain’s reaction to mechanical injury. Species such as pigs and non-human primates offer the advantage of having a brain more similar to humans, but their cost and in the case of non-human primates availability limit their wider use for TBI research.
To model various types of TBI in experimental animals, several methods have been developed . Among the more widely used models, controlled cortical impact (CCI) produces focal contusions with pericontusional axonal injury while fluid percussion models produce more diffuse axonal injury. Weight drop methods can produce a range of injuries depending on the force applied (mass x distance of the drop), and whether an open skull or closed skull technique is used. There has been recently increased interest in models of blast injury, due primarily to its importance in military head trauma . Importantly, these models are associated with significant deficits in cognitive and motor function. In addition, anxiety and depression are common features of the postconcussion syndrome and evidence for impairment in both domains have been found as sequelae of TBI in some animal models . There are several recognized limitations of the animal models. While human TBI represents a heterogeneous injury, most animal models try to replicate more isolated pathological factors . Human TBI is frequently accompanied by hypoxia, hypotension and ischemia, factors that are not prominent in many animal models . Accordingly, TBI models can be utilized in combination with additional insults such as hemorrhagic shock which often accompanies blast TBI . Another limitation of traditional TBI models in replicating CTE is that most produce relatively severe focal or diffuse damage that is more similar to the type of injury found in moderate to severe rather than mild TBI. Significant efforts have been made to adapt these models to produce effects of mild TBI. For example, the CCI device has been modified to deliver impacts to the intact mouse skull resulting in a more mild TBI-like outcome . The weight drop technique has also been used to produce repetitive mild TBI in the mouse [74, 75], and the lateral fluid percussion model has been modified to deliver milder injuries in the rat . Additional models have been developed to mimic mild TBI in combat conditions including a closed‐head projectile concussive impact in rats , and a model of blast induced repetitive mild TBI in the rat that has been found to induce chronic behavioral changes [78, 79].
Animal models of single‐episode TBI have been valuable in determining the time course and the extent of cytoskeletal derangements which are a key feature of CTE. In both humans and experimental animals, TBI-induced axonal damage is associated with extensive accumulation of multiple proteins [65, 81]. Axonal microtubule and neurofilament (NF) proteins are altered acutely after TBI , and they are more pronounced following moderate injury . In pigs subjected to a rotational acceleration injury, diffuse axonal damage is characterized by co-accumulation of tau and Aβ together with NF and APP throughout the white matter, while in cortical regions phospho-tau aggregates appear in axonal bulbs as well as in structures resembling NFT . Similar changes occur in rodent models of TBI in which alterations in tau and other microtubule associated proteins can be rapid and transient [84, 85]. For example, in rats subjected to a mechanical compression injury increased tau phosphorylation occurs in cortical regions in as little as 10 min following injury but then is undetectable by 12 hours . Transient elevations of serum and CSF tau can also be detected following TBI in rats [86, 87]. More sustained increases in a cleaved form of tau have been found in the cortex and hippocampus of rats following a CCI injury , and increased phospho-tau has been observed in cortex of mice 30 days after 5 mild TBI injuries were delivered utilizing a weight drop device . A single blast-induced TBI resulted in acute (up to two weeks) axonal injury in the form of silver impregnated neuronal processes in rats  and increased levels of phosphorylated tau were detected in NFT like lesions in mice . In rats, increased levels of tau have been found in multiple brain regions at 71 days following a blast injury . Thus acute to subacute changes in tau are common across a spectrum of experimental TBI models.
However, few studies have yet revealed whether a subsequent chronic neurodegenerative changes are induced. Indeed the only study to our knowledge that has addressed this issue is the study by Hoshino et al. who studied the chronic effects of fluid percussion injury in rats. They reported a progressive loss of cortical neurons over a six-month period accompanied by appearance of increasing numbers of phospho-tau immunoreactive neurons . As noted above, rodent models of TBI are widely used because of their accessibility and relatively low cost. However, in addition to the anatomic differences between rodent and human brain, rodent models for CTE are potentially limited by the fact that mice and rats do not readily develop human like neurofibrillary pathology, a key histopathological feature of CTE. Rodents and humans differ in life spans, and species differences in tau also contribute to the difficulty of inducing NFT like lesions in rodents. The lack of human-like NFT pathology in rats and wild type mice has in particular been a limiting factor in the development of CTE models and has led to attempts to create more human like tauopathy models by introducing human tau transgenes into mice.
The non-traumatic neurodegenerative diseases that most closely resemble CTE pathologically are some forms of frontotemporal dementia (FTD). While most FTD cases can occur without evidence of family history, in some families the disease is inherited and caused by mutations in the tau gene on chromosome 17 . Mice expressing either human wild type or FTD-‐mutant tau develop a neurodegenerative disease spontaneously and accumulate NFT‐like lesions with aging . These lines have been used to investigate tauopathy‐related dementias and offer potentially relevant models for CTE . However to date only limited use has been made of these mice to study TBI. One study  examined the effects of mild repetitive TBI using a CCI injury in transgenic mice expressing the shortest human tau isoform. Transgenic and non-transgenic mice were subjected to a total of 16 mild TBI injuries over a period of 4 weeks and animals were examined histopathologically at 9 months after injury. Despite this aggressive injury protocol there was no general effect on histopathology or behavior of the tau transgene other than in one of the 18 transgenic mice that showed behavioral deficits and developed extensive telencephalic NFT like lesions and cerebral atrophy. In contrast, increases in total and phospho-tau immunoreactivity have been seen following a more severe CCI injury in JPNL mice which express the four repeat form of human tau containing the P301L mutation associated with FTD . In another study, mice that expressed the 6 isoforms of human tau and lacked murine tau were subjected to a single or repetitive mild TBI using an electromagnetically controlled impactor; three weeks later, phospho‐tau immunoreactivity, neuronal injury, and glial reaction were more pronounced in the group with repetitive mild TBI .
As discussed above, CTE is a heterogeneous disease with inconsistent pathology including not only tau but also Aβ lesions. Accordingly, several studies have investigated the effects of TBI in 3xTg-AD mice [94, 96, 97]. These mice also express the P301L mutation in tau associated with FTD but in combination with APP and presenilin mutations associated with familial Alzheimer’s disease. With aging these mice develop increased Aβ40 and Aβ42 levels, accumulate intraneuronal Aβ and exhibit amyloid plaques and NFT like lesions, thus exhibiting a more complete spectrum of AD like pathology when compared to other transgenic mouse models. Controlled cortical impact injury in 3xTg-AD mice accelerated the development of tau abnormalities  with increased phospho‐tau immunoreactivity seen histologically in the days following injury . Tau changes persisted for at least 7 days after injury and were associated with intra-axonal accumulation of several kinases that phosphorylate tau . In agreement with previous reports in other transgenic mouse models [98–100], the CCI injury in 3xTg-AD mice also resulted in intra-axonal Aβ accumulation . However, in this model combining tauopathy and amyloidosis, the anatomic pattern and time course of changes in Aβ and tau were distinct , and treatment with a γ‐secretase inhibitor blocked posttraumatic Aβ accumulation but had no effect on tau pathology suggesting that once initiated these two pathologies may take independent courses of progression . In contrast, reports from Loane et al. indicate that Aβ-reducing agents prevented TBI-induced neurodegeneration [101, 102].
Better animal models of CTE are an urgent need given that to date no injury in animals has replicated the full spectrum of pathological findings in human CTE. Acute to subacute changes in tau are common across a range of experimental TBI models suggesting that injured animals can manifest at least some initial cytoskeletal changes observed in brains of humans with CTE. However most studies have focused on acute effects of TBI and greater attention should be directed to determining whether a chronic neurodegenerative condition can be induced after TBI in animals. As mild TBI and concussions draw increasing attention as the most common type of civilian and military TBI, future studies of repetitive concussions in both rodent and non-rodent species will be needed to determine the optimal model.
Neuroimaging of CTE
Identification of specific imaging biomarkers for CTE has been challenged by the lack of correlation between any available neuroimaging studies and post-mortem tissue assessments demonstrating histopathologic hallmarks of CTE. To date, no systemic in vivo biological markers have been identified that reveal the presence of CTE. Given that most case reports of CTE involve individuals with a history of repetitive sports-related trauma, the neuroimaging portion of this review will focus upon abnormalities present in athletes with a history of concussion.
Common structural abnormalities often reported in the brain of professional boxers include cavum septum pellucidum (often with fenestrations), ventricular and sulcal enlargement, and cortical and cerebellar atrophy. Although CSP is often reported in studies of boxers and is postulated to be a sign of DP/CTE , and a marker of brain atrophy [44, 103, 104], its relatively high incidence in the normal adult population precludes its presence as a diagnostic specific to boxing . Despite the lack of specific in vivo findings in CTE, studies using both traditional and newer imaging methods have advanced our understanding of the consequences of repetitive head trauma. Newer imaging modalities and the use or development of advanced analytical methods (e.g., ref ) have revealed brain abnormalities in repetitive head trauma where more traditional methods found none, suggesting that comprehensive evaluation of CTE should include neuroimaging as part of an overall clinical assessment.
The major traditional structural imaging techniques used to evaluate brain function in boxers, and more recently in football players, are computed tomography (CT) and magnetic resonance imaging (MRI). In acute settings, these standard, structural imaging techniques have clinical utility in ruling out other acquired brain disorders such as tumor or stroke and have been utilized to rule out potentially fatal consequences of acute TBI such as hemorrhagic contusion, subdural and epidural hematomas, and subarachnoid hemorrhage. However, structural (or functional for that matter) imaging findings alone are not sufficient to diagnose CTE or determine who might eventually develop CTE. In addition, some of the structural imaging changes identified in CTE are similar to those seen in AD , and there may be similarities as well with normal aging. Early studies demonstrated that CT might not be as effective as MRI in identifying injury in the acute phase . In non-acute settings, high-field MRI may be the preferred modality in the evaluation of TBI due to its improved tissue clarity and contrast of pathology, and because it eliminates the risk of ionizing radiation associated with CT [103, 107, 109]. These features of MRI make it a valuable diagnostic tool for determining the extent of chronic TBI .
In view of the improved tissue contrast and additional biologically relevant information afforded by MRI, early studies began to investigate whether MRI was superior to CT as an imaging modality in boxers. A study conducted in 1990 did not demonstrate MRI superiority to CT in 47 retired amateur boxers as compared to two age-matched control groups: soccer and track and field athletes . However, another study published that same year found that some abnormalities detected by MRI were not shown by CT . There were several limitations in these early studies, including comparison of professional boxers to amateur boxers, who may not show neurologic damage because of their limited number of exposures, and incomplete information in professional boxers in terms of number of years spent boxing or the number of bouts fought. In addition, most studies were cross-sectional, thus it cannot be determined from these studies whether the abnormalities were present before or the result of, boxing . It should be noted that both MRI and CT have seen dramatic technological improvements over the past two decades.
Diffusion tensor imaging
Quantitative values used for spatially mapping DTI include apparent diffusion coefficient (typically mean diffusivity, MD), which measures the magnitude of the diffusion of water molecules, and fractional anisotropy (FA) or relative anisotropy (RA), which measure the directional preference of water molecules throughout brain fibers. White matter tracts normally constrain the isotropic diffusion of water. An FA value approaching 1.0 reflects maximal anisotropic diffusion, and values approaching zero indicate compromised white matter integrity. In addition to FA and RA, axial diffusivity and radial diffusivity describing magnitude of diffusion longitudinal and transverse to the dominant direction of white matter tracts may also be derived from the calculated diffusion tensor. DTI values are affected when there are changes to the microstructure of brain tissue. Disruption of axonal integrity due to shearing forces associated with head trauma results in a general reduction of FA values as the normal barrier to isotropic diffusion is altered. This type of information is not available from routine MRI; thus, white matter abnormalities that may be present due to repetitive TBI often go undetected with routine imaging.
Chappell et al. used a voxel-based analysis of DTI data to examine the ADC and FA in professional boxers and found previously unreported abnormalities that were assumed to reflect cumulative brain injury resulting from non-severe, repetitive head trauma . Regions were found to have increased ADC, decreased FA, and decreased ADC in gray matter in the boxer group compared to a group of controls with no neurological history. The regions affected included lower splenium and cortical regions laterally and dorsolaterally in the frontal and posterior lobes. The authors concluded that their findings represented evidence that sustained boxing activity causes structural abnormalities in the brain.
Functional magnetic resonance imaging (fMRI)
Distinct regional differences in BOLD signal have been reported in multiple studies of concussed athletes vs. controls. Chen et al. utilized fMRI with a working memory task to study 16 athletes (13 hockey players, 2 wrestlers, one snowboarder), most of whom had a history of > 5 career concussions. An interval of between 1 and 14 months had passed between the scan and time of last concussion. Although no differences in task performance were seen between groups, significantly different regional patterns of activation were seen within the mid-dorsolateral prefrontal cortex (MDPC) in the concussed athletes as compared to controls. In a separate study, Chen et al. utilized an fMRI working memory task to demonstrate abnormal activation patterns in the MDPC in 9 concussed athletes as compared to controls. Of note, no significant differences were seen with routine structural imaging or behavioral outcomes between groups. Lovell et al. employed an N-back working memory task to evaluate 28 athletes within a mean of 6.6 days after sustaining a concussion. A components analysis identified three distinct networks that were activated in both concussed athletes and controls during participation in the N-back task. One of these networks involving Brodman’s area 6 demonstrated increased levels of activity in concussed athletes compared with controls. Of note, the degree of increased activation in Brodmann’s area 6 in the concussed athletes correlated significantly with prolonged recovery time and delayed return to play.
Positron emission tomography (PET)
PET imaging allows for characterization of the uptake and spatial localization of radiotracers injected intravenously (IV). This imaging modality allows for the sensitive detection of small molar concentrations of radiotracers given its sensitivity for detecting the high-energy photons (512 keV) produced by radioactive decay through pair production. PET imaging in sports related TBI is currently limited and has generally been confined to use of 18fluoro-deoxyglucose (18FDG), a glucose analog that reflects metabolism. In brain, where glucose is the sole energy source, 18FDG is an excellent tracer for this purpose. Provenzano et al. employed 18FDG PET to study 19 boxers, aged 20 to 38 yrs, and compared them to 7 age-equivalent controls. The boxers had participated in an average of 17.3 matches, had performed poorly in a match or had been knocked out, and were referred for assessment because of clinical signs of neurological impairment. The PET scans were acquired as an element of the clinical work-up. Retrospective evaluation of these scans was performed. Specific regions of hypometabolism were seen in the boxers’ brains as compared to those of the controls, including the posterior cingulate cortex, parieto-occipital cortex, frontal lobes, and cerebellum.
In addition to assessing regional metabolism, PET can be used to detect the presence of specific molecules or abnormal cellular processes (molecular imaging). Aβ·deposition is an inconsistent feature in CTE. Diffuse plaques are found in about half (47%) of neuropathologically verified CTE cases , a figure that represents a greater frequency than that observed acutely after severe TBI (~30%) . PET imaging using Aβ probes are being currently used in large scale studies of AD. The use of amyloid imaging in suspected CTE has not been established but will be of interest given the similarity between AD and CTE phenotypes and may be useful in determining whether the presence of amyloid post TBI can help predict outcome. This will be of particular interest if the presence of amyloid is associated with worse outcomes, since interventions that reduce the trajectory of brain amyloid accumulation have already been identified in studies of AD.
The original Corsellis series identified diffuse amyloid in 50% of the cases of DP. As mentioned above, DeKosky reported acute amyloidosis within hours or days even in young patients . The natural history of these deposits remains to be established, and this is an important question that can now be addressed with amyloid imaging. Menon has recently reported just such a study, and his conclusion is that the initial burst of amyloidosis is rapidly cleared . One wonders, however, whether clearance might become less efficient as repeated TBI occurs, and longer term studies of such a possibility are underway in our center. In another study, about half of subjects in the chronic phase of recovery from a severe TBI showed positive amyloid scans .
In summary, neuroimaging in CTE holds promise in serving as an in vivo biomarker and should be used in adjunct with a comprehensive history and thorough clinical diagnostic evaluation in life. Prospective, longitudinal neuroimaging studies are needed to help define the clinical and biological markers associated with, and specific to, CTE. Body fluid markers may eventually complement neuroimaging markers, especially in medical centers without access to PET. These body fluid markers have recently been reviewed in detail elsewhere .
The association of CTE with certain sports and with battlefield blast exposure provides a mandate for the construction of accurate databases and epidemiological studies. Securing valid incidence, prevalence, and relative risk data are essential. Current academic papers continue to meet with criticism that the risk is being overstated [127, 128]. While awaiting accurate data upon which to estimate relative risk, informed consent should be developed and offered to those contemplating exposure to repetitive TBI. While the administrative organizations of high impact sports and the military are the obvious organizations to begin informing potential athletes and recruits about the possible risk of CTE, another significant challenge will be the development of informed consent procedures for those overseeing the exposure of children and adolescents . Finding the right balance of established fact and informed opinion will be a challenge, so as not to create unnecessary concern. Extension of genetic epidemiology studies to the pediatric and adolescent population will also be a challenge, albeit a worthy one . The acquisition of definitive data about what genetic factors identified in adolescents are predictive of the eventual personal risk of CTE will require decades of study but are essential.
In parallel, application of validated laboratory models and execution of human clinical trials in the TBI/CTE area should be accelerated. Adaptation of repetitive TBI systems to the mouse holds promise for elucidating the molecular pathogenesis of CTE. The role of APOE genotype should be given high priority in both the animal and the human clinical studies [25, 27]. Compounds emerging from drug discovery efforts in academic and pharmaceutical neurodegenerative disease programs should be considered for assessment in TBI . Emerging data from the AD literature indicating the key role of immune- inflammatory processes may illuminate CTE as well. New data implicate IL-1β in facilitating the development of tauopathy while reducing amyloidosis . Tau oligomerization  may also contribute to the pathogenesis of CTE and may emerge acutely or after a delay . Taken together with the Aβ independence of progressive tauopathy as reported by Brody , the hypothesis that tauopathy and amyloidosis can be dissociated in TBI is supported. The strong association of PTSD with TBI should also be evaluated and clarified .
The challenge of accelerating molecular neuropathology research in an era of dwindling resources is a major concern. Recent alliances between the NFL and the NIH, between the NFL and General Electric, and between the Department of Defense and the NIH Alzheimer’s Disease Neuroimaging Initiative provide some optimism that all the stakeholders are becoming engaged. Permanent commitment and substantial resources from these stakeholders will be required to offset the general reductions in federal support (including NIH and the Department of Defense) due to policies resulting in the recent sequestration of federal funds. In the absence of reliable prevalence data, the calculation of the potential healthcare savings by reduction of TBI exposure is not possible. The total cost of TBI exposure, of course, must take into account what may be enormous payouts from potential class action litigation verdicts. In addition to significant fiscal savings, the support of translational and clinical research programs in TBI/CTE and of development of policies that mitigate some or all of the attributable dementia risk represented by TBI/CTE is obviously justifiable on compassionate grounds. TBI, whether deliberate or unavoidable exposures, represents a source of pain and suffering that could be eliminated or at least greatly reduced with the pooled commitment and resources of the medical, sports, and military sectors. The high visibility of CTE in the media in the early 21st century makes this an opportune moment to apply the information reviewed herein so as to make important advances in elucidation of pathogenesis and in drug discovery.
The authors gratefully acknowledge the support of NIH grants P01NS30318, P01AG14449 and P50AG05133 (S. T. DeKosky and M. D. Ikonomovic), P01AG25204 (M. Ikonomovic), and VA MERIT review grants 1I01BX000348 (S. Gandy), 1 I01 RX000684 (S. Gandy), 1 I01RX000511 (M. D. Ikonomovic), 1I01RX000179 (G.Elder), 1I01RX000996-01 (G.Elder), and I01 CX000190 (E. Mitsis). E. Mitsis was also supported by the Mount Sinai School of Medicine CTSA grant UL1-RR‐029887. Gandy also acknowledges the support of the Cure Alzheimer’s Fund and of US NIH P50 AG05138. Ikonomovic also acknowledges support from The Pittsburgh Foundation grant M2010‐0041. Ahlers acknowledges support from the Office of Naval Research: 0601153 N.0000.00A0702. The authors also acknowledge Defense Health Program-US Army MRMC contracts W81XWH-09-2-0055 (J. Stone), W81XWH-11-2-0109 (J. Stone), W81XWH-09-2-0160 (S. Ahlers, J. Stone), and USUHS award HU0001-08-1-0001 (S. Ahlers, J. Stone). The authors thank P. Davies (North Shore-Hofstra) for helpful discussions. The authors also thank Corey Fernandez for outstanding administrative support. The opinions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or of the Naval Service at large.
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