Chronic Traumatic Encephalopathy

Case series identifying chronic traumatic encephalopathy (CTE) in former athletes and military veterans have been, and continue to be, reported. Recently, there have also been substantial descriptions of the neuropathological similarities and differences between CTE and other neurodegenerative diseases such as Alzheimer disease (AD). Finally, there is growing evidence that neurodegenerative diseases, including Parkinson disease (PD), afflict those with a history of head trauma and blast exposure at higher rates than the general population.1-4 Despite the strong supporting evidence, there is still debate about the relationship between neurotrauma and neurodegeneration, particularly CTE.5-7 In this work, we provide a brief summary of the origin of CTE as it relates to dementia pugilistica (DP) while discussing common clinical presentations of CTE and neuropathological features required for diagnosis. We highlight the role of injury severity, namely concussive or subconcussive injury, in the risk of development of CTE. Additionally, we discuss other risk factors for CTE and elaborate on the relationship between CTE and other neurodegenerative diseases such as AD. Finally, we suggest possible mechanisms of mitigating CTE going forward on the basis of current knowledge and potential changes to playing styles and rules. CTE: AN EXTENSION OF DP? Chronic effects after an extensive history of traumatic brain injury (TBI) were first recognized in a cohort of boxers by Martland8 in the 1920s and referred to as “punch drunk” syndrome. This condition, DP, was later expanded on in numerous other studies that detailed more cases and characterized gross and microscopic pathological findings.9-11 Although DP is a form of traumatic encephalopathy, it is believed to represent a more severe form of traumatic encephalopathy and, by definition, is restricted to boxers. DP is characterized, according to Corsellis et al,10 as a tetrad of gross and microscopic findings: (1) abnormalities (cavum) of the septum pellucidum, (2) scarring of the cerebellum and other brain regions, (3) degeneration of the substantia nigra, and (4) the regional presence of neurofibrillary tangles (NFTs).12,13 Notably, modern CTE, defined initially by Omalu et al,14 is not represented by gross neuroanatomical changes, which is distinct from DP.15-33 CTE SYMPTOMOLOGY AND PRESENTATION CTE can be defined as a progressive neurodegenerative syndrome caused by single, episodic, or usually repetitive blunt force impacts to the head and transfer of acceleration-deceleration and rotational forces to the brain. CTE presents clinically after a prolonged latent period as a composite syndrome of mood disorders, neuropsychiatric symptoms, and cognitive impairment (Figure 1). Typically, a latency period of 6 to 12 years follows the end of a playing career in a contact sport. Thereafter, symptoms consisting of difficulties with personal, business, and financial affairs ensue, with an evolution to depression, often alcohol and substance abuse, and progressive disorganization in activities of life. CTE sufferers may go on to develop mild cognitive impairment and dementia, and many lives end by suicide. Frequently reported CTE symptoms generally fall into 4 broad classifications: behavior, cognition, mood, and motor.22 Behavioral changes reported include those related to heightened aggression, increased impulsive and often risky behaviors, and impaired judgment.34,35 These behavioral changes collectively may occasionally lead to or be associated with a tendency toward violent and explosive outbursts.24 Cognitive changes include short-term memory loss and learning impairments.23 In fact, our prior studies indicate that former professional football players may have a greater risk of severe memory impairment and an increased incidence of mild cognitive impairment and depression compared with the general population.36,37 Common mood changes associated with CTE include depression, apathy, and irritability, potentially leading to an increased risk of suicide. This heightened suicidal risk is in stark contrast to other tauopathies such as AD.15,16,18,38,39 Finally, rare cases of CTE have been associated with motor deficits, possibly a tribute to degeneration within the substantia nigra and loss of dopaminergic neurons.32,40,41 Reported deficits center on decreased reaction time, disordered eye movements, and frequent falls.15,32,33,40,41FIGURE 1: Chronic traumatic encephalopathy timeline. The disease usually presents clinically after a prolonged latent period as a composite syndrome of mood disorders and neuropsychiatric and cognitive impairment.Most patients with CTE have exhibited only some of these symptoms, and consequently, 2 broad classifications of CTE presentation have been described.25 The first, occurring at a younger age of onset, involves primarily mood and behavioral changes.25 These behavioral changes may be attributable to the pathology in the midbrain and pontine dopaminergic, noradrenergic, and serotonergic neurotransmitter alterations (see neuropathology description below). The second, occurring at an older age of onset, manifests itself primarily with cognitive deficits.25 These 2 presentation paradigms demonstrate the continuum of CTE, a disease that has variable latency between neurotrauma exposure and disease onset. Case series have outlined the rarity, range, and continuum of neurobehavioral and cognitive symptoms.6,13-22,26,29-31 GROSS, MICROSCOPIC, AND IMAGING CHARACTERIZATION OF CTE The emerging picture for CTE diagnosis in retired amateur or professional contact sport athletes has been defined in a recent National Institutes of Health report and by research groups.15,26,42 Postmortem brain tissue has revealed the presence of topographically distributed NFTs and neuritic threads with or without the presence of diffuse amyloid plaques (Figure 2 and Table 1). In the pure form, there is usually absence of classic or neuritic amyloid plaques and pathognomonic changes of other types of tauopathies such as progressive supranuclear palsy, corticobasal degeneration, postencephalitic parkinsonism, Guam Parkinson dementia, Lewy bodies, or Lewy neurites. CTE has been a neuropathological diagnosis and is defined most generally as a tauopathy.FIGURE 2: Tau immunohistochemical staining showing (A) a normal control and (B) a chronic traumatic encephalopathy specimen, with characteristic tau protein deposits within the neurofibrillary tangles and neuritic threads.TABLE 1: Neuropathology of Chronic Traumatic EncephalopathyaBecause numerous other neurodegenerative diseases are characterized as tauopathies and, in the case of AD and PD, are associated with neurotrauma, it becomes critically important to delineate between tauopathies. Both clinical presentation and neuropathological abnormalities can be used in this regard. Compared with CTE, AD exhibits more generalized cerebral atrophy and the consistent presence of diffuse and neuritic amyloid plaques. However, diffuse and neuritic plaques are found in an estimated 40% to 50% and 25% to 30% of CTE cases, respectively.33 Focusing on tau, a defining feature of both CTE and AD, reveals differences in not only distribution but also density. NFTs in CTE are generally perivascular and more superficial within the cortex, being most prominent in layers II and III. In AD, in addition to laminar neuritic tau changes in the neutrophil, NFTs are found predominantly in not only layers III but also deeper layers of the cortex, layers V and VI.43 Other differences in NFT distribution can be seen within the hippocampus and parahippocampal gyrus. In CTE, NFTs are seen throughout the Ammon horn (CA1-CA4), whereas NFTs are most heavily focused within CA1 for AD. However, although NFTs can be seen in the locus ceruleus and raphe nucleus in AD, in a number of young individuals without amyloid plaques, these areas can be profoundly affected (Figure 3). Furthermore, in CTE, NFTs are seen in the substantia nigra, an unusual finding in strictly AD cases.43 It is also characteristic to find NFTs throughout the entire amygdala, pontine tegmentum (outside the locus ceruleus and raphe nucleus), and thalamus (particularly within the pulvinar) in CTE.44FIGURE 3: Chronic traumatic encephalopathy in a 41-year-old former professional football player. A, low-power view of the pontine tegmentum with paired helical filament-1 (PHF-1) tau staining of the locus ceruleus (LC) and the raphe nuclei (RN). B, high-power view of the LC PHF-1–positive neurofibrillary tangles. C, high-power view of the RN PHF-1–positive neurofibrillary tangles.Attempts have been made to develop standardized scoring/staging systems for CTE, akin to Braak staging for AD, with leading groups in the CTE field proposing unique classification schemes.15,26,45 The cellular pathophysiology for CTE remains unclear but under active investigation by our group and others.46,47Figure 4 shows possible mechanisms whereby TBI leads to formation of tau oligomers in the neuronal soma. Additional mechanisms that occur after TBI and are potential targets for preventing CTE include endoplasmic reticulum dysfunction, elevation in tau kinases compared with phosphatases, glutamate excitotoxicity, and microglial activation.46 Furthermore, the recent development of imaging technologies recognizing tau deposits and tau distribution in former athletes suspected of having CTE may prove invaluable in tracking disease development and progression in an in vivo study rather than the traditional postmortem analysis. Studies at the University of California Los Angeles using F18DDNP positron emission tomography have shown a characteristic binding density and distribution not seen in other neurodegenerative syndromes (Figure 5).48 Although this radionucleotide labels both tau and amyloid-β (Aβ), the latter may be seen in 10% to 15% of CTE cases, and CTE appears to be in distinct patterns.48,49FIGURE 4: Factors contributing to the pathology of chronic traumatic encephalopathy. Traumatic brain injury (TBI) can lead to diffuse traumatic axonal injury and the shearing of axons. This results in the disruption of tau binding to tubulin, leading to hyperphosphorylation of tau and the formation of tau oligomers in the neuronal soma. Eventually, neurofibrillary tangles form and secreted into the extracellular milieu or spread to other neurons via transsynaptic propagation. Additionally, TBI can cause a rapid blood pressure spike, resulting in disruption of the blood-brain barrier (BBB). This leads to an inflammatory cascade and thus microglia and astrocyte activation.FIGURE 5: Coronal and transaxial 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile (FDDNP) positron emission tomography scan results for National Football League (NFL) players and a control. The players' scans show consistently high signals in the amygdala and subcortical regions and a range of cortical binding from extensive to limited, whereas the control subject shows limited binding in these regions. Red and yellow areas indicate high-FDDNP binding signals.SUMMARY OF REPORTED CTE CASES CTE, originally described by Omalu and colleagues20 in 2005, has been characterized extensively in recent years with cases in professional football players (both the National Football League and Canadian Football League),17,19,26,50 professional wrestlers (World Wrestling Entertainment),16,26 military veterans,14,27 and ice hockey players.26 In fact, recent reports have described and summarized CTE-related neuropathological findings over the course of the past decade alone, including a few cases in athletes who played exclusively in high school or college football.14-17,19,20,22,27,50 Importantly, these cases may increase because we are just beginning to more clearly understand the clinical problem. TBI remains a prominent problem across the globe, with upward of 3.8 million independent events occurring each year in the United States alone.51 Maroon et al52 recently published an excellent systemic review of all CTE cases. ROLE OF CONCUSSION AND SUBCONCUSSIVE INJURY Although the risk of developing CTE has historically been discussed in the context of concussive injury and extensive neurotrauma exposure, emerging evidence indicates that a history of diagnosed or major concussions is not a requirement; instead, repetitive subconcussive injury may play a prominent role in CTE development.53 This finding is based on a lack of documented concussive injury in numerous individuals diagnosed with CTE, although a lack of self-reporting by athletes was common, and concussion without loss of consciousness was not recognized and treated as seriously as it is today. Perhaps the most alarming evidence related to subconcussive injury and possible predilection to neurodegenerative disease is based on (1) documented rates and severity of impacts in football linemen, a position in which retired athletes are commonly diagnosed with CTE49; (2) demonstration of neuroimaging and cognitive changes in those without a history of documented concussions54,55; and (3) laboratory evidence indicating cellular and ultrastructural alterations without changes in levels of alertness or behavior.56 EVOLVING RISK FACTORS FOR CTE: ROLE OF GENOTYPE AND ENVIRONMENT Despite the large number of people exposed to concussive and subconcussive injury, CTE appears problematic for only a small subset of the population exposed to neurotrauma. Other variables may be involved as risk factors for CTE. Identification of these variables remains in its early stage, with speculation that genetics and lifestyle may be implicated.25 Just as in other forms of neurodegeneration such as AD, it has been postulated that the role of the apolipoprotein E (ApoE) ε4 (ApoE4) allele may be a susceptibility factor for the development of CTE; however, this has yet to be borne out. Thus far, no definitive genetic marker has emerged to define CTE risk.52 ApoE is a ligand for low-density lipoprotein receptors and mediates the receptor binding of ApoE-containing lipoproteins to the low-density lipoprotein receptor for cellular uptake and intracellular cholesterol metabolism. In the central nervous system, ApoE is synthesized and secreted primarily by astrocytes and microglia, and its importance is underscored by the absence of most other plasma apolipoproteins in the brain. It is the primary cholesterol transporter in the brain, where it is proposed to function as a ligand directing the delivery of lipids for neuronal repair and remodeling after injury.15,25 In our original cohort, all CTE-positive cases exhibited either an E3/E3 or E3/E4 genotype, with the majority (71%) having the E3/E3 genotype.15 Overrepresentation of the ApoE3 allele has been reported in patients with tangle-only dementia,25,26 whereas the ApoE4 allele has been associated with an increase in the risk of AD, with ApoE4/E4 homozygotes demonstrating a 19-fold increased risk of the development of AD. Those with a CTE diagnosis carry a similar rate of ApoE4 homozygosity as the AD population. In the AD population, it is the greatest risk factor associated with sporadic development of the disease.25,57 The question of whether ApoE4 may be a risk factor for CTE development is consistent with preclinical work in which ApoE4 polymorphism correlated with increased amyloid-β (Aβ) deposition, microgliosis, tau phosphorylation, and neuronal loss after neurotrauma.58,59 The role that lifestyle and environment play in the risk of CTE development remains less investigated and is poorly understood at this time. Our group has shown that administration of anabolic steroids, either before or after neurotrauma, had no effect on amyloid precursor protein expression in the corticospinal tracts after impact-acceleration injury in a rodent model. However, we did not assess tau hyperphosphorylation, the development of NFTs, or damage in other brain regions.60 OVERLAP WITH OTHER NEURODEGENERATIVE DISEASES Over the past few years as autopsy-based CTE diagnoses have become more common in those with histories of neurotrauma, a number of studies have documented the effects of prior TBI, including subconcussion, in the risk of developing other neurodegenerative diseases.1-4,43,53 Perhaps the most well documented of these include AD and PD. Previously, it was felt that AD and CTE were distinct to within the evidence that this may not be the case and that patients may clinical and neuropathological features consistent with both AD and CTE (Figure These case presentations for the presence of CTE the development of CTE and AD within a CTE a progressive or course with It is possible that CTE may that with AD These are clearly to in a clinical population, but has been preclinical The development of a preclinical of CTE has to the that it is possible to both and behavioral deficits consistent with CTE. of neurotrauma in preclinical AD has shown that repetitive neurotrauma the rate of AD, CTE, and with chronic traumatic encephalopathy (CTE) may clinical and neuropathological features consistent with other neurodegenerative AD, Alzheimer PD, Parkinson CTE Although numerous case reports and case series CTE patients have been the incidence and of the disease unclear and be without this research be and the but has the potential not only to to of CTE but also to provide into disease progression clinical and neuroimaging which occur before neuropathological at the of such a study be in groups of exposed and and tracking of In these disease progression can be while from of cognitive dementia, and other neurodegenerative diseases in retired The first study has been for and imaging to AND OF CTE there are no for CTE. the risk for CTE development becomes the and the exposure to concussive and subconcussive head impacts is an of CTE by professional and research as well as the has to extensive of this changes in with a high incidence of with may the and severity of a football has the of and in to the of contact in The National Football National and National of also have to of and changes in the of for activities and contact Although each of these may the number of impacts particularly linemen, who impacts on these changes may not go to the number and severity of the remains that other changes may to be of which involves of the the and in a more position not only in but also at the of both the and of for the of impacts in football is the and number of in the concussion via and also to repetitive changes, in may the incidence of at preventing TBI have to on in the form of Although are in preventing the or of the have to the acceleration-deceleration mechanisms that lead to concussive can or the effects of repetitive head trauma is to also have preclinical studies found that an in the number of brain in a laboratory rodent concussion It is believed that mitigating by blood within within the the for between the and its to preventing CTE of or in cellular and may be on the targets for such are shown in the effects of proposed changes, and to be in the context of CTE studies be These studies imaging to microscopic and cases of CTE are reported in the for of thus only case reports and series have been and studies are for The to in vivo imaging to to the progression of tau protein and to whether it is or which is an are many about CTE and although the incidence and are the that only a small of former contact sport athletes develop the clinical and neuropathological syndrome. The potential for role of neurodegenerative syndrome and numerous other factors and are still Tau and the effects of the 6 of tau to be as the genetic no end being a major contributing factor as to which individuals are at risk concussion with loss of and subconcussive as well as exposure to The importance of age at of exposure and whether the brain is more at a age also are 2: of Chronic Traumatic cases of CTE reported thus have been primarily in those athletes from prior who in contact the 4 a of the that in in ice and other to the related to head the playing styles and of these CTE individuals were under be The of contact in the of in the in and of and the in and other that the incidence of CTE may be in the 3: of Chronic Traumatic TBI, particularly TBI, remains an important in both and after the of CTE as a possible of repetitive concussive or subconcussive neurotrauma. Although the of CTE remains unclear and is to be in the because of the it is that CTE is a problem athletes and military veterans emerging evidence indicates that the of TBI, particularly with repetitive injury, are not limited to increased risk for CTE, AD, and but also may to the development of these diseases these develop and potentially after neurotrauma remains but is a of going studies the relationship between neurotrauma factors age at of injury, and development of CTE, AD, PD, and are to provide into disease our of disease we can changes and that can or the development and progression of CTE. in vivo diagnosis may provide of many of The have no personal, or in of the or described in this

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