Portal de Periódicos da CAPES

Chronic Traumatic Encephalopathy

2015; Lippincott Williams & Wilkins; Volume: 62; Issue: Supplement 1 Linguagem: Inglês

10.1227/neu.0000000000000811

1524-4040

Julian E. Bailes, Ryan C. Turner, Brandon Lucke‐Wold, Vimal Patel, John M. Lee,

Cardiac Arrest and Resuscitation

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 entities, failing to exist within the same patient. Emerging evidence demonstrates that this may not be the case and that patients may exhibit clinical and neuropathological features consistent with both AD and CTE (Figure 6).25 These case presentations raise further questions for future investigation. Does the presence of CTE accelerate the development of AD? Can CTE and AD coexist within a patient? Does CTE exhibit a progressive or nonprogressive course with aging? It is entirely possible that CTE may exhibit age-dependent characteristics that act synergistically with AD development. These questions are clearly difficult to answer in a clinical population, but significant insight has been provided through preclinical investigation. The development of a preclinical model of CTE has led to the observation that it is possible to recreate both biochemical and behavioral deficits consistent with CTE. Likewise, application of neurotrauma in preclinical AD models has shown that repetitive neurotrauma accelerates the rate of AD, CTE, and PD development.35,61,62FIGURE 6: Patients with chronic traumatic encephalopathy (CTE) may exhibit clinical and neuropathological features consistent with other neurodegenerative diseases. AD, Alzheimer disease; PD, Parkinson disease.ADVANCING CTE EPIDEMIOLOGY THROUGH LONGITUDINAL STUDIES Although numerous case reports and case series involving CTE patients have been reported, the precise incidence and scope of the disease remain unclear and cannot be answered without prospective, long-term studies.6,52 Undertaking this research will be costly and time consuming, much like the Framingham Heart Study, but has the potential not only to contribute to elucidation of CTE epidemiology but also to provide insight into disease progression through serial clinical and neuroimaging assessments, which would occur before eventual neuropathological analysis at the time of death. Likewise, such a study would ideally be initiated in demographically matched groups of exposed and unexposed patients, allowing chronological monitoring and tracking of symptoms. In these regards, disease progression can be mapped while eliminating recall bias from retrospective reporting of cognitive impairment, dementia, and other neurodegenerative diseases in retired players.3,36,63-65 The first longitudinal prospective study has been initiated for mixed martial arts fighters and uses functional magnetic resonance imaging to track changes.38 PREVENTION AND MITIGATION OF CTE Currently, there are no established treatments for CTE. Therefore, reducing the risk for CTE development becomes the goal, and limiting the exposure to concussive and subconcussive head impacts is an obvious approach. Widespread acceptance of CTE by professional medical and research personnel, as well as the lay public, has led to extensive discussion of this topic. Rule changes in sports with a high incidence of concussion, along with proper enforcement, may reduce the frequency and severity of concussion. Pop Warner Football, a youth football league, has endorsed the prevention of cranial collisions and in 2012 added regulations to limit the amount of contact allowed in practice.50,66 The National Football League, National Collegiate Athletic Association, and National Federation of High Schools also have taken steps to limit cranial collisions through tougher enforcement of targeting penalties and changes in the length of time permitted for organized team activities and contact practicies.67 Although each of these steps may reduce the number of cranial impacts sustained, particularly among linemen, who sustain impacts on every play, these changes may not go far enough to address the number and severity of impacts. Therefore, the possibility remains that other rule changes may need to be implemented, one of which involves elimination of the 3-point stance along the offensive and defensive lines.53 Having linemen start in a more upright, squatting position not only would reduce cranial involvement in collisions but also would decelerate linemen at the point of contact, thereby reducing both the frequency and magnitude of cranial impacts.53 Another option for reducing the frequency of cranial impacts in football is slowing the tempo and number of plays in the game. Acute concussion management via education, culture change, and proper medical surveillance should also minimize detrimental exposures to repetitive TBI. Beyond rule changes, further improvements in technology may substantially reduce the incidence of concussion. Efforts aimed at preventing TBI have continued to focus on extracranial protection in the form of improved helmet technology. Although helmets are effective in preventing the infrequent penetration or fracture of the skull, they have little ability to limit the high-velocity acceleration-deceleration mechanisms that lead to concussive injury.68 Whether headgear can prevent or reduce the cumulative effects of repetitive head trauma is unknown. Efforts to reduce intracranial slosh phenomenon also have potential. Published preclinical studies found that internal jugular vein compression produced an 80% reduction in the number of torn brain fibers in a standard laboratory rodent concussion model.69,70 It is believed that mitigating slosh by increasing blood volume within venous structures within the skull will significantly reduce the propensity for differential motion between the skull and its contents. Likewise, pharmacological approaches to preventing CTE through modulation of membrane integrity or reduction in cellular stress and subsequent tauopathy may be on the horizon.71,72 Potential molecular targets for such intervention are shown in Figure 4. For the beneficial effects of any proposed rule changes, preventive technologies, and therapeutics to be fully assessed in the context of CTE development, prospective studies must be conducted. These studies must incorporate advanced imaging to track neurometabolic, microscopic neurostructural, and neurofunctional changes. CONCLUSION Approximately 150 cases of CTE are reported in the literature, if one accounts for publication of duplicative cases.52 Because thus far only case reports and retrospective selected series have been published, long-term and longitudinal studies are needed for clarification. The ability to perform in vivo imaging will allow us to follow living subjects to track the progression of tau protein deposition and to learn whether it is dynamic, reversible, or treatable, which is an exciting scientific frontier. There are many remaining uncertainties about CTE (Table 2), and although the true incidence and prevalence are unknown, the senior author (J.E.B.) believes that only a small minority of former contact sport athletes will develop the full clinical and neuropathological syndrome. The potential for confounders, environmental factors, role of comorbidities, neurodegenerative syndrome overlap, natural history, and numerous other factors and their impact are still presently unknown. Tau proteinopathy and the effects of the 6 different isoforms of tau remain to be elucidated. And as always, the genetic influence will no doubt end up being a major contributing factor as to which individuals are at risk if they sustain multiple concussions, concussion with loss of consciousness, and subconcussive impacts, as well as total lifetime exposure to TBI. The importance of age at onset of exposure and whether the human brain is more vulnerable at a specific age also are unclear.TABLE 2: Uncertainties of Chronic Traumatic EncephalopathyThe cases of CTE reported thus far have been primarily in those athletes from prior decades who participated in contact sports during the last 4 decades. As a result of the reforms that occurred in 2010 in football, ice hockey, and other sports to address the issues related to head contact, the playing styles and management of these CTE individuals were under what would now be considered outdated protocols. The limitation of head-to-head contact in practice; the outlawing of egregious head-to-head hits in games; the improvement in education, coaching techniques, and reporting of concussions; and the advances in helmets, biosensors, and other protective equipment make us optimistic that the incidence of CTE may be significantly reduced in the future (Table 3).TABLE 3: Elimination of Chronic Traumatic EncephalopathyaWorldwide, TBI, particularly "mild" TBI, remains an important topic in both lay and scientific communities after the emergence of CTE as a possible consequence of repetitive concussive or subconcussive neurotrauma. Although the epidemiology of CTE remains unclear and is unlikely to be resolved in the near future because of the inherent challenges, it is clear that CTE is a burgeoning problem affecting athletes and military veterans alike. Similarly, emerging evidence indicates that the consequences of TBI, particularly with repetitive injury, are not limited to increased risk for CTE, AD, and PD independently but also may predispose to the development of these diseases concurrently. How these conditions develop and potentially coalesce after neurotrauma remains unknown but is a point of interest going forward. Future studies addressing the relationship between neurotrauma factors (severity, number, interinjury interval, age at time of injury, etc) and development of CTE, AD, PD, and CTE-AD are needed to provide further insight into disease pathophysiology. By increasing our understanding of disease pathophysiology, we can better implement rule changes and preventive strategies that can mitigate or prevent the development and progression of CTE. Emerging in vivo diagnosis may provide clarification of many aspects of CTE.49 Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.