Chapter 18 - The long-term consequences of repetitive head impacts: Chronic traumatic encephalopathy

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Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). Although described in boxers for almost a century, scientific and public interest in CTE grew tremendously following a report of postmortem evidence of CTE in the first former professional American football player in 2005. Neuropathologic diagnostic criteria for CTE have been defined, with abnormal perivascular deposition of hyperphosphorylated tau at the sulcal depths as the pathognomonic feature. CTE can currently only be diagnosed postmortem, but clinical research criteria for the in vivo diagnosis of CTE have been proposed. The clinical phenotype of CTE is still ill-defined and there are currently no validated biomarkers to support an in-life diagnosis of “Probable CTE.” Many knowledge gaps remain regarding the neuropathologic and clinical make-up of CTE. An increased understanding of CTE is critical given the millions that could potentially be impacted by this disease. This chapter describes the state of the literature on CTE. The historical origins of CTE are first presented, followed by a comprehensive description of the neuropathologic and clinical features. The chapter concludes with discussion on future research directions, emphasizing the importance of diagnosing CTE during life to facilitate development of preventative and intervention strategies.

Section snippets

Chronic Traumatic Encephalopathy: Historical Origins

The historical origins of CTE have been described in detail by Montenigro et al. (2015). CTE dates back to 1928, when Harrison Martland introduced the term “Punch Drunk” to describe his observation of a clinical syndrome in prizefighters. The prizefighters exhibited early onset behavioral disturbances, characterized by Martland as “goofy,” “slug nutty,” and “cuckoo,” followed by later onset “mental deterioration” (Martland, 1928). Following Martland's paper, numerous different nosologic terms

Neuropathologic Features of Chronic Traumatic Encephalopathy

Corsellis et al. (1973) and Omalu et al. (2005) were among the first to describe the neuropathologic features of CTE. Through the case reports from Omalu (Omalu et al., 2010a, Omalu et al., 2010b, Omalu et al., 2011), and the extensive, ongoing studies by McKee and colleagues at the Boston University (BU) Alzheimer's Disease and CTE Centers and the Veterans Administration-BU–Concussion Legacy Foundation (VA-BU-CLF) Brain Bank (McKee et al., 2013), the neuropathologic descriptions of CTE have

Macroscopic Pathology in CTE

Gross pathology is unremarkable in stage I CTE. In stage II, various macroscopic pathologies are present, including mild enlargement of the lateral ventricles, mild enlargement of the third ventricle, sharp concavity of the third ventricle, cavum septum pellucidum, and pallor of the locus coeruleus and/or substantia nigra. In stage III CTE, there is mild cerebral atrophy and dilation of the lateral and third ventricles. Approximately 40% of stage III cases exhibit septal abnormalities (e.g.,

P-τ

Stage I CTE involves focal perivascular epicenters of p-τ NFT and astrocytic tangles at the sulcal depths, particularly in the superior, dorsolateral, and inferior frontal cortices. In stage II, p-τ NFT become dispersed throughout the cortex and extend into the superficial layers of the cortex adjacent to the perivascular epicenters formed in stage I CTE. There are moderate NFT densities in the nucleus basalis of Meynert and locus coeruleus. P-τ NFT spread further throughout the cerebral cortex

Comorbid Neuropathology

CTE is frequently comorbid with other neurodegenerative diseases, including Lewy body disease (LBD), AD, motor neuron disease (MND), and frontotemporal lobar degeneration (FTLD) (McKee et al., 2013; Mez et al., 2017). The presence of one disease may increase risk for another, possibly due to the interaction between various proteins (e.g., tau, α-synuclein) (Jellinger, 2012; Stein et al., 2014). The comorbidity between CTE and AD is noteworthy given the extant research associating traumatic

The Role of Repetitive Head Impacts in Chronic Traumatic Encephalopathy

Repetitive head impacts refer to the cumulative lifetime exposure of an individual to recurrent concussive (or mild TBI) and subconcussive injuries (Montenigro et al., 2016). RHI can also include recurrent moderate and severe TBIs, but the majority of all head trauma is mild in nature. CTE has been studied and characterized largely in the context of exposure to sport-related concussive and subconcussive head impacts, and to a lesser extent, head trauma in military veterans. In the following

Concussion

Concussion, a mild TBI subtype, is a complex pathophysiologic process affecting the brain secondary to biomechanical forces induced from direct or indirect blows to the head (McCrory et al., 2013). An estimated 1.6–3.8 million concussions occur from sports and recreational activities each year in the United States (Langlois et al., 2006). The true prevalence of concussion is likely much greater, given that many or most are not reported. Sport-related concussion rates are highest in American

Repetitive Head Impacts

Recurrent concussion is a component of RHI, but it is the numerous lifetime subconcussive head impacts that appear to play a prominent role in the pathogenesis of CTE. For example, 16% of neuropathologically confirmed cases of CTE have no history of reported concussions, but did have significant subconcussive exposure (Stein et al., 2015a). Furthermore, McKee et al. (2013) concluded that family-reported number of concussions was unrelated to CTE pathologic stage, yet all 68 cases diagnosed with

Repetitive Head Impacts and CTE: Potential Mechanisms

The mechanisms underlying the association between RHI and CTE are not currently known and are likely multifaceted. The acceleration and deceleration of the head during concussion can result in shearing and tensile forces on long fibers, such as axons and blood vessels, and cause traumatic axonal injury and an array of neurometabolic pathophysiologic changes (e.g., ionic flux and glutamate release, neuroinflammation, altered neurotransmission, microvasculopathy) (Maxwell et al., 1997; Medana and

Military Veterans and Chronic Traumatic Encephalopathy

A majority of neuropathologically diagnosed cases of CTE have been former contact sport athletes, but military veterans may also be at risk. McKee et al. (2013) found 16 of 21 military veterans with CTE were also contact sport athletes (8 former NFL players) and 9 of the veterans saw combat (4 in Iraq and Afghanistan, 1 in Gulf War, 2 in Vietnam, and 2 in World War II), and 3 were exposed to blast. A history of blast exposure in military veterans is of particular concern in terms of CTE risk.

Postmortem retrospective data

McKee et al. (2013) provided an initial description of the clinical symptoms associated with CTE that included a combination of behavior (e.g., aggression, explosivity), mood (e.g., depression, suicidal ideations), and cognitive symptoms (e.g., executive dysfunction, episodic memory impairment). These findings were consistent with earlier reports of boxers (Mawdsley and Ferguson, 1963; Corsellis et al., 1973). Stern et al. (2013) conducted a comprehensive study to better delineate the clinical

Clinical Research Diagnostic Criteria

Three different author groups (Jordan, 2013; Victoroff, 2013; Montenigro et al., 2014) have proposed similar clinical research diagnostic criteria that are compared in detail elsewhere (Baugh et al., 2014). The primary difference among the criteria is the central role of motor features for the clinical diagnosis of CTE in the Jordan (2013) criteria, whereas motor symptoms are supportive features of CTE in the other criteria. Montenigro et al. (2014) coined the nosology “Traumatic Encephalopathy

Potential Biomarkers of CTE

The use of biomarkers has become the gold standard for diagnosing “Probable AD” during life (Jack et al., 2011; McKhann et al., 2011), and a similar approach is being adopted in CTE. The Montenigro et al. (2014) TES clinical research criteria proposed the following biomarkers to designate “Probable CTE”: Cavum septum pellucidum, normal β-amyloid cerebrospinal fluid (CSF) levels, elevated CSF p-τ/τ ratio, negative amyloid imaging, positive tau imaging, cortical thinning, and cortical atrophy.

Risk and Protective Factors

As previously highlighted, neuropathologic evidence supports RHI as a necessary risk factor for CTE diagnosis, and we present research below that has examined RHI exposure and later-life neurologic impairment in living subjects. Because RHI exposure history alone is not sufficient for the development of CTE, other risk factors are believed to interact with RHI to either (1) contribute to the development of CTE, and/or (2) contribute to the symptom heterogeneity observed in CTE. Despite the

Conclusions and Future Directions

Chronic traumatic encephalopathy is a unique neurodegenerative disease associated with a history of exposure to RHI. Neuropathologic and clinical research in CTE has evolved rapidly over the past decade and has led to improved understanding of this progressive and devastating, but potentially preventable, brain disease. In particular, neuropathologic diagnostic criteria have been developed and clinical research criteria for the in vivo diagnosis of CTE have been proposed. The existing

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