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Author: Ann C. McKee
The variety of clinical symptoms associated with boxing was first described in 1928 by Harrison Martland, who found abnormalities in “nearly one half of the fighters who have stayed in the game long enough.” The general public referred to the condition as “punch drunk,” “goofy,” and “slug-nutty” (Critchley 1957; Parker 1934), and the scientific terms were dementia pugilistica (Millspaugh 1937) and chronic traumatic encephalopathy (CTE) (Critchley 1949).
The clinical symptoms of CTE typically develop insidiously, years to decades after exposure to repetitive brain trauma (Corsellis et al. 1973; McKee et al. 2013; Stern et al. 2013), although occasionally they develop while an individual is still active in a sport and may be difficult to distinguish from prolonged postconcussive syndrome. A distinguishing feature between postconcussive syndrome and CTE is that symptoms of the former do not progress to become more debilitating (Mez et al. 2016b).
The age at onset of CTE symptoms is often midlife (mean = 44.3 years, standard error of the mean [SEM] = 1.5, range 16–83 years), decades after retirement from the sport (mean = 14.5 years, SEM = 1.6, n = 104). Nearly a quarter of individuals later diagnosed with CTE were symptomatic at the time of their retirement from sports. The clinical course is often protracted (mean duration = 15.0 years, SEM = 1.2, n = 125) (McKee et al. 2013; Stein et al. 2014, 2015).
Clinical Features of CTE
The clinical presentation of CTE characteristically begins in one or more of four distinct domains: mood, behavior, cognitive, and motor. The mood disorder is most commonly depression. Behavioral symptoms include explosivity, verbal and physical violence, loss of control, impulsivity, paranoia, and rage behaviors (Montenigro et al. 2014; Stern et al. 2013). Cognitively, the most prominent deficits are in memory, executive functioning, and attention. Approximately 45 percent of subjects with CTE develop dementia, and in individuals over the age of 60 years at the time of death, dementia was found in 66 percent. Motor symptoms such as dysarthria (unclear articulation), dysphagia (difficulty swallowing), coordination problems, and Parkinsonism (tremor, decreased facial expression, rigidity, and gait instability) may also develop (Mez et al. 2013). Chronic headaches also occur in 30 percent (Stern et al. 2013).
Stern and colleagues (2013) distinguish two courses of clinical presentation. The first presents with mood and behavioral symptoms early in life (mean age = 35 years) and progresses in severity to include cognitive symptoms later in the disease course. The second presents with cognitive symptoms later in life (mean age = 60 years) and often progresses to include mood and behavioral symptoms.
Preliminary criteria for the clinical diagnosis of CTE have been proposed by three groups (reported in Jordan 2013; Montenigro et al. 2014; Victoroff 2013). The criteria differentiate between possible and probable CTE based on various clinical symptomology and follow a structure similar to the National Institute on Aging–Alzheimer’s Association clinical diagnostic criteria for other neurodegenerative diseases (McKhann et al. 2011). The Montenigro criteria distinguish between the clinical syndrome of CTE, referred to as traumatic encephalopathy syndrome (TES), and the pathological diagnosis of CTE, which is based on postmortem evaluation. TES is further characterized in subtypes—behavioral/mood variant, cognitive variant, mixed variant, and TES dementia—based on the presence or absence of various groups of symptoms (Montenigro et al. 2014).
To date, nearly all information collected regarding the clinical presentation of CTE has come from retrospective analysis of subjects analyzed after death (McKee et al. 2013; Stern et al. 2013). Ongoing large-scale retrospective studies, such as the recently funded Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) UO1 project funded by the National Institute of Neurological Disease and Stroke (NINDS) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB), examine the clinical presentation of brain donors designated as “at risk” for the development of CTE, develop a blinded consensus clinical diagnosis, and compare that diagnosis to equally blinded postmortem neuropathological assessment (Mez et al. 2015).
Preliminary indications are that the clinical criteria for CTE are highly sensitive but lack specificity (Mez et al. 2016a). Additional analyses using data from the UNITE study will provide detailed information on the specificity of item-level symptoms to allow further refinements in the clinical criteria. Recent funding of large-scale longitudinal prospective studies will also help clarify the precise clinical distinctions between CTE and other neurodegenerative and neuropsychiatric disorders.
In Vivo Biomarkers
The use of in vivo biomarkers could greatly improve the accurate diagnosis of CTE during life, as well as facilitate the monitoring of disease progression and the efficacy of disease-modifying therapies. While no diagnostic biomarkers are currently available, several promising techniques are being developed.
Tau-specific ligands used in positron emission tomography have demonstrated encouraging results in Alzheimer’s disease (Chien et al. 2013; Xia et al. 2013) and mild cognitive impairment (Johnson et al. 2015). Studies using diffusion tensor imaging have detected changes in white matter integrity after head trauma (Koerte et al. 2012). Other studies have examined functional connectivity through the use of functional magnetic resonance imaging, magnetic resonance spectroscopy, and cerebrospinal fluid and plasma protein markers (including phosphorylated [p-tau] and total tau) (Buerger et al. 2006; Lin et al. 2012; McKhann et al. 2011) as potential in vivo diagnostic tools.
Neuropathology of CTE
The neuropathology of CTE is distinctive. Although grossly identifiable changes are minimal in early stages of CTE, in advanced disease there may be macroscopic changes such as reduced brain weight, cerebral atrophy (most severe in the frontal, anterior temporal, and medial temporal lobes), fenestrations in the cavum septum pellucidum, enlargement of the lateral and third ventricles, thinning of the corpus callosum, atrophy of the diencephalon and mammillary bodies, and depigmentation of the locus coeruleus and substantia nigra.
Microscopically, CTE is characterized by the deposition of hyperphosphorylated tau protein as neurofibrillary tangles (NFTs), thorned astrocytes (TAs), and neurites in a unique pattern in the brain. The tau pathology is characteristically a perivascular distribution and shows a predilection for the depths of the cerebral sulci.
In 2013 my colleagues and I described a spectrum of p-tau pathology in 68 male subjects, ranging in age from 17 to 98 years (mean 59.5 years), with a history of exposure to repetitive brain trauma and neuropathological evidence of CTE. Based on our findings we proposed provisional criteria for neuropathological diagnosis and a 4-tiered staging scheme of pathological severity (McKee et al. 2013).
Stage I CTE is characterized by isolated perivascular foci of p-tau as NFTs and TAs present at the sulcal depths of the cerebral cortex. In stage II multiple foci of p-tau are found in the cerebral cortices, and in stage III NFTs appear in the superficial cortices adjacent to the focal epicenters, with involvement of the medial temporal lobe structures (hippocampus, amygdala, and entorhinal cortex). In Stage IV CTE there is severe widespread p-tau pathology in the cortices, diencephalon, brainstem, and cerebellum (figure 1) (McKee et al. 2013).
Other abnormalities encountered in severe CTE include abnormal deposits of the phosphorylated transactive response DNA-binding protein (TDP-43) that occasionally colocalizes with p-tau, and varying degrees of beta-amyloid (Aβ) pathology, axonal dystrophy, and neuroinflammation (McKee et al. 2010, 2013).
It is worth noting that, among former American football players, we found that the stages of CTE severity correlated significantly with the duration of exposure to football, age at death, and years since retirement from the game (McKee et al. 2013).
Beta-amyloid plaques are present in 52 percent of individuals with CTE (Stein et al. 2015). In contrast to the extensive Aβ plaques that characterize nearly all cases of Alzheimer’s disease, Aβ plaques in CTE, when they occur, are less dense and predominantly diffuse (McKee et al. 2009). They are also significantly associated with accelerated tauopathy, Lewy body formation, dementia, Parkinsonism, and inheritance of the ApoE4 allele (Stein et al. 2015).
As the first part of a series of consensus panels funded by the NINDS/NIBIB to define neuropathological criteria for CTE, the criteria set forth in McKee et al. (2013) were used by seven neuropathologists to evaluate 25 cases of various tauopathies: CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and Parkinsonism-dementia complex of Guam. The researchers evaluated the cases blinded to all information on age, gender, clinical symptoms, diagnosis, athletic exposure, and gross neuropathological findings and determined that there was good agreement between reviewers and the diagnosis of CTE and excellent identification of the cases of CTE.
Based on these results, the panel refined the diagnostic pathological criteria for CTE and defined a pathognomonic lesion for CTE, an accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The panel also defined supportive but nonspecific features of CTE (NINDS 2015).
Recently, two large neurodegenerative disease brain banks have reported comorbid CTE in their series (Bieniek et al. 2015; Ling et al. 2015). Bieniek and colleagues reported that 21 of 66 (31.8 percent) former athletes had cortical tau pathology consistent with CTE on postmortem neuropathological examination, whereas no CTE pathology was detected in 198 individuals who had no exposure to contact sports, including 33 individuals with documented single-incident traumatic brain injury (TBI) (Bieniek et al. 2015). Ling and colleagues found the occurrence of CTE in 11.9 percent of 268 screened cases of neurodegenerative diseases, associated with a history of TBI in 94 percent of those who exhibited CTE.
CTE is a neurodegenerative disease that occurs after exposure to repetitive head trauma. Cumulative exposure to trauma, not the number of concussions, is associated with the severity of p-tau pathology, suggesting that subconcussive impacts are important for disease development.
CTE most commonly manifests in midlife and produces clinical symptoms of disordered cognition, memory loss, executive dysfunction, depression, apathy, disinhibition, and irritability as well as Parkinsonism. The neuropathology of CTE is increasingly well defined; a NINDS/NIBIB panel of expert neuropathologists has identified preliminary criteria and a pathognomonic lesion for the neuropathological diagnosis of CTE. Currently, neuropathologic examination of postmortem brain tissue is the only way to diagnose CTE, although intense research efforts are under way to identify biomarkers to detect and monitor the disease during life and to develop therapies to slow or reverse its course.
Newly funded longitudinal, prospective research efforts will shed additional light on critical variables related to head trauma exposure, genetics, and lifestyle factors that influence the development of CTE.
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