The neuropathology of chronic traumatic encephalopathy

Handbook of Clinical Neurology, Vol. 158 (3rd series) Sports Neurology B. Hainline and R.A. Stern, Editors https://doi.org/10.1016/B978-0-444-63954-7.00028-8 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 28

The neuropathology of chronic traumatic encephalopathy ANN C. MCKEE1,2*, BOBAK ABDOLMOHAMMADI2, AND THOR D. STEIN1,2 1 VA Boston Healthcare System, Boston, MA, United States 2

Departments of Neurology and Pathology, Boston University School of Medicine, and Boston University CTE Center, Boston, MA, United States

Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head trauma, including concussion and subconcussion. CTE was first recognized in boxers nearly a century ago as “dementia pugilistica” or “punch drunk,” but has been recently identified in contact sports athletes (including American football, ice hockey, soccer, baseball, rugby, boxing, and wrestling) and military veterans exposed to blast. Similar to many other neurodegenerative diseases, CTE is diagnosed conclusively only by neuropathologic examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau as neurofibrillary tangles, abnormal neurites, and inclusions in astrocytes around small blood vessels with a tendency to occur in clusters at the sulcal depths of the cortex. Using the McKee criteria, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic CTE lesion that has only been found in individuals exposed to brain trauma. Recently, 177 instances of CTE were reported in a convenience sample of 202 former American football players, including 110 of 111 former National Football League players (99%), 48 of 53 former college football players (91%), and 3 of 14 former high school players (21%), by far the largest case series ever reported. Significant increases in active microglia and inflammation also occur after repetitive head impact injury and in CTE. A preliminary study showed that inflammatory cytokines were elevated in the brain tissue and cerebrospinal fluid of individuals with pathologically confirmed CTE compared to controls and individuals with Alzheimer disease, which may some day be useful in diagnosis of CTE during life. Although many fundamental questions remain to be answered regarding CTE, postmortem analysis of tissue from brain donors and tissue-based research have accelerated and expanded our current understanding of CTE and its pathogenesis. Guided by the neuropathologic findings, current research efforts are underway to develop biomarkers to diagnose CTE and effective ways to treat the disorder during life.

INTRODUCTION The notion that repetitive blows to the head can induce permanent cognitive and behavioral difficulties was first posited by Harrison Martland in 1928. Martland, a pathologist, described a syndrome of progressive neurologic deterioration in boxers, a clinical condition he termed “punch-drunk.” Over the next few decades, the condition was referred to as “dementia pugilistica” (Millspaugh, 1937), “the psychopathic deterioration of

pugilists” (Courville, 1962), “traumatic progressive encephalopathy” (Parker, 1934), and “chronic traumatic encephalopathy” (CTE) (Critchley, 1949). By the 1990s, the last term was generally accepted, highlighting the idea that neurodegeneration after trauma was not limited to boxers (Hof et al., 1991; Jordan, 1992; Geddes et al., 1996, 1999), and is found in men and women exposed to a wide variety of repetitive closed-head injuries, including physical abuse (Roberts et al., 1990), head banging (Hof et al., 1991;

*Correspondence to: Ann C. McKee, MD, VA Boston Healthcare System, 150 S. Huntington Avenue, Boston MA 02130, United States. Tel: +1-617-414-1326, Fax: +1-617-414-1197, E-mail: [email protected]

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Geddes et al., 1999; McKee et al., 2013), rugby (Geddes et al., 1999), poorly controlled epilepsy (Geddes et al., 1999), and circus “dwarf throwing” (Williams and Tannenberg, 1996). In the 2000s, CTE was reported in association with American football (Omalu et al., 2005, 2006; McKee et al., 2009, 2013), ice hockey (McKee et al., 2013), mixed martial arts (McKee et al., 2013), soccer (McKee et al., 2014), baseball (McKee et al., 2014), and military personnel exposed to blast injury (Omalu et al., 2011; Goldstein et al., 2012; McKee et al., 2013).

HISTORIC PERSPECTIVE In 1973, the first large case series of boxers with dementia pugilistica was reported by Corsellis and colleagues, who described clinical and pathologic findings in 15 former male boxers from 57 to 91 years old. Macroscopically, the most common abnormalities were reduced brain weight, widening of the lateral and third ventricles, cavum septum pellucidum with fenestrations, thinning of the hypothalamic floor, atrophy of the fornices and mammillary bodies, thinning of the corpus callosum, depigmentation of the substantia nigra, and scarring of the cerebellar tonsils. In addition, using cresyl violet, von Braunmuhl silver, and King’s amyloid stains, they found neuronal loss and gliosis in the hippocampus and medial temporal lobe, moderate densities of neurofibrillary tangles (NFTs) in the frontal and temporal cortices, uncus, amygdala, hippocampus, parahippocampal and fusiform gyri, diencephalon substantia nigra, and locus coeruleus. Approximately 20% showed widespread subcortical myelin loss and senile plaques. In 1990, Roberts and colleagues described the first case of CTE in a female, a 76-year-old woman who was physically abused for decades and developed memory loss, confusion, and dementia before her death. In 1991, CTE was described in a 24-year-old woman with autism and prominent head-banging behaviors (Hof et al., 1991). She had perivascular clusters of thioflavin and Gallyas-positive NFTs and neurites at the depths of the cerebral sulci and in the superficial layers of the inferior temporal, entorhinal, and perirhinal cortices, but no beta amyloid (Aß) plaques (Hof et al., 1991). Hof and colleagues (1992) also observed that the superficial distribution of the NFTs was similar to the laminar distribution in two other environmentally acquired tauopathies, postencephalitic parkinsonism and Guamanian parkinsonism dementia complex, but not characteristic of Alzheimer disease (AD). In 1999, using a variety of antibodies to hyperphosphorylated forms of tau (p-tau), including AT8 (Ser 202/Thr205), AT180 (Thr231), and AT270 (Thr181), Geddes and colleagues (1999) described patchy, perivascular

deposits of NFTs in the brain of a 23-year-old boxer. They compared immunohistochemical findings from that brain and those of 4 other 23–28-year-old men exposed to repetitive brain trauma from head banging, poorly controlled epilepsy, rugby, and boxing, to 21 age-matched controls. Geddes and colleagues (1999) described argyrophilic, tau-positive cortical NFTs and neuropil threads strikingly arranged in groups around small intracortical blood vessels and diffuse granular cytoplasmic immunopositivity in some neurons. They also noted that the topography of the pathologic findings principally involved the depths of sulci. The hippocampus of all the young cases was normal. A single perivascular cluster of NFTs was found in the transentorhinal cortex of one young boxer, and no Aß deposits were evident. None of the age-matched controls showed similar perivascular NFT pathology (Geddes et al., 1999). Individual reports of clinical findings and neuropathologic features of 2 former professional National Football League (NFL) players were published in 2005 and 2006 (Omalu et al., 2005, 2006). In the first case, the authors described sparse NFTs in a nonspecific cortical distribution and diffuse Aß plaques. There was no mention of a perivascular pattern, clustering, or laminar distribution of the p-tau pathology, characteristics of CTE, previously emphasized by Hof et al. (1991) and Geddes et al. (1999). Accordingly, the evidence presented by the authors supported the presence of a tauopathy, but there was little to substantiate the specific diagnosis of CTE. In addition, in later references to the paper, the authors made the claim that they were the first to name the disease “chronic traumatic encephalopathy,” despite the introduction of that term over 50 years earlier (Critchley, 1949). In the second NFL case, frequent NFTs were described in the frontal and temporal cortices, diencephalon, and brainstem. In spite of the authors’ lack of detail to support a specific diagnosis, inspection of Figure 1 in that paper shows a perivascular pattern of NFTs in the frontal cortex, confirming the presence of CTE (Omalu et al., 2006). In 2009, the unique immunocytochemical features and regional distribution of the p-tau pathology in CTE were detailed in 2 former boxers and an American football player, in addition to a systematic review of all 48 previous neuropathologically verified cases of CTE in the literature (McKee et al., 2009). Cavum septum pellucidum or septal fenestrations were common gross neuropathologic findings, present in 69% and 49% of the CTE cases, respectively. Microscopically, neuronal loss and gliosis were found in severe cases, most pronounced in the medial temporal structures (amygdala, hippocampus, entorhinal cortex) and often accompanied by severe neurofibrillary degeneration. Using whole-mount landscape slides as a

THE NEUROPATHOLOGY OF CHRONIC TRAUMATIC ENCEPHALOPATHY novel method of illustrating regional p-tau pathology, the irregular, patchy distribution of NFTs and the prominent perivascular pattern were noted. Also described were astrocytic inclusions and dot-like and spindle-shaped neurites, abnormalities not previously noted. The report emphasized the striking predilection for the depths of the cortical sulci in the frontal, temporal, insular, septal, and parietal cortices; sparing of primary visual cortex; and involvement of the subcortical U-fibers, corpus callosum, and subcortical white matter. In 2011, Omalu and colleagues reported finding CTE at postmortem examination in 10 of 17 athletes ranging from 18 to 50 years, including 6 of 7 American football players, 1 of 3 high school football players, 2 of 4 wrestlers, and 1 professional boxer. They proposed criteria for neuropathologic diagnosis of CTE and set forth four “emerging phenotypes.” The neuropathologic criteria for the four emerging phenotypes of CTE were based solely on the presence of NFTs and neuritic threads (NTs) in the cerebral cortex, subcortical nuclei, and brainstem in the presence or absence of diffuse Aß plaques. The criteria did not include specific characteristics of the tau pathology or distinctive distribution patterns of the NFTs or NTs. In all four phenotypes, NFTs and diffuse Aß plaques could be present or absent in the hippocampus (Table 28.1). In addition, the phenotypes did not distinguish the tauopathy of CTE from those seen in AD, primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, or any other tauopathy. The authors recommend that caution be exercised “to avoid confusing CTE with Alzheimer’s disease pathology, normal aging-related changes in the brain, and/or chronic ischemic changes/small vessel disease changes in the brain.” Using this phenotype scheme, the presence of even a few nonspecific NFTs in the cortex or brainstem would merit diagnosis of CTE type 4 (incipient CTE).

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Furthermore, AD would be classified as CTE type 2. The authors also proposed assessing NFT density using a semiquantitative scale designed expressly for Aß plaques (the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) plaque density scoring system) (Mirra et al., 1991). In 2013, CTE was described in a case series of 68 men from 17 to 98 years old (mean 59.5 years). These cases were compared to 18 age-and sex-matched individuals without a history of brain trauma (McKee et al., 2013). Unique patterns and distributions of tau pathology in CTE were described that were unlike all other tauopathies, including AD. Distinctive features of CTE included the presence of perivascular foci of NFTs irregularly distributed in the cortex, with a predilection for sulcal depths; NFTs distributed in the superficial layers of cortex; and subpial p-tau astrocytes at the sulcal depths. The authors proposed preliminary criteria for the neuropathologic diagnosis of CTE (McKee criteria, Fig. 28.1 and Table 28.2). These include the presence of at least one perivascular p-tau lesion consisting of NFTs and neurites around a small vessel, often distributed at the depths of the sulci in the cerebral cortex. McKee and colleagues further proposed a staging scheme for characterizing progressive p-tau pathology in CTE (staging of CTE pathology; Fig. 28.2). The McKee staging scheme for CTE was adapted from the work of Braak and Braak (1991), who examined 83 brains from people with AD at autopsy and described a six-tiered hierarchic distribution pattern of NFTs and NTs. The Braak staging scheme forms the basis for the neuropathologic diagnosis of AD used by all National Institute on Aging-supported studies (Hyman and Trojanowski, 1997). Similar staging schemes are now used for Aß plaques in AD (Thal et al., 2006) and Lewy bodies in Parkinson disease (Braak et al., 2003).

Table 28.1 Four emerging histologic phenotypes of chronic traumatic encephalopathy

Type

Cerebral cortex

Type 1 Type 2 Type 3 Type 4 (incipient)

1–3 + 1–3 + 0–1 + 0–1 + (several)

Subcortical nuclei/basal ganglia 0/+ 0/+ 0–1 + 0–1 + (several)

Brainstem

Cerebellum

Hippocampus NFTs/ NTs

1–3 + 1–3 + 1–3 + 0–1 + (several)

0 0 0 0

0–3 + 0–3 + 0–3 + 0–3 +

Aß plaques in cortex

Aß plaques in hippocampus

0 1–33 + 0 0

0/+ 0/+ 0/+ 0/+

Reproduced rom Omalu B, Hammers JL, Bailes J, et al. (2011) Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg Focus 31: E3.339. None ¼ 0; sparse ¼ 1; moderate ¼ 2; frequent ¼ 3. NFT, neurofibrillary tangle; neuritic thread.

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Fig. 28.1. McKee criteria for the neuropathologic diagnosis of chronic traumatic encephalopathy (CTE) (McKee et al., 2013). Microscopic CTE p-tau pathology. (A) Clusters of neurofibrillary tangles (NFTs) and glial tau pathology are often found at the depths of the sulci in the frontal, insular, and temporal cortices (*), often associated with clusters of subpial astrocytic tangles (ATs) (●). (B, D, E, G, H) There is often an accentuation of the NFTs around small blood vessels. (C, F) The NFTs preferentially involve the superficial layers of cortex, a feature that is often most prominent in the temporal lobe. *Clusters of subpial ATs are also common in CTE. Table 28.2 McKee criteria for the neuropathologic diagnosis of chronic traumatic encephalopathy 1. Perivascular foci of p-tau immunoreactive neurofibrillary tangles (NFTs) and astrocytic tangles (ATs) in the neocortex 2. Irregular distribution of p-tau immunoreactive NFTs and ATs at the depths of cerebral sulci 3. NFTs in the cerebral cortex located preferentially in the superficial layers (often most pronounced in temporal cortex) 4. Supportive features: clusters of subpial ATs in the cerebral cortex, most pronounced at the sulcal depths Reproduced from McKee AC, Stern RA, Nowinski CJ, et al. (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136: 43–64.

Based on 68 cases of CTE, McKee and colleagues (2013) identified four pathologic stages of CTE: stage I–IV (Fig. 28.2). The earliest stage of CTE, stage I, is

characterized by one or two isolated perivascular epicenters of NFTs and dot-like and grain-like neurites (i.e., “CTE lesions”) at the depths of the cerebral sulci usually found in the frontal, temporal, or parietal cortices. CTE lesions surround small arterioles and may be associated with p-tau immunopositive thorned astrocytes in the subpial region. In stage II CTE, three or more CTE lesions are present in multiple cortical regions, superficial NFTs are present along the sulcal wall and at gyral crests, and NFTs are present in the locus coeruleus and nucleus basalis of Meynert. In stage III CTE, confluent patches of p-tau immunoreactive neurons and astrocytes are centered on arterioles at the sulcal depths and in the superficial laminae of cortex. NFTs are also in medial temporal lobe structures, including the hippocampus, entorhinal cortex, and amygdala, as well as the substantia nigra, dorsal and medial raphe, and olfactory bulbs. Neurofibrillary degeneration in the hippocampus includes CA4, CA2, and CA1. In CTE stage IV, CTE lesions and NFTs are densely distributed throughout the cerebral cortex,

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Fig. 28.2. The four pathologic stages of chronic traumatic encephalopathy (CTE) (McKee et al., 2013). For images (A–D), hemispheric 50-mm tissue sections were immunostained with mouse monoclonal antibody CP-13, directed against phosphoserine 202 of tau (courtesy of Peter Davies, PhD, Feinstein Institute for Medical Research; 1:200); positive ptau immunostaining appears dark brown. For images (E–H), 10-mm paraffin-embedded tissue sections were immunostained with mouse monoclonal antibody for phosphorylated tau (AT8) (Pierce Endogen). Positive p-tau immunostaining appears dark red, hematoxylin counterstain; calibration bar indicates 100 mm. (A) Stage I CTE. Two perivascular p-tau CTE lesions are present at sulcal depths of the frontal cortex; there is no neurofibrillary degeneration in the medial temporal lobe (open arrowhead). (B) Stage II CTE. There are multiple perivascular p-tau CTE lesions at depths of the sulci in the frontal cortex; there is no neurofibrillary degeneration in the medial temporal lobe (open arrowhead). (C) Stage III CTE. Multiple CTE lesions are found throughout the cortex, the CTE lesions are large and confluent, and there is diffuse neurofibrillary degeneration of the hippocampus and entorhinal cortex (black arrowhead). (D) Stage IV CTE. Multiple CTE lesions are found in the frontal cortex, the CTE lesions are large and confluent, and there is intense neurofibrillary degeneration of the hippocampus, entorhinal cortex, and parahippocampal gyrus (black arrowhead). (E–H) Corresponding appearance of perivascular CTE lesion in all stages of CTE pathology. With increasing CTE stage, the perivascular lesions increase in size, show more p-tau neurofibrillary tangles, and neuritic abnormalities and astrocytes.

diencephalon, brainstem, cerebellar dentate nucleus, and spinal cord. Other features include neuronal loss, gliosis in the frontal and temporal cortices, and astrocytic p-tau pathology. CTE pathology in stages I and II is considered mild; and in stages III and IV, severe. Using the McKee staging scheme for CTE severity in American football players, the stage of CTE pathology is significantly correlated with age at death, supporting the McKee staging scheme as representative of increasing pathologic severity. Furthermore, duration of football career and years since retirement from football are also associated with pathologic CTE stage, supporting an association between cumulative exposure to repetitive head trauma and CTE severity. By contrast, number of concussions, years of education, lifetime steroid use, and position played are not significantly associated with CTE stage (McKee et al., 2013). In 2015, as part of a National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of

Biomedical Imaging and Bioengineering (NIBIB)funded consensus meeting, a panel of expert neuropathologists evaluated 25 cases of various tauopathies using the McKee criteria (McKee et al., 2013). The tauopathies included CTE, AD, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. A single laboratory processed all cases uniformly; the resulting slides were scanned into digital images that were provided to the panel, who were blinded to all clinical, demographic, and gross neuropathologic information. The panel submitted their independent evaluations prior to meeting in person. Using the McKee criteria, the panel found that CTE was reliably distinguished from other tauopathies and made further refinements, as the preliminary NINDS criteria for the diagnosis of CTE (Table 28.3). The panel further established that there was a pathognomonic lesion for CTE that distinguishes it from other

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Table 28.3 Preliminary National Institute of Neurological Disorders and Stroke criteria for the pathologic diagnosis of chronic traumatic encephalopathy (CTE) Required for diagnosis of CTE 1 The pathognomonic lesion consists of p-tau aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at the depths of the cortical sulci Supportive neuropathologic features of CTE p-tau-related pathologies 1 Abnormal p-tau immunoreactive pretangles and NFTs preferentially affecting superficial layers (layers II–III), in contrast to layers III and V as in Alzheimer disease 2 In the hippocampus, p-tau pretangles and NFTs preferentially affecting CA2 and CA4, in contrast to the preferential involvement of CA1 and subiculum in Alzheimer disease 3 p-tau immunoreactive NFTs in subcortical nuclei, including the mammillary bodies and other hypothalamic nuclei, amygdala, nucleus accumbens, thalamus, midbrain tegmentum, nucleus basalis of Meynert, raphe nuclei, substantia nigra, and locus coeruleus 4 p-tau immunoreactive thorny astrocytes in the subpial and periventricular regions 5 p-tau immunoreactive large grainlike and dotlike structures (in addition to some threadlike neurites) Non-p-tau-related pathologies 1 Macroscopic features: disproportionate dilatation of the third ventricle, septal abnormalities, mammillary body atrophy, and contusions or other signs of previous traumatic injury 2 TDP-43 immunoreactive neuronal cytoplasmic inclusions and dotlike structures in the hippocampus, anteromedial temporal cortex, and amygdala Age-related ptau astrogliopathy that may be present; nondiagnostic and nonsupportive (Kovacs et al., 2016) 1 Patches of thorn-shaped astrocytes in subcortical white matter 2 Subependymal, periventricular, and perivascular thorned astrocytes in the mediobasal regions 3 Thorn-shaped astrocytes in amygdala or hippocampus Reproduced from McKee AC, Cairns NJ, Dickson DW, et al. (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131: 75–86. NFTs, neurofibrillary tangles.

neurodegenerative diseases, including aging and nonspecific astrotauopathy (Kovacs et al., 2016). They noted that the p-tau neurites were often dot-like and that the TDP-43-immunoreactive inclusions in CTE were distinctive from other types of neurodegeneration. They also observed that the pattern of hippocampal degeneration was unlike AD, and made

recommendations for a process of diagnosis and evaluation for potential cases of CTE to be used by other neuropathologists (McKee et al., 2016). Recently, using the preliminary NINDS criteria for CTE, the clinical and pathologic features of an 8-year brain bank series of 202 American football players were described (Mez et al., 2017). CTE was neuropathologically diagnosed in 177 individuals (87% of the series). The median age at death was 67 years (interquartile range (IQR) 52–77). The mean years of football participation was 15.1 years (5.2). CTE was not diagnosed in either of the 2 pre-high school players (0%). However, CTE was found in 3 of 14 high school players (21%), 48 of 53 college players (91%), 9 of 14 semiprofessional players (64%), 7 of 8 Canadian Football League players (88%), and 110 of 111 NFL players (99%). All former high school players had mild pathology. A majority of former college players (27, or 56%), semiprofessional players (5, or 56%), and professional players (101, or 86%) had severe pathology. Among the 27 players with mild CTE pathology, 26 (96%) had behavioral or mood symptoms, or both; 23 (85%) had cognitive symptoms; and 9 (33%) had symptoms of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. The median age at death for American football players with mild CTE pathology (stages I and II) was 44 years (IQR 29–64), and for those with severe CTE pathology (stages III and IV) was 71 years (IQR 64–79). The most common cause of death for cases with mild CTE pathology (n ¼ 12, 27%) was suicide. For the 62 individuals (47%) with severe CTE pathology, the most common cause of death was neurodegeneration (i.e., dementiarelated and parkinsonian-related causes of death) (Mez et al., 2017). Semiquantitative assessment of p-tau pathology across widespread brain regions showed progressive increases in p-tau density in all areas with increasing CTE stage, further validating the hierarchical McKee CTE staging scheme. CTE has also been found in young veterans of the Iraq and Afghanistan exposed to repetitive head impacts (RHIs) or explosive blasts (Omalu et al., 2011; Goldstein et al., 2012; McKee and Robinson, 2014). Omalu et al. (2011) reported CTE in the brain of a 27-year-old Marine veteran with exposure to explosive blasts during two deployments to Fallujah and Ramadi. However, the veteran also played American football and ice hockey, was involved in a serious motor vehicle accident, and had several documented concussions; these factors all may have contributed to the development of CTE.

THE NEUROPATHOLOGY OF CHRONIC TRAUMATIC ENCEPHALOPATHY McKee and colleagues reported CTE in 4 male military veterans 22–45 years old (mean age 32.0 years) with histories of blast exposure ranging from 1 to several years before death (Goldstein et al., 2012; McKee and Robinson, 2014). All 4 subjects were diagnosed with mild CTE (stage I or II). The brains of all 4 also showed varying degrees of axonal degeneration, astrocytosis, and neuroinflammation as perivascular microgliosis in the white matter. Two died of spontaneous intracerebral hemorrhage several years after the blast exposure, one from a basilar artery aneurysm and one (a 22-year-old with no history of hypertension) from an intrathalamic hemorrhage. The unusual nature of the vascular events may indicate blast trauma-induced vascular injury with subsequent degeneration. Older military veterans have also been reported with advanced CTE. Two veterans who developed CTE experienced moderate to severe traumatic brain injury (TBI) from assaults or motor vehicle accidents while in service. One had intraparenchymal TBI with persistent and poorly controlled posttraumatic epilepsy; the other had a spinal cord injury (McKee and Robinson, 2014).

NEUROPATHOLOGY Gross pathology Macroscopic changes in CTE are typical of advanced disease and may be absent in mild cases. Gross changes include reduced brain weight, cerebral atrophy (most severe in the frontal and temporal lobes), enlargement of the lateral and third ventricles, cavum septum pellucidum, septal fenestrations, and depigmentation of the locus coeruleus and substantia nigra. In severe cases, there may be atrophy of the thalamus and hypothalamus, including the mammillary bodies. Although cerebellar abnormalities were described in the early reports of CTE affecting boxers (Corsellis et al., 1973), in more recent reports, grossly identifiable cerebellar abnormalities are rarely found (McKee et al., 2013).

Microscopic pathology CTE is characterized by the deposition of p-tau protein as NFTs and disordered neurites around small arterioles in the cortex, typically at the sulcal depths. The tau isoform profile and phosphorylation state are similar to AD (Schmidt et al., 2001) and the neuronal p-tau pathology shows immunoreactivity to both 3-repeat (3R) and 4-repeat (4R) tau (McKee et al., 2013; Stein et al., 2014). The 4R isoform of tau is predominantly expressed in the thorned astrocytes in in the subpial regions of the sulcal depths (McKee et al., 2013; Stein et al., 2014). Astrocytic p-tau 4R pathology increases in prominence

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with age and disease severity. Kanaan and colleagues (2016) reported that tau oligomers and exposure of an N-terminal motif in tau, the phosphatase-activating domain, occur in CTE and co-localize in perivascular CTE lesions. In addition, tau truncated at D421, TauC3, which is abundant in AD, is relatively sparse in CTE.

Axonal pathology in chronic traumatic encephalopathy Axonal injury, axonal degeneration, myelin degeneration, and white-matter loss are consistent features of CTE, and may play a critical role in initiating p-tau pathology. The degree of axonal dysintegrity parallels the severity of the p-tau neurodegeneration. In early CTE (stages I and II), scattered axonal varicosities are found in the deep layers of the cortex, subcortical white matter, and deep white-matter tracts; these changes are more severe in advanced CTE. Using ex vivo diffusion magnetic resonance imaging with high spatial resolution, Holleran and colleagues (2017) showed substantial axonal microstructural disruption in the white matter underlying cortical sulci with p-tau pathology.

TDP-43 pathology in chronic traumatic encephalopathy Most cases of CTE also show abnormally phosphorylated TDP-43 protein, with positive neuronal and glial inclusions and large rounded and dot-like neurites that may co-localize with p-tau inclusions (McKee et al., 2010, 2013). TDP-43 immunoreactivity is found in many stage IV CTE cases, often as TDP-43-positive rounded and threadlike neurites, and inclusions in cerebral cortex, medial temporal lobe, diencephalon, brainstem, and, occasionally, spinal cord. In cases with severe TDP-43 deposition, dense accumulations of TDP-43 inclusions and neurites are found in all layers of the neocortex, particularly layer II, as well as occasional TDP-43-positive inclusions in the dentate fascia of the hippocampus, a distribution pattern that overlaps with the distribution of TDP-43 found in those with frontotemporal lobar degeneration (Cairns et al., 2007).

Aß pathology in chronic traumatic encephalopathy Unlike AD, CTE is a primary tauopathy, and the tauopathy of CTE appears first in the progression of pathology, prior to the appearance of Aß plaques. Aß-containing plaques, mostly as diffuse Aß plaques, were present in 52% of individuals with CTE in one case series (Stein et al., 2015); they were not found in those with earlystage disease. In CTE, the presence of Ab plaques is

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significantly associated with accelerated tauopathy, Lewy body formation, dementia, parkinsonism, and inheritance of the ApoE4 allele (Stein et al., 2015).

Blood–brain barrier disruption Other pathologies that contribute to CTE include microvascular changes and disruption of blood–brain barrier (BBB) integrity. The BBB is comprised of a network of capillary endothelial cells joined by tight junctions, surrounded by basal lamina, pericytes, and astrocytic perivascular endfeet. Astrocytes provide the cellular link to neurons (Marchi et al., 2004). After a single season of college-level play and in the absence of overt concussion, 37 American football players showed evidence of BBB disruption on diffusion tensor imaging, suggesting an association with exposure to “subconcussive” impacts (Marchi et al., 2013). BBB disruption has been found after blast injury (Huber et al., 2016). In addition, 47% of late survivors of a single moderate-severe TBI had multifocal, abnormal, perivascular, and parenchymal fibrinogen and immunoglobulin G deposits in their cerebral cortex, suggesting that widespread BBB disruption persists for years after the traumatic insult (Hay et al., 2015). BBB dysfunction and immunoglobulin G extravasation are also found after acute concussive injury in humans and in experimental models of CTE (Tagge et al., 2018).

Inflammatory response In American football players with and without CTE, total years of football play, development of CTE, and its severity are associated with increased inflammation, shown as increased CD68 immunoreactive microglia and conversion to a reactive microglial morphology (Cherry et al., 2016). In a simultaneous equation regression model, exposure to RHIs directly and significantly affected CD68 cell density ( p < 0.0001) and p-tau pathology (p < 0.0001), independent of age at death. The effect of RHI on p-tau pathology was partially mediated through increased density of activated microglia. In addition, the diagnosis of clinical dementia was significantly predicted by CD68 cell density independent of age, but this effect disappeared when p-tau pathology was included in the model. These results suggest that the length of a player’s career in American football is associated with chronic activation of microglia, which may partially mediate the effects of RHI on development of p-tau pathology and dementia in CTE. A recent study reported that levels of the cytokine CCL11 are significantly increased in the frontal cortex of brain donors with CTE compared to controls or subjects with AD (Cherry et al., 2017). In that study, a

regression analysis demonstrated that CCL11 levels were significantly associated with a diagnosis of CTE, independent of age and sex. In contrast, CCL11 levels were not increased in frontal cortex in subjects with AD. A preliminary examination of cerebrospinal fluid indicated that CCL11 levels significantly discriminated CTE from control and AD subjects. This finding could have important implications for the development of biomarkers to aid in the clinical diagnosis of CTE during life.

CTE in diverse brain bank collections CTE is currently a diagnosis that can only be made by neuropathologic examination of the brain. Using the preliminary NINDS criteria, Bieniek et al. (2015) reviewed the clinical records and neuropathologic findings of 1721 cases in the Mayo Clinic brain bank over the previous 18 years, and found 32% of amateur contact sport athletes had evidence of CTE pathology. No cases of CTE were found in 162 age- and sex-matched control brains without a history of contact sports or brain trauma, or in 33 cases with a history of a single TBI. Of the 21 deceased athletes with CTE pathology, 19 had participated in football or boxing, and many participated in multiple sports, including rugby, wrestling, basketball, and baseball. One athlete played only baseball, and another athlete only played basketball. In another report of 268 cases with neurodegenerative disease, CTE changes were seen in 11.9% of cases compared to controls. Among those with CTE, 93.8% had a history of TBI; 34% had participated in high-risk sports, including rugby, soccer, cricket, lacrosse, judo, and squash; and 18.8% were military veterans (Ling et al., 2015).

Chronic traumatic encephalopathy with comorbidities As with other neurodegenerative diseases, CTE can occur with comorbid pathologies (McKee et al., 2013; Stein et al., 2015; Mez et al., 2017). In the largest case series of CTE in American football players (mean age of participants ¼ 67 years), the most frequent neuropathologic comorbidities were AD (13%), Lewy body disease (19%), frontotemporal lobar degeneration (8%), and amyotrophic lateral sclerosis (ALS) (6%) (Mez et al., 2017). The frequency of these comorbidities increased with age. TBI and RHI may be risk factors for multiple other types of neurodegeneration (Lehman et al., 2012; Crane et al., 2016). Therefore, both age and a history of RHI may contribute to development of comorbidities found in CTE.

THE NEUROPATHOLOGY OF CHRONIC TRAUMATIC ENCEPHALOPATHY

Alzheimer disease AD is one of the most frequent comorbidities in CTE (Mez et al., 2017). Although Ab plaques are observed in CTE, they are typically diffuse. In cases of CTE with a moderate to severe burden of neuritic plaques (CERAD B or C), p-tau pathology is severe, as expected with two overlapping tauopathies (CTE and AD). In cases of severe CTE (stage IV) and high Braak stage AD, the density of the p-tau pathology may be so great as to obscure the perivascular and depth of sulcus p-tau pathology specific to CTE, and thus prevent a definitive diagnosis of CTE. In these cases, presence of supportive features of CTE (e.g., neurofibrillary degeneration in the mammillary bodies, dentate nucleus of the cerebellum, pontine base, superior colliculus, and pulvinar) are helpful since these features are usually are not affected in AD. In subjects with CTE and AD, Ab plaques and total levels of Ab1–40 are increased at the depths of the cortical sulcus compared to the gyral crests (Stein et al., 2015). When present, neuritic plaques are associated with increased CTE tauopathy stage, comorbid Lewy body disease, and antemortem clinical dementia, when controlled for age. Thus, deposition of Ab is associated with both pathologic and clinical progression of CTE independent of age. Overall, Ab deposition may be altered and accelerated in CTE compared to normal aging. The pathology of CTE, including axonal damage, inflammation, and p-tau pathology, may influence the development of AD pathologies. Alternatively (or in addition), a history of RHI that leads to CTE may accelerate the development of AD in susceptible individuals, as suggested by the association of APOE E4 with Ab deposition in CTE (Stein et al., 2015). Future work examining genetic risks for comorbid AD among subjects with CTE will help to clarify the relationships between these risk factors and disease pathogenesis.

Lewy body disease and parkinsonism TBI has been associated with the development of Parkinson disease (Lee et al., 2012; Jafari et al., 2013; Gardner et al., 2015; Perry et al., 2016). Among cohorts of pooled brain donations, including a community-aging cohort, Crane et al. (2016) found an association between TBI with loss of consciousness greater than 1 hour, occurring before 25 years of age, and increased risk of cortical Lewy bodies. They found a clinical association between TBI with loss of consciousness and incident Parkinson disease in one cohort, and with progression of parkinsonian signs in two others (Crane et al., 2016). However, the role of RHI associated with contact sports and CTE in the development of Lewy bodies and parkinsonism is largely

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unknown. Overall, it appears that both trauma and the presence of CTE pathology may influence a-synuclein deposition. Enhanced a-synuclein deposition may, in turn, explain the extrapyramidal motor symptoms that sometimes occur in CTE (Stein et al., 2015).

Amyotrophic lateral sclerosis Approximately 6–12% of individuals with CTE develop a progressive motor neuron disease characterized by profound weakness, atrophy, spasticity, and fasciculations; these symptoms fulfill criteria for clinical diagnosis of ALS (McKee et al., 2010, 2013). In addition, in the Mayo Clinic Jacksonville ALS brain bank and the Boston Veterans Affairs (VA) ALS brain bank, 6/91 (6.6%) and 5/113 (4.4%) of the ALS cases, respectively, had pathologic features of CTE (all Caucasian men) (Bieniek et al., 2014). In the Veterans Affairs-Boston UniversityConcussion Legacy Foundation (VA-BU-CLF) brain bank (McKee, personal observations), most individuals with both CTE and motor neuron disease present with symptoms of ALS and develop mild cognitive and behavioral symptoms several years after the onset of motor weakness and fasciculations. Individuals with motor neuron disease and CTE tend to die from respiratory failure at younger ages and in earlier stages of CTE compared to CTE subjects without ALS. Approximately one-third of those with CTE and ALS present with depression and behavioral or cognitive changes related to CTE many years before developing ALS symptoms; at autopsy; they are diagnosed with grade III or IV CTE and ALS at autopsy. Such individuals often show more severe TDP-43 pathology than subjects with CTE alone (McKee, personal observations).

REGIONAL INVOLVEMENT IN CHRONIC TRAUMATIC ENCEPHALOPATHY Mufson and colleagues (2016) found increased NFTs in cholinergic basal forebrain neurons within the nucleus basalis of Meynert across the pathologic stages of CTE. There was also an increase in pretangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The same group later assessed genetic signatures of neurons containing p-tau pretangles in the nucleus basalis of Meynert using laser capture microdissection and microarray analysis (Mufson et al., 2018). They reported downregulation of several genes associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics. Armstrong and colleagues (2017) also showed p-tau pathology and neuronal loss in the superior colliculus in a subset of CTE cases.

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SUMMARY CTE is characterized by progressive neurodegeneration and is associated with repetitive concussion, subconcussion, and blast injury. Pathologically, stage I CTE is defined by isolated CTE lesions consisting of p-tau immunoreactive NFTs and dot-like or spindle-shaped neurites arranged around small arterioles. Lesions tend to develop at traumatic stress points of the brain, including the depths of the cortical sulci and around small vessels. Stage II CTE is characterized by multiple CTE lesions in multiple cortical sites. The hippocampus and medial temporal lobe structures are relatively free of NFTs. Large brain bank series reveal that stage I and II CTE are most often found in younger individuals (McKee et al., 2013; Mez et al., 2017). Behavioral or mood symptoms (or both) and cognitive symptoms have been reported in most individuals who were diagnosed with stage I and II CTE. In stage III CTE, CTE lesions are often large and confluent. NFTs are widely distributed in the brain, and there is neurofibrillary involvement of medial temporal lobe structures, including the hippocampus, entorhinal cortex, and amygdala. In the brain bank series of 177 deceased American football players with CTE (Mez et al., 2017), stage III CTE is most often found in individuals who died over the age of 40 years and who retired from contact sport years before. The apparent progression of CTE pathology with advancing age without continued exposure to trauma suggests continuing tau deposition and spread via trauma-independent mechanisms. Similar progressive p-tau changes are found in a mouse model of head impact injury, with local deposits of p-tau at 24 hours, spread to the opposite side at 2 weeks, and spread to distant cortical sites at 5.5 months (Tagge et al., 2018). Potential independent mechanisms of p-tau deposition and spread include tau prion templating (Woerman et al., 2016), tau secretion, damaged tau clearance in extracellular cerebrospinal fluid, leakage of the BBB, and persistent neuroinflammation (Tagge et al., 2018). Although many fundamental questions remain to be answered, examination of donated brains has been foundational to increasing our knowledge of CTE. Current research efforts include identifying in vivo biomarkers for the diagnosis of CTE during life, and developing therapeutic strategies to treat CTE.

REFERENCES Armstrong RA, McKee AC, Cairns NJ (2017). Pathology of the superior colliculus in chronic traumatic encephalopathy. Optom Vis Sci 94: 33–42. Bieniek K, Stein T, Alvarez V et al. (2014). Chronic traumatic encephalopathy and amyotrophic lateral sclerosis. Brain Pathol: 84.

Bieniek KF, Ross OA, Cormier KA et al. (2015). Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol. 130: 877–889. Braak H, Braak E (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82: 239–259. Braak H, Del Tredici K, R€ ub U et al. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24: 197–211. Cairns NJ, Bigio EH, Mackenzie IRA et al. (2007). Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 114: 5–22. Cherry JD, Tripodis Y, Alvarez VE et al. (2016). Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta Neuropathol Commun 4: 112. Cherry JD, Stein TD, Tripodis Y et al. (2017). CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer’s disease. PLoS ONE 12: e0185541. Corsellis JA, Bruton CJ, Freeman-Browne D (1973). The aftermath of boxing. Psychol Med 3: 270–303. Courville CB (1962). Punch drunk. Its pathogenesis and pathology on the basis of a verified case. Bull Los Angel Neuro Soc 27: 160–168. Crane PK, Gibbons LE, Dams-O’Connor K et al. (2016). Association of traumatic brain injury with late-life neurodegenerative conditions and neuropathologic findings. JAMA Neurol 73: 1062–1069. Critchley M (1949). Punch-drunk syndromes: the chronic traumatic encephalopathy of boxers. In: Hommage a` Clovis Vincent, Maloine, Paris. Gardner RC, Burke JF, Nettiksimmons J et al. (2015). Traumatic brain injury in later life increases risk for Parkinson disease. Ann. Neurol. 77: 987–995. Geddes JF, Vowles GH, Robinson SF et al. (1996). Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol. Appl. Neurobiol. 22: 12–16. Geddes JF, Vowles GH, Nicoll JA et al. (1999). Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol. 98: 171–178. Goldstein LE, Fisher AM, Tagge CA et al. (2012). Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4: 134ra60. Hay JR, Johnson VE, Young AMH et al. (2015). Blood-brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J. Neuropathol. Exp. Neurol. 74: 1147–1157. Hof PR, Knabe R, Bovier P et al. (1991). Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathol. 82: 321–326. Hof PR, Bouras C, Buee L et al. (1992). Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer’s disease cases. Acta Neuropathol. 85: 23–30. Holleran L, Kim JH, Gangolli M et al. (2017). Axonal disruption in white matter underlying cortical sulcus tau

THE NEUROPATHOLOGY OF CHRONIC TRAUMATIC ENCEPHALOPATHY pathology in chronic traumatic encephalopathy. Acta Neuropathol. 133: 367–380. Huber BR, Meabon JS, Hoffer ZS et al. (2016). Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction. Neuroscience 319: 206–220. Hyman BT, Trojanowski JQ (1997). Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J. Neuropathol. Exp. Neurol. 56: 1095–1097. Jafari S, Etminan M, Aminzadeh F et al. (2013). Head injury and risk of Parkinson disease: a systematic review and meta-analysis. Mov. Disord. 28: 1222–1229. Jordan B (1992). Medical aspects of boxing, CRC Press, Boca Raton, FL. Kanaan NM, Cox K, Alvarez VE et al. (2016). Characterization of early pathological tau conformations and phosphorylation in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 75: 19–34. Kovacs GG, Ferrer I, Grinberg LT et al. (2016). Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol. 131: 87–102. Lee P-C, Bordelon Y, Bronstein J et al. (2012). Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease. Neurology 79: 2061–2066. Lehman EJ, Hein MJ, Baron SL et al. (2012). Neurodegenerative causes of death among retired National Football League players. Neurology 79: 1970–1974. Ling H, Holton JL, Shaw K et al. (2015). Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases. Acta Neuropathol. 130: 891–893. Marchi N, Cavaglia M, Fazio V et al. (2004). Peripheral markers of blood-brain barrier damage. Clin. Chim. Acta 342: 1–12. Marchi N, Bazarian JJ, Puvenna V et al. (2013). Consequences of repeated blood-brain barrier disruption in football players. PLoS ONE 8: e56805. Martland HS (1928). Punch Drunk. JAMA 91: 1103. McKee AC, Robinson ME (2014). Military-related traumatic brain injury and neurodegeneration. Alzheimers Dement 10: S242–S253. McKee AC, Cantu RC, Nowinski CJ et al. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy following repetitive head injury. J Neuropathol Exp Neurol 68: 709–735. McKee AC, Gavett BE, Stern RA et al. (2010). TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69: 918–929. McKee AC, Stern RA, Nowinski CJ et al. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain 136: 43–64. McKee AC, Daneshvar DH, Alvarez VE et al. (2014). The neuropathology of sport. Acta Neuropathol 127: 29–51. McKee AC, Cairns NJ, Dickson DW et al. (2016). The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131: 75–86.

307

Mez J, Daneshvar DH, Kiernan PT et al. (2017). Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318: 360–370. Millspaugh J (1937). Dementia pugilistica. US Naval Med Bull 35: 297–303. Mirra SS, Heyman A, McKeel D et al. (1991). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41: 479–486. Mufson EJ, Perez SE, Nadeem M et al. (2016). Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. Brain Inj 30: 1399–1413. Mufson EJ, He B, Ginsberg SD et al. (2018). Gene profiling of nucleus basalis tau containing neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. J. Neurotrauma 35: 1260–1271. Omalu BI, DeKosky ST, Minster RL et al. (2005). Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57: 128–134; discussion 128–134. Omalu BI, DeKosky ST, Hamilton RL et al. (2006). Chronic traumatic encephalopathy in a National Football League player: part II. Neurosurgery 59: 1086–1092; discussion 1092–1093. Omalu B, Hammers JL, Bailes J et al. (2011). Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg Focus 31: E3. Parker HL (1934). Traumatic encephalopathy (‘punch drunk’) of professional pugilists. J Neurol Psychopathol 15: 20–28. Perry DC, Sturm VE, Peterson MJ et al. (2016). Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis. J. Neurosurg. 124: 511–526. Roberts GW, Whitwell HL, Acland PR et al. (1990). Dementia in a punch-drunk wife. Lancet 335: 918–919. Schmidt ML, Zhukareva V, Newell KL et al. (2001). Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol. 101: 518–524. Stein TD, Alvarez VE, McKee AC (2014). Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res Ther 6: 4. Stein TD, Montenigro PH, Alvarez VE et al. (2015). Betaamyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol. 130: 21–34. Tagge CA, Fisher AM, Minaeva OV et al. (2018). Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141: 422–458. Thal DR, Capetillo-Zarate E, Del Tredici K et al. (2006). The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowledge Environ 2006, re1. Williams DJ, Tannenberg AE (1996). Dementia pugilistica in an alcoholic achondroplastic dwarf. Pathology 28: 102–104. Woerman AL, Aoyagi A, Patel S et al. (2016). Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc. Natl. Acad. Sci. U.S.A. 113: E8187–E8196.