Accepted Manuscript

The Current Status of Research on Chronic Traumatic Encephalopathy

Kenneth Perrine, Ph.D., Jacqueline Helcer, M.S., M.A., Apostolos John Tsiouris,M.D., David J. Pisapia, M.D., Philip Stieg, Ph.D., M.D.

PII: S1878-8750(17)30257-7

DOI: 10.1016/j.wneu.2017.02.084

Reference: WNEU 5315

To appear in: World Neurosurgery

Received Date: 1 October 2016

Revised Date: 15 February 2017

Accepted Date: 16 February 2017

Please cite this article as: Perrine K, Helcer J, Tsiouris AJ, Pisapia DJ, Stieg P, The Current Statusof Research on Chronic Traumatic Encephalopathy, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.02.084.

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The Current Status of Research on Chronic Traumatic Encephalopathy Kenneth Perrine, Ph.D.,1 Jacqueline Helcer, M.S., M.A.,2,3 Apostolos John Tsiouris, M.D.,4 David J. Pisapia, M.D.,5 Philip Stieg, Ph.D., M.D.1 1 Department of Neurological Surgery

Weill Cornell Medical College 525 E. 68th Street, Box 99 New York, NY, USA, 10065

2 Department of Psychiatry Harvard Medical School

25 Shattuck Street Boston, MA, USA, 02115 3Department of Psychiatry

Massachusetts General Hospital 55 Fruit Street Boston, MA, USA, 02114

4 Department of Clinical Radiology, NYPH – Weill Cornell Medical College 525 E. 68th Street, Starr 630C New York, NY, USA, 10065

5 Department of Pathology and Laboratory Medicine Weill Cornell Medical College 1300 York Avenue New York, NY, USA, 10065

Corresponding Author:

Kenneth Perrine, Ph.D. krp2003@med.cornell.edu Weill Cornell Medical College 525 E. 68th St., Box 99 New York, NY 10021, USA Key words Chronic Traumatic Encephalopathy; Traumatic Encephalopathy Syndrome; Concussion; Mild Traumatic Brain Injury; Tauopathy Abbreviations and Acronyms

AD, (Alzheimer’s Disease);ALS, (Amyotrophic Lateral Sclerosis);APOE, (apolipoprotein);CERAD, (Consortium to Establish A Registry for Alzheimer’s Disease);CT, (Computed Tomography);CTE, (Chronic Traumatic Encephalopathy);DTI, (Diffusion Tensor Imaging);FA, (Fractional Anisotropy);FLAIR, (Fluid Level Attenuated Inversion Recovery);fMRI, (Functional Magnetic Resonance Imaging);FTD, (Frontotemporal Dementia);MPRAGE, (Magnetization-Prepared Rapid Gradient-Echo);MRI, (Magnetic

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2 Perrine Resonance Imaging);MRS, (Magnetic Resonance Imaging);NAA, (N-acetyl Aspartate);NCAA, (National Collegiate Athletic Association) ;NFL, (National Football League);NFTs, (Neurofibrillary Tangles);PEDs, (Performance Enhancing Drugs);PET, (Positron Emission Tomography);p-tau, (phosphorylated tau);PTSD, (Post-Traumatic Stress Disorder);SPGR, (Spoiled Gradient Echo);SWI, (Susceptibility Weighted Imaging);TBI, (Traumatic Brain Injury);TDP-43, (Transactive Response DNA Binding Protein 43 kDa);TES, (Traumatic Encephalopathy Syndrome); Conflicts of interest: None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This work has not been published previously, is not under consideration for publication elsewhere, has been approved by the authors, and, if accepted, will not be published elsewhere including electronically in the same form, in English or in any other language, without the written consent of copyright-holder. All authors made substantial contributions to the conception and design of the review, drafting the article or revising it critically for important intellectual content, and to final approval of the version being submitted. Highlights:

• Chronic Traumatic Encephalopathy (CTE) is a type of tauopathy seen at autopsy

• CTE may result from concussion or subconcussive blows to the head

• Stages of CTE with an accompanying set of clinical features have been proposed

• The prevalence of CTE is unknown given sampling bias in the brains examined

• The current article reviews evidence for multiple factors associated with CTE

ABSTRACT

Chronic Traumatic Encephalopathy (CTE) evolved from the term “dementia pugilistica”

describing the dementia found in many boxers to its current use in describing the dementia and

depression sometimes found in athletes subjected to multiple concussions or sub-concussive

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3 Perrine blows to the head. Concurrently, the neuropathology evolved to specify a unique type of

tauopathy found in perivascular spaces at the depth of sulci and other features not typically seen

in neurodegenerative tauopathies. Four stages of CTE have been proposed, with four

corresponding clinical syndromes of Traumatic Encephalopathy Syndrome. However, it remains

unclear whether this is a syndrome unique to repetitive head trauma, especially in contact sports,

as the epidemiology has been difficult to establish. In particular, research to date suffers from a

“denominator” problem in not establishing the total number of potential cases at risk for

developing CTE. The current review examines the evidence to date for these syndromes, and

contributing or complicating factors affecting the neuropathology, neuroimaging, and clinical

presentations associated with them.

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4 Perrine INTRODUCTION

A dramatic increase in the discussion of concussions and brain pathology in contact sport

athletes occurred in the last decade, both in the popular press and in the scientific literature.

Chronic Traumatic Encephalopathy (CTE) is implicated as a neurodegenerative condition

resulting from the repetitive head trauma often sustained by participation in contact sports such

as football and boxing. The first description of a disorder predating the term CTE dates back to

1928, when a “punch drunk” syndrome in 23 boxers was described by Martland.1 The term then

evolved to “traumatic encephalopathy” in 1934,2 “dementia pugilistica” in 1937,3 and finally,

Chronic Traumatic Encephalopathy by Critchley in 1949.4 This original description of CTE was

characterized by cerebellar or extrapyramidal disorders with dysarthria and motor deficits, and

was sometimes accompanied by dementia. Roberts et al.5 reported in 1990 that 17% of 224

retired boxers had CTE. Jordan6 reviewed the literature on boxers through 2000 and reported

clinical phenomenon of cerebellar and extrapyramidal signs along with cognitive and behavioral

problems. He noted that it was unclear whether the signs and symptoms observed were indicative

of a neurodegenerative disorder or a neurologic disorder exacerbated by aging. Other instances

of CTE had been reported in non-boxers, including patients with repeated head banging or

battery.7,8

CTE is thought to result from multiple concussions or repetitive head trauma, which are

more prevalent in athletes in contact sports. Coupled with substantial media attention

surrounding sport-related concussions, the research focus is dominated by investigations of CTE

in deceased football players. Renewed interest in CTE began when Omalu reported finding

evidence of CTE in three retired football players.9-11 McKee12 reported similar findings in 3 new

subjects when reviewing the world literature on CTE including one football player, followed by

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5 Perrine numerous reports and case studies of evidence of CTE in athletes, veterans, and others exposed

to repetitive head trauma.8,12-17

The neurobehavioral changes associated with CTE reportedly involve a wide spectrum of

pathologies, such as depression severe enough to lead to suicide, substance abuse, emotional

instability, aggressiveness, poor impulse control, irritability, and advanced dementia.16,17 Similar

to other neurodegenerative disorders, the cognitive difficulties seen in patients with CTE

typically have a gradual, progressive course and can include significant memory impairment,

executive dysfunction, language difficulties, and motor disturbances. The onset of behavioral and

cognitive symptoms is generally years after exposure to repetitive trauma and often presents in

midlife (e.g., after retirement from sports).16,17 However, neuropathologic changes can be seen at

a microscopic level in patients with a single traumatic brain injury (Omalu, 2011) or as early as

adolescence (i.e., in high school football players) in some case reports.8

Just as the demographics of CTE evolved from boxers to football players and other

contact sport athletes, the observed pathological features have also expanded from gross

morphological changes such as cavum septi pellucidi to specific locations involving p-tau, and

from clinical phenomena with extrapyramidal signs and Parkinsonian-like dementia to a very

broad spectrum of neurobehavioral disorders. The various definitional shifts since the first

description of CTE raise important questions about our current understanding of CTE that

remain unanswered: Is the modern description of CTE a new, distinct disorder or is modern CTE

merely a variant of the same essential pathological process initially described in the classic CTE

of boxers? Or is CTE a variant or co-morbidity of other unrelated more essential

neurodegenerative conditions such as frontotemporal dementia (FTD) and Alzheimer’s disease

(AD) to which individuals with exposure to trauma may have increased susceptibility?

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6 Perrine

Some of the challenges in studying CTE include the fact that there appears to be great

variability in the clinical presentation of CTE across studies, as well as signs and symptoms that

overlap with other neurodegenerative conditions. Second, there is considerable heterogeneity in

the histopathological changes cited for CTE with four “stages” and four “phenotypes”8,18

associated with histopathological findings. Third, as most studies acknowledge, many of the

brains examined for CTE were donated explicitly because of the presence of neurobehavioral

symptoms prior to death, resulting in a pronounced selection bias. Related to these problems and

perhaps more importantly with respect to the public’s perception of the disease and how CTE

may influence policy, the current literature based on case studies suffers from a “denominator

problem”. That is, there is still an absence of sufficient epidemiological evidence of CTE from a

broad, randomly sampled population of retired athletes with and without concussions or

subconcussive blows. The current review will explore these issues in more detail to present the

evidence of CTE as a unique neuropathological disorder accompanied by distinctive clinical

presentations with a presumptive cause of concussions or multiple subconcussive blows to the

head.

Pathophysiology of Head Injury

Despite the advances made in the neuropathological findings of CTE, mechanistic

information correlating particular clinical features with anatomical abnormalities is still missing.

It is feasible that the motor symptoms previously seen in boxers with CTE are reflective of

injuries to the pyramidal tracts, extrapyramidal system, or cerebellum. However, the injury

mechanisms behind the other cognitive and behavioral manifestations of CTE are less clear. For

example, Stern16 described some apparent clinical presentations of CTE in his study of athletes

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7 Perrine and attempted to differentiate them from symptoms seen in other dementias. However, he did not

relate how the clinical features may be correlated with the presence and degree of tauopathy,

whereas this association is established in other dementias, such as FTD and Alzheimer’s. The

impact of p-tau depositions in scattered perivascular spaces on depression and cognitive deficits

is also unclear. For example, some studies show that depression19,20 and word finding difficulty

lateralizes to injury to the left hemisphere, and a predominance of p-tau in the left hemisphere

would be expected to relate to associated deficits in these domains. However, lateralization is

discussed in CTE, further obscuring the mechanism causing depression and language deficits.

Similarly, little is known about the pathophysiology of concussions and the anatomical

correlates of its clinical features. Our knowledge on why concussions cause loss of

consciousness, photosensitivity, headaches, fatigue, poor concentration and other symptoms is

limited.21 Thus, in order to understand the mechanisms that contribute to the clinical features of

CTE, a more thorough comprehension of the physiology of concussions is needed. Moreover,

studies are mixed on whether concussions and mild TBI are distinct clinical entities, rather than

milder forms of moderate to severe TBI.21,22 Animal models help clarify some physiological

processes in the acute stages, but still do not paint a full picture.23-28

Neuropathology of CTE

There is substantial diversity in the clinical history and presentation of those patients who

are ultimately assigned a pathologic diagnosis of CTE, and many clinical symptoms may overlap

with those of other neurodegenerative diseases. Studies suggest that CTE is indeed a

neuropathologically distinct entity from disorders such as AD, Parkinson’s disease, FTD,

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8 Perrine sporadic amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Even so,

considerable heterogeneity exists across individual cases of CTE.

The initial neuropathology described CTE in boxers. In 1973, Corsellis et al.29 examined

15 boxers with “dementia pugilistica” and described the neuropathological substrate of CTE as

involving (a) neurofibrillary tangles in the absence of plaques, particularly involving the medial

temporal lobe and brainstem tegmentum, (b) neuronal loss in the substantia nigra, occasionally

with neurofibrillary tangles, (c) scarring of the cerebellar tonsils, and (d) cavum septi pellucidi.29

Considering that beta amyloid deposition has variably been considered a distinguishing

feature of CTE relative to AD, several studies have sought to further characterize beta amyloid in

CTE cases. The cases initially examined by Corsellis et al.29 were later re-examined by Roberts

et al. 5 for beta amyloid. This study revealed extensive, diffuse-type beta amyloid plaques that

had not been observed previously using less sensitive techniques. McKee et al.12 found beta

amyloid deposition, an essential feature of AD, in 40-45% of CTE cases.12 Further efforts to

characterize beta amyloid deposition in CTE cases by Stein et al.30 found beta amyloid

deposition in 52% of CTE patients. Importantly, this study distinguished between the diffuse

plaques observed with immunohistochemical staining (seen in 52% patients) versus neuritic

plaques as assessed by silver staining (36% of patients), the plaques which are also quantified to

assess the CERAD or “C” score for neuritic plaques in AD cases. The number of neuritic plaques

seen even in “late stage” CTE cases (with or without concommitant AD-diagnostic pathology)

was significantly lower than those found in pure AD controls. Additionally, distributional

differences in amyloid deposition were observed in CTE cases versus controls.

Geddes et al.,7 in an effort to detect early changes in CTE, examined the brains of 5

young adults in their twenties with a history of repetitive head trauma secondary to varied

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9 Perrine causes. Chronic neuropathological changes were found in four cases. Cases 1 and 2 (the two

boxers) were the most affected, while changes in cases 3 and 5 were much less frequent. The

pathology included argyrophilic, tau-positive neocortical NFTs, occasionally solitary except in

cases 1 and 2, in which they were more numerous and arranged in groups predominantly around

small intracortical blood vessels. The authors concluded that the perivascular topography of

NFTs in cases 1, 2 and 4 suggests that a vascular association might be important, and the fact

that NFTs were often seen around penetrating vessels in the depths of sulci suggests a

predominantly ischemic etiology. These CTE cases showed tau deposition in a prominent

perivascular distribution, and an absence of beta amyloid deposition using immunohistochemical

techniques, a pattern of neurodegenerative changes consistent with prior characterizations of

neurodegenerative changes in CTE and a pattern distinct from that typically seen in AD.15

Gardner et al.31 performed a systematic review of 85 athlete autopsies and found that only

20% had “pure” CTE, 52% appeared to have CTE plus other neuropathology, 5% had no CTE,

and 24% had no observed neuropathology, leading the authors to stress the heterogeneity of the

disease. However, despite the heterogeneity in pathology and clinical history seen in patients

with CTE, the first NINDS/NIH workshop to define neuropathological criteria for a pathologic

diagnosis of CTE32 was able to define the following common pathognomonic feature of CTE:

“p-tau aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular

pattern at the depths of cortical sulci.” In particular, neurofibrillary degeneration in CTE tends to

localize primarily in sulcal depths with irregular distribution in the frontal and temporal cortices,

in prominent periventricular, perivascular, and subpial distribution, as well as in the superficial

cortex (cortical layers II and III).12 CTE thus defined may represent a unique neuropathological

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10 Perrine entity, based primarily on modern immunohistochemical techniques showing accumulations of

p-tau in a topographical distribution that is distinct from other tauopathies.

TDP-43 accumulation has also been demonstrated in CTE in recurrent locations.

Accumulation of this protein is characteristic of both ALS and frontotemporal lobar degeneration

(FTD).33,13,14,34 It has more recently been identified as a common pathologic finding associated

with CTE.13 However, the causal relationship between the multifocal tauopathy and the clinical

symptoms remains poorly understood. 31 It is conceivable that CTE may represent a more

sophisticated pathological diagnosis than the older “dementia pugilistica” terminology, or a

series of different neuropathologies.

In the largest study on CTE neuropathology samples to date, McKee et al.8 examined the

brains of 85 former athletes, military veterans, and civilians with a history of repetitive traumatic

brain injuries, finding evidence of CTE in 68 male subjects. Of these, 33 were retired NFL

players and only 16 were considered to have “pure” CTE neuropathology (i.e., without

overlapping neurodegenerative conditions). McKee et al.8 posited that the observed changes in

CTE evolve from perivascular foci at the depths of sulci in the cerebral cortex, perhaps

representing those areas of the cortex with increased mechanical susceptibility to injury, and then

spread gradually to the superficial layers of the lateral convexities, medial temporal lobe,

diencephalon, basal ganglia, brainstem, and spinal cord. Localization of these neuropathological

changes is reportedly distinct from what is typically seen in other tauopathies including AD and

FTD. For example, in CTE, although the specific tau isoforms are indistinguishable from AD,12

the abnormal distribution and perivascular clustering of tau in the depths of sulci and early

involvement of neocortical foci suggest a distinct core pathology.12 There is also a greater

density of NFTs and glial tangles (GTs) in CTE compared to other tauopathies.35

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11 Perrine Stages of CTE

Furthermore, McKee et al.8 proposed four progressive stages of CTE and specified the

primary neuropathological features dependent upon each stage of degeneration (Figure 1). In

stage 1, brains are typically of normal weight and show focal epicenters of perivascular p-tau,

NFTs, neutrophil neurites, and astrocytic tangles involving the sulcal depths especially of the

superior and dorsolateral frontal cortices. Occasional p-tau immunoreactive glia and glial

processes, TDP-43 neurites, and white matter reactive microglia clusters with axonal swellings

are also found.

Stage 2 brains are typically of normal weight with more frequent epicenters at the depths

of the sulci and NFTs scattered throughout superficial cortical layers as well as locus coeruleus

and substantia innominata. The lateral and third ventricles are often mildly enlarged, along with a

cavum septi pellucidi and pallor of the locus coeruleus and substantia nigra.

In stage 3, the brain is typically reduced in weight with mild cerebral atrophy and

ventricular dilitation. Septal abnormalities are more common. There is depigmentation of the

locus coeruleus and substantia nigra, as well as atrophy of the mammillary bodies, thalamus, and

hypothalamus. Thinning of the corpus callosum is also typical. P-tau pathology is widespread in

the broader cortical areas, and NF pathology is seen in the olfactory bulbs, amygdala,

hippocampus, hypothalamus, mammillary bodies, nucleus basalis of Meynert, substantia nigra,

dorsal and median raphe nuclei, locus coeruleus, and entorhinal cortex.

Stage 4 brains have a marked reduction in weight due to generalized cerebral cortical

atrophy of the medial temporal lobe, thalamus, hypothalamus, and mammillary bodies. Septal

abnormalities are seen in most cases. Complete depigmentation of the locus coeruleus and

substantia nigra can be seen. Severe p-tau pathology affects most regions of the cerebral cortex

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12 Perrine and the medial temporal lobe, though sparing the calcarine cortex. Severe p-tau pathology is also

seen in the diencephalon, basal ganglia, brainstem and spinal cord. Marked axonal loss of

subcortical white matter tracts is also evident.

----------------------------- Insert Figure 1 about here ----------------------------------

Limitations to Stages

There are several limitations to this study8 and the proposed stages. First, not all cases

that were examined in this study showed all criteria for all stages. Rather, the staging

descriptions represent a collection of features seen together across multiple cases with the

essential feature of tau distribution and severity as perhaps the underlying abnormality defining a

given stage. For example, some staging features were only found in a minority of cases cited as

showing CTE, making the identification of stage-defining criteria complex.

Secondly, these stages arose from multiple case studies of the brains examined12, and are

therefore based on cross-sectional rather than longitudinal data. It is conceivable that each stage

could represent distinct disease processes rather than a progressive disease. In the absence of

longitudinal data, it is difficult to predict whether the pathology would progress in sequential

stages as defined.

Third, the contribution of other variables to each presentation requires larger, prospective,

and longitudinal studies. Age, psychiatric or substance use history, family or genetic risk factors,

and/or other comorbid neurodegenerative conditions that may have contributed to each

individuals’ neuropathological classification within a “stage” need to be considered.31

Fourth, it is well established that tau pathology and beta amyloid depositions can be

found in adults who are healthy or have diverse health conditions, 36,37 and therefore are not

unique to CTE, although the topography of pathology may be different in CTE. However,

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13 Perrine performing longitudinal histopathological studies is basically impossible unless sequential brain

biopsies were performed, given the lack of specific in vivo p-tau biomarkers.

Older studies with boxers did not show any such progression,38,39 and Gardner et al.31

noted that classic CTE does “not appear to advance in a predictable and sequential series of

stages”. Therefore, it should be emphasized that the pathological “stages” of CTE are descriptive

and the implication that one stage mechanistically follows another is a hypothesis requiring

further study.

Finally, a key limitation is the relatively limited number and characterization of control

subjects. As the authors note, it would be ideal to expand such control groups and include

individuals with dementia and depression who have never had subconcussive blows or other

head trauma as well as athletes of comparable age with a history of concussion but no

neurobehavioral changes to counter the inherent selection bias. A subsequent study by Bieniek et

al.40 attempted to reduce selection bias in the athletic population by screening more broadly a

neurodegenerative brain bank. In this study they found cortical tau pathology consistent with

CTE in 32% of 66 athletes with a history of contact sports as compared to 0% of 198 age-

matched controls in the same bank. Omalu et al.18 also proposed a histopathological

classification of CTE with many similarities to McKee’s stages. He did not report a marked

accumulation of τ-immunoreactive astrocytes as a hallmark feature, whereas McKee did.8,12,18

It is also unclear how frequently neuropathologists use the specific stains32 shown to

adequately identify the presence of abnormalities said to be specific to CTE in non-athletes,

normal elderly individuals, or in those with other pathologies unique to similar

neurodegenerative disorders (e.g., AD, FTD, ALS).

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14 Perrine

Several researchers explored the development of CTE histopathology in animal

models.23-28 Mild traumatic brain injury was induced by controlled blasts, direct impact, or

percussion techniques, and the animals were followed for up to six months with histopathology.

Although p-tau developed in several of the studies, especially in mice with tau mutations

predisposing them to accumulation, the distributions did not resemble those seen in human

histopathology. Specifically, deposition of p-tau in perivascular regions in the depths of the sulci

has not been confirmed in animal models.23-28,41,42 Rather, the findings contradict the data from

that in human CTE cases, and show tau depositions in the hippocampus.23,26,27

The National Institute of Neurological Diseases and Stroke cautioned32 that a causal

relationship between the multifocal tauopathy observed in CTE and antecedent clinical

symptoms remains poorly understood. It is likely that CTE as it is currently defined represents a

more inclusive pathological diagnosis that encompasses those cases earlier designated as

“dementia pugilistica”, classically described in boxers, and is now associated with patients with

other forms of trauma including patients with a history of other contact sports.

Clinical presentation

The heterogeneity in the clinical presentations of CTE further obscures its

operationalization and distances researchers from defining a set of distinct diagnostic criteria.

Case reports show variable neurobehavioral and neurocognitive changes,10-12,16 but without any

definitive core criteria. Efforts to define the clinical diagnostic criteria of CTE are hindered by a

lack of prospective studies with living subjects. The evidence to date relies solely on

retrospective reviews of case reports and next of kin interviews, without a review of medical

records, limiting their validity. Apparently, most of the brains submitted for detailed autopsy

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15 Perrine with stains to detect tau phenotypes and TDP-43 were sent to centers by relatives of the deceased

who were distressed by the patient’s clinical depression or dementia. It is not clear how many of

the brains reported as having CTE were submitted by families of decedents with no history of

mental disorders or dementia. Consequently, reliance on histories of psychiatric problems,

neurological disorders, or co-morbidities without medical record verification cannot be regarded

as reliable. And as already noted, these studies are cross-sectional, rather than longitudinal.

However, what can be inferred from the current data is that the clinical presentation of CTE

involves symptoms in at least one of three possible domains: cognition, behavior/mood, and

motor functioning.

The cognitive and behavioral symptoms of CTE are nonspecific in that they are

frequently seen in the general population as well as in other medical, psychiatric, and

neurological disorders. For example, some of the cognitive features seen (i.e., impaired

concentration, language, and memory, as well as executive dysfunction, visuospatial difficulties,

and dementia) are common in other neurodegenerative conditions, as well as in normal

aging.21,43 The motor features seen in boxers (e.g., dysarthria, spasticity, ataxia, tremors, gait

disturbance) resemble those of individuals with Parkinson’s disease. The behavioral

manifestations (i.e., apathy, aggression, impulsivity, depression, delusions, and suicidality) are

seen in the general population or psychiatric disorders and are hallmark features of some

neurodegenerative conditions (e.g., FTD).21 Iverson et al.44 found that high school athletes with

no history of concussion reported one or more concussion symptoms with 19% of boys and 28%

of girls showed enough symptoms to resemble a diagnosis of post-concussion syndrome.

The absence of a definitive clinical diagnostic criteria makes it challenging to clinically

differentiate CTE from other neurodegenerative diseases. For example, it is unclear whether the

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16 Perrine dementia from CTE is distinct from the tauopathy phenotype of frontotemporal dementias

(FTD),45 as most of the signs and symptoms cited as evidence for CTE can be found in criteria

for FTD. 46 Episodic memory impairments seen in some cases of CTE16 could also be confused

with those seen in Alzheimer’s disease (AD), just as motor features seen in other cases of CTE

could be confused with Parkinsonian syndromes. Despite the frequent overlap in symptoms,

there are some distinctions in the clinical presentations of CTE that help differentiate CTE from

non-traumatic neurodegenerative disorders (e.g., AD, FTD, Parkinson’s).

Stern et al.16 examined the clinical presentation of CTE in 36 subjects with

neuropathologically confirmed CTE with retrospective reports of their clinical presentations. The

results of the study suggested the existence of two distinct clinical presentations of CTE. One

(n=22) had initial changes in behavior (n=13) or mood (n=9) prior to the onset of cognitive

disturbances and with an earlier age of onset (n =22), and the other with initial changes in

cognition and an older age of onset (n = 11). There was also an understated third group of who

were asymptomatic (n = 3). The behavior/mood group was thought to be distinct from FTD in

that cases of disinhibition and inappropriate behavior were not seen in this sample. However, this

contradicts the description of these patients as “explosive, out of control, physically and verbally

violent, and depressed”16 (p. 1125). Furthermore, the onset of behavioral changes with later

developed cognitive changes is one of the hallmarks of FTD.45 Memory disturbances were

predominant in subjects in the cognitive group who were also older, but three-quarters of the

behavior/mood group also had significant memory impairments.

There were no motor features in the subjects, which diverges from previous cases of such

symptoms in boxers1,31 but is consistent with a distinction of the clinical presentation between

football players and boxers.8 Boxers have predominantly motor symptoms, such as ataxia,

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17 Perrine dysarthria, and parkinsonism.6 In contrast, cognitive and neurobehavioral features predominate

in football players with histopathological evidence of CTE, with very few motor features. This

stark difference is also reflected in the neuropathology, with studies finding more cerebellar

scarring in boxers compared to football players.47 Stern et al. suggested that these differences

could be attributable to the variance in the biomechanics of the injuries, specific to the nature of

each sport. For example, some studies found that although boxers may sustain more angular

acceleration and torsional injuries, while football players may be more likely to sustain

transverse and linear acceleration/deceleration injuries,48 more research is needed to determine if

there actually are differences in injury mechanisms between these two contact sports. These

findings suggest that it cannot be concluded that repetitive brain trauma in multiple contexts will

certainly cause CTE.

Another major challenge is determining a causal relationship between clinical features

and neuropathological abnormalities. They are not consistently correlated, and experimental

evidence is lacking that links the specific neuropathological features of CTE to the clinical

presentation presented in the literature. CTE neuropathology has been found in subjects who

were clinically asymptomatic.8,16,35,49 Other neuropathological abnormalities similar to CTE and

Alzheimer’s diseases are also found in samples of asymptomatic older adults.50 Conversely,

many subjects who initially presented with the cognitive and behavioral symptoms consistent

with a traumatic encephalopathic syndrome were later found to lack the neuropathological

changes of CTE at autopsy.8,21 The inability to determine causality given these disparities

highlights the need to design further studies that address moderating variables and attempt to

mitigate methodological limitations.

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18 Perrine McKee et al.8,12-15,51-53 proposed four stages of clinical CTE corresponding to the

proposed four stages of the neuropathological progression of CTE,8 and described common

clinical features seen at each stage. Initially, Stage I symptoms were said to include headaches

and decreased attention and concentration. Stage II symptoms were said to progress to

depression, explosivity, and memory loss, and then to executive dysfunction and cognitive

impairment in stage III. Finally, individuals in stage IV were said to exhibit word-finding

difficulty, aggression, and dementia.8 In their more recent studies however, the authors state that

individuals with stage I neuropathology are unlikely to be symptomatic at all and that subjects

with stage II pathology may also be asymptomatic.15,53

Traumatic Encephalopathy Syndrome

In 2014, a new diagnosis in order to classify the clinical presentation of CTE, termed

Traumatic Encephalopathy Syndrome (TES), was proposed.49,54 The general proposed criteria for

TES includes: 1) a history of multiple head impacts (defined by injury and exposure type), 2) an

exclusion of any neurologic disorder that could account for clinical features, but with the caveat

that, “concomitant diagnoses of substance abuse, post-traumatic stress disorder (PTSD),

mood/anxiety disorders, or other neurodegenerative diseases (for example, AD and

frontotemporal dementia) or a combination of these can be present”,54 3) symptoms must be

present for at least 12 months, 4) the presence of at least one of the core clinical features (i.e.,

cognitive, behavioral, mood) representing a change from baseline functioning, and 5) the

presence of at least two supportive features (e.g., impulsivity, anxiety, apathy, paranoia,

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19 Perrine suicidality, headache). Given that a history of ADHD or a learning disability is regarded as an

antecedent risk factor, perhaps it should be excluded from a diagnosis of TES.55-62

The rationale for designating TES as distinct from CTE was to separate the observed

neurobehavioral symptoms from the neuropathological underpinnings. Since CTE can only be

diagnosed through confirmation of neuropathological abnormalities postmortem, similar to AD,

the introduction of TES would allow for an in vivo classification. However, the proposed

syndrome is significantly far-reaching and broad in that it encompasses many individuals with a

history of head injuries, ranging from those with subconcussive trauma, itself broadly defined as

“biomechanical force to the head or body” that does not lead to concussive symptoms,54 to those

with two or more severe TBIs. It also broadly encompasses individuals from mild depression to

late stage dementia. For example, an individual with subconcussive blows, perhaps from contact

sports, who also had problems with depression, anxiety, and headaches, would meet criteria for

TES. Victoroff 63 noted the absence of an operational definitions of CTE and TES, and after

reviewing 92 boxers and 4 football players suggested the adoption of provisional diagnostic

criteria for CTE research. Montenigro et al.64 presented clinical features thought to relate

repetitive traumatic brain injury with CTE that could be used in research, emphasizing the use of

clinical signs and symptoms present in more than 70% of reported cases of CTE. Reams et al.65

recently published a comprehensive set of diagnostic criteria to establish a clinical diagnosis of

TES in living patients without necessitating the use of autopsy proven changes. A flow chart was

created that incorporates trauma exposure, repetitive head trauma, comorbid conditions, onset,

progression over time, evidence for other neurodegenerative disease, presence of cognitive

decline documented by neuropsychological testing, and one or more clinical features of TES.

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20 Perrine These precise criteria should help researchers develop a better clinical construct for the diagnosis

of TES.

Comorbidities and Moderating Variables

An attempt to attribute clinical features solely to concussive or subconcussive blows

sustained during play would need to account for comorbidities that may contribute to and

confound the neuropathology and clinical presentation of CTE. 31 Asken et al.66 stressed that

biopsychosocial factors can have an strong influence of the clinical manifestations of CTE,

including the athlete’s developmental environment, neurodevelopmental disorders, normal aging,

adjustment to retirement, drug and alcohol abuse, surgeries and anesthesia, and sleep

disturbances. For example, in the early case descriptions of retired boxers,2 many had extensive

psychiatric histories (e.g., severe substance abuse), as well as other psychiatric, medical, or

neurological comorbidities. The same is true for the more recent CTE studies. Some studies have

not adequately controlled for or addressed certain factors (e.g., genetic, lifestyle) that could help

account for the neuropathological or neurobehavioral symptoms seen in NFL players, or that

may make players more susceptible to developing neurodegenerative conditions.

The extent to which athletes' family histories of neurodegenerative conditions or potential

genetic risk contributes to the neuropathology and clinical presentation of CTE is still unknown.

It has been suggested that the apolipoprotein (ApoE) ε4 allele may increase susceptibility for

CTE. 67 In fact, Jordan et al. found the APOE ε4 allele to be overrepresented among boxers

diagnosed with CTE.68 However, the precise relationship or mechanisms involved in determining

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21 Perrine the magnitude of genetic risk on CTE is yet to be determined. Prospective studies could consider

genetic testing for the ApoE ε4 allele, along with investigation of other genes that merit

consideration, as well as more rigorous reviews of family pedigrees.

Family socioeconomic background, including income, education, occupation, access to

medical care, and early cognitive stimulation significantly affects adult functioning.

Socioeconomic background is associated both with childhood disorders such as learning

disabilities or ADHD, which in turn affect the functioning of professional athletes66 and

influences later expression of neurodegenerative disorders.69

Another potentially important variable is professional athletes’ use of anabolic steroids or

other performance enhancing drugs (PEDs). The NFL began testing for PEDs in 1987, with

approximately 6 to 7 percent of 2,600 players testing positive for anabolic steroid use in that first

year.70 The adverse physical and psychiatric effects of PEDs are well documented across

studies,71-80 with numerous case reports of violence, aggression, mania, and suicide discussed in

the media. In high doses, PEDs are associated with manic-like affective symptoms (e.g., hostility

and aggressiveness, mood swings, poor impulse control), cognitive symptoms (e.g., deficits in

memory, attention, and orientation), and psychosis.71,81 Steroid withdrawal can result in

depression and suicidal ideation.79,81 Given that they are illegal, it is difficult to determine the

true prevalence of PEDs in NFL players. However, several former players admitted to PED use,

some of whom were also diagnosed with CTE. For example, Mike Webster, who committed

suicide and was the first NFL player found to have CTE,11 was among those with an unequivocal

history of steroid use.82 Another former player, Steve Courson, asserted in his autobiography that

75 percent of his teammates on the offensive line used steroids.83 These assertions certainly raise

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22 Perrine questions about the effect of PEDs on the development of CTE in former players, or at the very

least, marks the importance of controlling for such variables when possible.

In addition to the use of PEDs, the use of other illicit or prescription drugs may be worthy

of attention as well. Opioid abuse in particular is especially prevalent in NFL players, both

during play and post-retirement. Opiod abuse can also contribute to significant psychiatric

disorders.84 Cottler et al.73 conducted a telephone survey of 644 retired NFL players from the

2009 Retired Players Association Directory, finding that 52% (n=336) of retired NFL players

reported opioid use during their NFL careers, with 71% of those reporting misuse. Compared to

players who only used the medications as prescribed, misusers were found to be more likely to

have poor overall health at retirement. Furthermore, undiagnosed concussions, which were

reported by 81% of the sample, were found to be the strongest predictor of opioid misuse. It

would thus be prudent for CTE researchers to consider the potential neurological and

neurobehavioral impacts of these drugs.

The varying lifestyle factors of NFL players, both while playing and later when retired,

make it crucial to consider alternative explanations or theories for their neurobehavioral

presentation. The additive effects of substance abuse can certainly have an effect on individuals’

mood and behavior, but there are other unique circumstances that are particularly relevant to elite

athletes. For example, many elite athletes can become depressed after they retire, merely as a

result no longer being in the limelight or having focused nearly all of their life to one objective

and then abruptly stopping that pursuit. Torre85 reported that as many as 78% of retired NFL

players develop financial hardship within 2 years of retirement. Financial difficulties in

conjunction with substance abuse problems could cause or exacerbate major depression.

Additionally, normal aging should be considered when examining later-life neurobehavioral

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23 Perrine functioning66, especially given the increased risk of subsequent dementia after TBI.86,87 Asken et

al.66 also noted that the higher incidence of surgeries, most with general anesthesia, may impact

the risk of later neurodegenerative disorders, and that sleep disorders also contribute to the

development of dementia.

To best clarify the effects of concussions on dementia or neurodegeneration, other

variables such as comorbid illnesses (e.g., heart disease, diabetes, metabolic syndrome), lifestyle

factors (e.g., diet, stress), age at trauma, and other specific aspects of head injuries (e.g., severity,

frequency, type, duration of trauma) should also be investigated as any of these could potentially

initiate or exacerbate tau aggregation.15,31,34,44,52,67 Future studies should thus consider

implementing genetic testing, collecting rigorous family history data, and more thoroughly

investigating the association between these factors and CTE-related proteinopathies.

Neuroimaging

Given that the diagnosis of CTE is a post-mortem neuropathological diagnosis, currently

there are no retrospective studies reviewing any structural or advanced neuroimaging biomarkers

in patients diagnosed posthumously with the disease. However, as with all traumatic brain injury,

the objectives of neuroimaging should include the better characterization and classification of

brain injuries, prognostication, and identifying patients that would benefit from early specialist

referral.

Currently, structural MRI is the primary imaging modality for subacute to chronic TBI.88

It is sensitive for detecting and characterizing brain injuries, particularly cerebral atrophy in

chronic TBI. The literature is most complete for moderate to severe TBI, where cerebral atrophy

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24 Perrine is a consistent finding.89-91 Three-dimensional isotropic short echo spoiled gradient-recalled echo

(SPGR) and magnetization-prepared rapid gradient-echo (MPRAGE) sequences can be used to

assess TBI-associated cerebral atrophy.91-94 A few studies correlated the severity of injury with

chronic cerebral atrophy95 and functional outcomes to post-TBI cerebral atrophy,90,96-98 although

only weak correlations were found between the patterns of atrophy and their neurocognitive

sequelae.91,94

Relatively new structural MRI techniques such as susceptibility weighted imaging (SWI),

which uses the magnitude component of the T2* gradient echo data and the phase of the MRI

signal to increase sensitivity, are exquisitely sensitive to identifying blood products within the

brain, showing approximately 30% more hemorrhagic lesions when directly compared to CT.99

The number, size, and location of MRI abnormalities are correlated with the severity of TBI in

the chronic stage and were used to predict clinical outcomes among patients with early

posttraumatic vegetative state.100

Additional advanced neuroimaging techniques assessing chronic traumatic brain injury

include diffusion tensor imaging (DTI) to determine axonal integrity,101 magnetic resonance

spectroscopy (MRS) and positron emission tomography (PET) to examine brain metabolism, and

functional magnetic resonance imaging (fMRI) to evaluate brain function.19,26,101-110 Intense

research in DTI over the past 10 years demonstrated the utility of DTI in identifying TBI-

associated changes in the cerebral white matter in group-based analyses, some of which correlate

with injury outcomes.107,111 However, there is insufficient evidence for the use of DTI to

characterize, diagnose and/or prognosticate at the individual patient level.107,111,112 Although DTI

remains a very promising imaging technique and continues to be the subject of intense research

interest, the accuracy and precision of the test in individual patient is unknown.

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25 Perrine Although some neuroimaging studies show evidence of alterations in brain structure,

function, and metabolism in football players, none demonstrated a direct link to CTE. With

regard to white matter changes, Strain et al.101 used DTI to examine 26 retired NFL players, and

found a significant association between depression symptom severity and disruption of white

matter integrity. However, they were unable to determine the presence of CTE in the sample.

Hart et al.103 performed a small cross-sectional study of retired NFL players and found that those

with cognitive impairment and depression showed diffusely reduced fractional anisotropy (FA)

values within the cerebral white matter on DTI that were not evident in matched controls or in

the unimpaired retired NFL players. Retired impaired NFL players also demonstrated an increase

in deep white matter lesions on T2-weighted FLAIR when compared to matched controls but not

when compared to the unimpaired retired NFL players. Given the small number of subjects and

the study design, this study can only conclude that white matter abnormalities identified on DTI

are correlated with cognitive impairment and depression. Hampshire et al.102 reported abnormal

functional changes on fMRI in the activation of the dorsal frontoparietal network of retired NFL

players when compared to healthy controls; however, the former NFL participants already had

complaints of cognitive deficits, creating a significant selection bias. Furthermore, only small

differences were noted between the retired players and controls on a computerized test of

executive functioning.102 A few studies investigated metabolic disturbances in athletes post-

concussion using MRS. Results examining young athletes with concussions showed disturbances

in brain metabolism after a single concussion, both in the acute and chronic phases.108,113 Small

prospective cross-sectional and case-control longitudinal cohort studies show spectroscopic

metabolite levels with neuropsychological outcomes in moderate-to-severe TBI. Decreased NAA

is significantly correlated with poor outcomes in most of these studies.114-116

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26 Perrine

Although neuroimaging may show promise in identifying future biomarkers for CTE, the

scientific rigor in most of the currently published neuroimaging studies is significantly limited.

Larger future prospective and well-controlled studies are needed that relate neurocognitive

measures to imaging biomarkers to inform interpretations of causal mechanisms.

Epidemiology Data on the epidemiology of CTE in football players are limited due to a “denominator

problem”. To date there broad samples of populations such as retired NFL players are lacking,

and there are no completed longitudinal or prospective studies with sufficient sample sizes. Early

case reports of classic CTE in boxers are not necessarily generalizable to other populations such

as NFL players due to the differing nature of the sport already noted by CTE researchers, small

sample sizes, non-controlled confounding variables (e.g., psychiatric or medical comorbidities),

changes in sport safety procedures (e.g., abolishment of bare-knuckle boxing, increased medical

monitoring), and limited immunohistochemical technologies. Indeed, the incidence of CTE

specific to a broad range of athletes with varying degrees of head injury is presently unknown.31

The most important risk factor for CTE is hypothesized to be increased exposure to

concussions and subconcussive blows.12,31,34,44 For football players, this risk may depend on the

total number of games and contact practices, number of hits, position played, pre-existing

conditions, genetic risk (e.g., family history of neurodegenerative conditions), age they began

playing, career duration, and age of retirement. Gardner et al.31 calculated a rough estimate of the

incidence of CTE using the number of cases obtained in a given period versus the number of

athletes who died during the same period, thus finding it to be less than 4% of NFL players. If all

professional athletes at risk were to be used as the “denominator”, then the estimated incidence

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27 Perrine rate drops to less than 0.01%.31 Of course these estimates cannot account for the number of

athletes who might have had neuropathological changes of CTE but who were never referred to

autopsy, irrespective of their clinical phenotype.

Conclusions At present, the available evidence underlying the mechanisms of the neuropathology and

clinical features of CTE is still limited. The fundamental challenge is that there are no published

prospective, longitudinal, or comprehensive epidemiological studies. Therefore there is as yet

insufficient epidemiological or experimental evidence to ascertain the extent to which an

individual’s particular clinical presentation is related to CTE-specific neuropathology versus

neuropathology associated with other entities including, in some cases, the aging process.

Despite initially proposed consensus criteria for a neuropathological diagnosis of CTE32, the

considerable heterogeneity of histopathological changes seen in CTE and the practical aspect of

using the criteria across institutions and laboratories will require time to implement consistently.

Some researchers question the establishment of CTE as a single distinct entity given the

heterogeneity of the neuropathology and clinical features described as CTE.

The precise relationship of CTE to the proposed potentially causative risk factor of

multiple subconcussive blows remains unclear, especially given the limited comparisons to

relevant control groups. There is a lack of autopsies on non-demented and psychologically intact

athletes with equivalent concussive histories. The problem of selection bias is especially

significant given that many of the brains diagnosed with CTE were donated by families of

individuals who committed suicide or had overt neurobehavioral features, with reported mental

health issues or dementia. This selection bias is compounded by the problems inherent in

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28 Perrine subjective retrospective reporting of clinical symptoms, often without adequate objective

medical record documentation.

Biopsychosocial factors, including those from childhood, time spent playing contact

sports, and later activities, significantly affect the development of the type of psychiatric and

neurodegenerative disorders now being attributed to the effects of concussions or subconcussive

blows and CTE. Childhood history including socioeconomic factors, learning disabilities, and

ADHD, adult factors such as psychiatric disorders and drug, alcohol, opioid, and PED abuse, and

post-career variables including adjustment to retirement and financial stress all contribute to

functioning in middle age and later life. A biopsychosocial model incorporating these factors

should be applied when studying CTE.66,117

Rule changes in football will presumably result in fewer concussions, making prospective

studies more challenging. However, there is a need for more longitudinal and prospective

research on retired athletes with head injuries in order to better control for potential moderating

variables, utilize more appropriate control groups, and eliminate selection bias. Capturing and

following an in vivo history of clinical features from living athletes in addition to postmortem

assessments will improve the ability to study CTE. Future studies should specifically utilize

control groups that include individuals with depression and dementia and larger samples of

athletes, but without a history of head trauma. For example, a good control group would be body

builders, who have a similar body habitus and history of steroid use to that of American football

players but who often have little to no history of concussions. It would also be prudent for

researchers to clarify overlapping terminology, so as to avoid confusion. For example, the term

“footballer” is sometimes used interchangeably to describe both soccer players and American

football players in the CTE literature.7,21,118,119

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29 Perrine

With the growing development of brain banks of individuals irrespective of their

neurological history (e.g., at the National Institute of Child Health and Human Development, the

Tissue Bank for Development Disorders at the University of Maryland, and the Sports Legacy

Institute in Boston) the hope is that there will be a greater ability to conduct controlled

epidemiological studies of CTE in athletes vs. non-athletes, those with vs. without concussion

histories, and those with more robustly annotated clinical data (i.e., those bolstered by medical

records and not solely reliant on non-medical sources).32

Many groups and funding agencies are now endeavoring to identify biomarkers for p-tau

that could help identify potential living individuals with CTE who could be followed

longitudinally through death and autopsy. This effort could provide valuable information on the

progression of CTE, and neuroimaging studies are showing particular promise. The upside to the

media emphasis on concussions is a growing awareness among athletes, as well as a greater

willingness to recognize or admit to concussions. This awareness in turn should improve the

reliability of scientific studies, as well as the accuracy of incidence rates and perhaps in the

future, clearer risk factors (e.g., age of greatest vulnerability, etc). Furthermore, the NFL and the

NCAA are increasingly committed to educating players about concussions and encouraging them

to participate in empirical studies, all of which should help advance our knowledge on the

relationship between sports-related injuries and CTE. Taken together, although there is

insufficient empirical evidence to date to determine for certain the extent to which concussive or

subconcussive blows contribute to neuropathological or neurobehavioral changes in the future,

this area of research is rapidly growing, and numerous studies are currently underway.

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REFERENCES

1. Martland HS. Punch drunk. Journal of the American Medical Association. 1928;91(15):1103-1107.

2. Parker HL. Traumatic encephalopathy (`punch drunk') of professional pugilists. J Neurol Psychopathol. 1934;s1-15:20-28.

3. Millspaugh J. Dementia pugilistica. US Naval Med Bull. 1937;35:297-303. 4. Critchley M. Punch-drunk syndromes: the chronic traumatic encephalopathy of

boxers. Hommage a Clovis Vincent (ed). Maloine, Paris. 1949. 5. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg

Psychiatry. 1990;53(5):373-378. 6. Jordan BD. Chronic traumatic brain injury associated with boxing. Semin

Neurol2000: 179-186. 7. Geddes J, Vowles G, Nicoll J, Revesz T. Neuronal cytoskeletal changes are an early

consequence of repetitive head injury. Acta Neuropathol. 1999;98(2):171-178. 8. McKee AC, Stern RA, Nowinski CJ, et al. The spectrum of disease in chronic traumatic

encephalopathy. Brain. Jan 2013;136(Pt 1):43-64. 9. Omalu BI, Bailes J, Hammers JL, Fitzsimmons RP. Chronic traumatic encephalopathy,

suicides and parasuicides in professional American athletes: the role of the forensic pathologist. Am J Forensic Med Pathol. Jun 2010;31(2):130-132.

10. Omalu BI, DeKosky ST, Hamilton RL, et al. Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery. Nov 2006;59(5):1086-1092; discussion 1092-1083.

11. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic Traumatic Encephalopathy in a National Football League Player. Neurosurgery. 2005;57(1):128-134.

12. McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. Jul 2009;68(7):709-735.

13. McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. Sep 2010;69(9):918-929.

14. McKee AC, Robinson ME. Military-related traumatic brain injury and neurodegeneration. Alzheimers Dement. Jun 2014;10(3 Suppl):S242-253.

15. McKee AC, Stein TD, Kiernan PT, Alvarez VE. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. May 2015;25(3):350-364.

16. Stern RA, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81(13):1122-1129.

17. Stern RA, Riley DO, Daneshvar DH, Nowinski CJ, Cantu RC, McKee AC. Long-term consequences of repetitive brain trauma: chronic traumatic encephalopathy. Phys Med Rehabil Clin N Am. Oct 2011;3(10 Suppl 2):S460-467.

18. Omalu B, Bailes J, Hamilton RL, et al. Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery. Jul 2011;69(1):173-183; discussion 183.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

31 Perrine 19. Gasparrini WG, Satz P, Heilman K, Coolidge FL. Hemispheric asymmetries of

affective processing as determined by the Minnesota Multiphasic Personality Inventory. J Neurol Neurosurg Psychiatry. May 1978;41(5):470-473.

20. Gainotti G. Emotional behavior and hemispheric side of the lesion. Cortex. Mar 1972;8(1):41-55.

21. McCrory P, Meeuwisse WH, Kutcher JS, Jordan BD, Gardner A. What is the evidence for chronic concussion-related changes in retired athletes: behavioural, pathological and clinical outcomes? Br J Sports Med. Apr 2013;47(5):327-330.

22. Laskowski RA, Creed JA, Raghupathi R. Pathophysiology of Mild TBI: Implications for Altered Signaling Pathways. In: Kobeissy FH, ed. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton FL: Taylor & Francis Group; 2015.

23. Petraglia AL, Plog BA, Dayawansa S, et al. The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surg Neurol Int. 2014;5:184.

24. Turner RC, Lucke-Wold BP, Logsdon AF, et al. The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience. Front Neurol. 2015;6:222.

25. Xu L. Animal model of repetitive mild traumatic brain injury for human traumatic axonal injury and chronic traumatic encephalopathy. Neural Regen Res. Nov 2015;10(11):1731-1732.

26. Yang Z, Wang P, Morgan D, et al. Temporal MRI characterization, neurobiochemical and neurobehavioral changes in a mouse repetitive concussive head injury model. Sci Rep. 2015;5:11178.

27. Mannix R, Berglass J, Berkner J, et al. Chronic gliosis and behavioral deficits in mice following repetitive mild traumatic brain injury. J Neurosurg. Dec 2014;121(6):1342-1350.

28. Ojo JO, Mouzon BC, Crawford F. Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men. Exp Neurol. Jan 2016;275 Pt 3:389-404.

29. Corsellis JA, Bruton CJ, Freeman-Browne D. The aftermath of boxing. Psychol Med. Aug 1973;3(3):270-303.

30. Stein TD, Montenigro PH, Alvarez VE, et al. Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol. Jul 2015;130(1):21-34.

31. Gardner A, Iverson GL, McCrory P. Chronic traumatic encephalopathy in sport: a systematic review. Br J Sports Med. Jan 2014;48(2):84-90.

32. NINDS. Report on the neuropathology of chronic traumatic encephalopathy workshop. 2012; http://www.ninds.nih.gov/news_and_events/proceedings/201212_CTE_workshop_report.htm.

33. Daneshvar DH, Goldstein LE, Kiernan PT, Stein TD, McKee AC. Post-traumatic neurodegeneration and chronic traumatic encephalopathy. Mol Cell Neurosci. May 2015;66(Pt B):81-90.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

32 Perrine 34. Saulle M, Greenwald BD. Chronic traumatic encephalopathy: a review. Rehabil Res

Pract. 2012;2012:816069. 35. Gavett BE, Cantu RC, Shenton M, et al. Clinical appraisal of chronic traumatic

encephalopathy: current perspectives and future directions. Curr Opin Neurol. Dec 2011;24(6):525-531.

36. Gelber RP, Launer LI, White LR. The Honolulu-Asia Aging Study: epidemiologic and neuropathologic research on cognitive impairment. Curr Alzheimer Res. 2012;9:664-672.

37. Snowden DA. Healthy aging and dementia: findings for the Nun Study. Ann Intern Med. 2003;139:450-454.

38. LaCava G. Boxer's encephalopathy. J Sports Med Phys Fitness. 1963;168:87-92. 39. Guterman A, Smith R. Neurological sequelae of boxing. Sports Med. 1987;4:194-210. 40. Bieniek KF, Ross OA, Cormier KA, et al. Chronic traumatic encephalopathy pathology

in a neurodegenerative disorders brain bank. Acta Neuropathol. 2015;130:877-889. 41. Goldstein LE, McKee AC, Stanton PK. Considerations for animal models of blast-

related traumatic brain injury and chronic traumatic encephalopathy. Alzheimers Res Ther. 2014;6(5):64.

42. Xu L, Ryu J, Nguyen JV, et al. Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury. Exp Neurol. Nov 2015;273:168-176.

43. Jordan BD. The clinical spectrum of sport-related traumatic brain injury. Nat Rev Neurol. Apr 2013;9(4):222-230.

44. Iverson GL, Gardner AJ, McCrory P, Zafonte R, Castellani RJ. A critical review of chronic traumatic encephalopathy. Neurosci Biobehav Rev. Sep 2015;56:276-293.

45. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546-1554.

46. Mendez MF, Shapira JS, McMurtray A, Licht E, Miller BL. Accuracy of the clinical evaluation for frontotemporal dementia. Arch Neurol. 2007;64(6):830-835.

47. Baugh CM, Robbins CA, Stern RA, McKee AC. Current understanding of chronic traumatic encephalopathy. Curr Treat Options Neurol. Sep 2014;16(9):306.

48. Viano DC, Casson IR, Pellman EJ, et al. Concussion in Professional Football: Comparison with Boxing Head Impacts—Part 10. Neurosurgery. 2005;57(6):1154-1172.

49. Riley DO, Robbins CA, Cantu RC, Stern RA. Chronic traumatic encephalopathy: contributions from the Boston University Center for the Study of Traumatic Encephalopathy. Brain Inj. 2015;29(2):154-163.

50. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. May 2012;71(5):362-381.

51. McKee AC, Cairns NJ, Dickson DW, et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. Jan 2016;131(1):75-86.

52. McKee AC, Daneshvar DH. The neuropathology of traumatic brain injury. Handb Clin Neurol. 2015;127:45-66.

MANUSCRIP

T

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ACCEPTED MANUSCRIPT

33 Perrine 53. McKee AC, Daneshvar DH, Alvarez VE, Stein TD. The neuropathology of sport. Acta

Neuropathol. Jan 2014;127(1):29-51. 54. Montenigro PH, Baugh CM, Daneshvar DH, et al. Clinical subtypes of chronic

traumatic encephalopathy: Literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimers Res Ther. 2014;6(68):1-17.

55. Adeyemo BO, Biederman J, Zafonte R, et al. Mild traumatic brain injury and ADHD: a systematic review of the literature and meta-analysis. J Atten Disord. Oct 2014;18(7):576-584.

56. Biederman J, Feinberg L, Chan J, et al. Mild Traumatic Brain Injury and Attention-Deficit Hyperactivity Disorder in Young Student Athletes. J Nerv Ment Dis. Nov 2015;203(11):813-819.

57. Ellis MJ, Ritchie LJ, Koltek M, et al. Psychiatric outcomes after pediatric sports-related concussion. J Neurosurg Pediatr. Dec 2015;16(6):709-718.

58. Hehar H, Yeates K, Kolb B, Esser MJ, Mychasiuk R. Impulsivity and Concussion in Juvenile Rats: Examining Molecular and Structural Aspects of the Frontostriatal Pathway. PLoS One. 2015;10(10):e0139842.

59. Nelson LD, Guskiewicz KM, Marshall SW, et al. Multiple Self-Reported Concussions Are More Prevalent in Athletes With ADHD and Learning Disability. Clin J Sport Med. Mar 2016;26(2):120-127.

60. Tator CH, Davis HS, Dufort PA, et al. Postconcussion syndrome: demographics and predictors in 221 patients. J Neurosurg. Feb 26 2016:1-11.

61. Elbin RJ, Kontos AP, Kegel N, Johnson E, Burkhart S, Schatz P. Individual and combined effects of LD and ADHD on computerized neurocognitive concussion test performance: evidence for separate norms. Arch Clin Neuropsychol. 2013;28(5):476-484.

62. Zuckerman SL, Lee YM, Odom MJ, Solomon GS, Sills AK. Baseline neurocognitive scores in athletes with attention deficit-spectrum disorders and/or learning disability. J Neurosurg Pediatr. 2013;12(2):103-109.

63. Victoroff J. Traumatic encephalopathy: review and provisional research diagnostic criteria. NeuroRehabilitation. 2013;32(2):211-214.

64. PH M, C B, RC C. Clinical features of repetitive traumatic brain injury and chronic traumatic encephalopathy. Brain Pathol. 2015;25(3):304-317.

65. Reams N, Eckner JT, Almeida AA, et al. A clinical approach to the diagnosis of traumatic encephalopathy syndrome: A review. JAMA Neurol. 2016;73(6):743-749.

66. Asken BM, Sullan MJ, Snyder AR, et al. Factors influencing clinical correlates of Chronic Traumatic Encephalopathy (CTE): a review. Neuropsychol Rev. 2016 August 25;[Epub ahead of print].

67. Gandy S, DeKosky ST. APOE ε4 Status and Traumatic Brain Injury on the Gridiron or the Battlefeld. Sci Transl Med. 2012;4(134):1-3.

68. Jordan D, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein Chronic Traumatic Brain Injury in Boxing. JAMA Neurol. 1997;278(2):136-140.

69. Borenstein AR, Copenhaver CI, Mortimer JA. Early-life risk factors for Alzheimer's disease. Alzheimer Dis Assoc Disorders. 2006;20(1):63-72.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

34 Perrine 70. Shikles JL, Jojokian AB, MacLennan BW, Martinez R, Baskin MD. Drug misuse:

Anabolic steroids and human growth hormone 1989. Rep. No. GAO/HRD-89-109. 71. Trenton AJ, Currier GW. Behavioural manifestations of anabolic steroid use. CNS

Drugs. 2005;19(7):571-595. 72. Cotlar MJ. Androgen-androgenic steroids, the athlete, and mortality. J Insur Med.

2001;33(3):251-256. 73. Cottler LB, Ben Abdallah A, Cummings SM, Barr J, Banks R, Forchheimer R. Injury,

pain, and prescription opioid use among former National Football League (NFL) players. Drug Alcohol Depend. Jul 1 2011;116(1-3):188-194.

74. Dodge TL, Jaccard JJ. The effect of high school sports participation on the use of performance-enhancing substances in young adulthood. J Adolesc Health. Sep 2006;39(3):367-373.

75. Franckowiak B. Performance-Enhancing Drugs and the High School Athlete. NASN Sch Nurse. Jul 2015;30(4):214-216.

76. Gregory AJ, Fitch RW. Sports medicine: performance-enhancing drugs. Pediatr Clin North Am. Aug 2007;54(4):797-806, xii.

77. Haugen KK, Nepusz T, Petroczi A. The multi-player performance-enhancing drug game. PLoS One. 2013;8(5):e63306.

78. Strain EC. Drug use and sport--a commentary on: Injury, pain and prescription opioid use among former National Football League football players by Cottler et al. Drug Alcohol Depend. Jul 1 2011;116(1-3):8-10.

79. Thiblin I, Pärlklo T. Anabolic androgenic steroids and violence. Ann Clin Psychiatry. 1999;11(4):223-231.

80. Todd T. Anabolic steroids: the gremlins of sport. Journal of Sport History. 1987;14(1):87-107.

81. Lester D, Gunn JF. Suicide in Professional and Amateur Athletes: Incidence, Risk Factors, and Prevention: Charles C Thomas Publisher; 2013.

82. Fainaru-Wada M, Fainaru S. League of denial: The NFL, concussions, and the battle for truth: Three Rivers Press; 2013.

83. Courson S, Schreiber LR. False Glory: Steelers and Steroids: the Steve Courson Story: Longmeadow Press; 1991.

84. Ilyuk R, Gromyco D, Kiselev A, Torban M, Krupitsky E. Hostility and anger in patients dependent on different psychoactive drugs. ANS: J Neurocog Res. 2013;54(3-4).

85. Torre P. How and why athletes go broke 2009; http://www.si.com/vault/2009/03/23/105789480/how-and-why-athletes-go-broke.

86. Gardner RC, Burke JF, Nettiksimmons J, Kaup A, Barnes DE, Yaffe K. Dementia risk after traumatic brain injury vs. nonbrain trauma: the role of age and severity. JAMA Neurol. 2014;71(12):1490-1497.

87. Nordstrom P, Michaelsson K, Gustafson Y, Nordstrom A. Traumatic brain injury and young onset dementia: a nationwide cohort study. Ann Neurol. 2014;75(3):374-381.

88. Wintermark M, Sanelli PC, Anzai Y, et al. Imaging evidence and recommendations for traumatic brain injury: conventional neuroimaging techniques. J Am Coll Radiol. Feb 2015;12(2):e1-14.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

35 Perrine 89. MacKenzie JD, Siddiqi F, Babb JS, et al. Brain atrophy in mild or moderate traumatic

brain injury: a longitudinal quantitative analysis. AJNR Am J Neuroradiol. Oct 2002;23(9):1509-1515.

90. Tomaiuolo F, Carlesimo GA, Di Paola M, et al. Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a T1 weighted MRI study. J Neurol Neurosurg Psychiatry. Sep 2004;75(9):1314-1322.

91. Levine B, Kovacevic N, Nica EI, et al. The Toronto traumatic brain injury study: injury severity and quantified MRI. Neurology. Mar 4 2008;70(10):771-778.

92. Zhou Y, Kierans A, Kenul D, et al. Mild traumatic brain injury: longitudinal regional brain volume changes. Radiology. Jun 2013;267(3):880-890.

93. Cohen BA, Inglese M, Rusinek H, Babb JS, Grossman RI, Gonen O. Proton MR spectroscopy and MRI-volumetry in mild traumatic brain injury. AJNR Am J Neuroradiol. May 2007;28(5):907-913.

94. Bendlin BB, Ries ML, Lazar M, et al. Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging. Neuroimage. Aug 15 2008;42(2):503-514.

95. Trivedi MA, Ward MA, Hess TM, et al. Longitudinal changes in global brain volume between 79 and 409 days after traumatic brain injury: relationship with duration of coma. J Neurotrauma. May 2007;24(5):766-771.

96. Tomaiuolo F, Worsley KJ, Lerch J, et al. Changes in white matter in long-term survivors of severe non-missile traumatic brain injury: a computational analysis of magnetic resonance images. J Neurotrauma. Jan 2005;22(1):76-82.

97. Himanen L, Portin R, Isoniemi H, Helenius H, Kurki T, Tenovuo O. Cognitive functions in relation to MRI findings 30 years after traumatic brain injury. Brain Inj. Feb 2005;19(2):93-100.

98. Gale SD, Baxter L, Roundy N, Johnson SC. Traumatic brain injury and grey matter concentration: a preliminary voxel based morphometry study. J Neurol Neurosurg Psychiatry. Jul 2005;76(7):984-988.

99. Beauchamp MH, Ditchfield M, Babl FE, et al. Detecting traumatic brain lesions in children: CT versus MRI versus susceptibility weighted imaging (SWI). J Neurotrauma. Jun 2011;28(6):915-927.

100. Kampfl A, Schmutzhard E, Franz G, et al. Prediction of recovery from post-traumatic vegetative state with cerebral magnetic-resonance imaging. Lancet. Jun 13 1998;351(9118):1763-1767.

101. Strain J, Didehbani N, Cullum CM, et al. Depressive symptoms and white matter dysfunction in retired NFL players with concussion history. Neurology. Jul 2 2013;81(1):25-32.

102. Hampshire A, MacDonald A, Owen AM. Hypoconnectivity and hyperfrontality in retired American football players. Sci Rep. 2013;3:2972.

103. Hart J, Jr., Kraut MA, Womack KB, et al. Neuroimaging of cognitive dysfunction and depression in aging retired National Football League players: a cross-sectional study. JAMA Neurol. Mar 1 2013;70(3):326-335.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

36 Perrine 104. Koerte IK, Lin AP, Willems A, et al. A review of neuroimaging findings in repetitive

brain trauma. Brain Pathol. May 2015;25(3):318-349. 105. Koerte IK, Mayinger M, Muehlmann M, et al. Cortical thinning in former professional

soccer players. Brain Imaging Behav. Aug 19 2015. 106. Singh R, Meier TB, Kuplicki R, et al. Relationship of collegiate football experience and

concussion with hippocampal volume and cognitive outcomes. JAMA. May 14 2014;311(18):1883-1888.

107. Shenton ME, Hamoda HM, Schneiderman JS, et al. A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav. Jun 2012;6(2):137-192.

108. Henry LC, Tremblay S, Leclerc S, et al. Metabolic changes in concussed American football players during the acute and chronic post-injury phases. BMC Neurol. 2011;11:105.

109. Davenport EM, Whitlow CT, Urban JE, et al. Abnormal white matter integrity related to head impact exposure in a season of high school varsity football. J Neurotrauma. Oct 1 2014;31(19):1617-1624.

110. Abbas K, Shenk TE, Poole VN, et al. Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study. Brain Connect. Mar 2015;5(2):91-101.

111. Niogi SN, Mukherjee P. Diffusion tensor imaging of mild traumatic brain injury. J Head Trauma Rehabil. Jul-Aug 2010;25(4):241-255.

112. Eierud C, Craddock RC, Fletcher S, et al. Neuroimaging after mild traumatic brain injury: review and meta-analysis. Neuroimage Clin. 2014;4:283-294.

113. Vagnozzi R, Signoretti S, Tavazzi B, et al. Temporal window of metabolic brain vulnerability to concussion: a pilot 1H-magnetic resonance spectroscopic study in concussed athletes--part III. Neurosurgery. Jun 2008;62(6):1286-1295; discussion 1295-1286.

114. Brooks WM, Stidley CA, Petropoulos H, et al. Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma. Aug 2000;17(8):629-640.

115. Friedman SD, Brooks WM, Jung RE, et al. Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology. Apr 22 1999;52(7):1384-1391.

116. Friedman SD, Brooks WM, Jung RE, Hart BL, Yeo RA. Proton MR spectroscopic findings correspond to neuropsychological function in traumatic brain injury. AJNR Am J Neuroradiol. Nov-Dec 1998;19(10):1879-1885.

117. McCrea M, Broshek D, Barth J. Sport concussion assessement and management: future research directions. Brain Injury. 2015;29(2):276-282.

118. Montenigro PH, Corp DT, Stein TD, Cantu RC, Stern RA. Chronic traumatic encephalopathy: historical origins and current perspective. Annu Rev Clin Psychol. 2015;11:309-330.

119. Kaye AH, McCrory P. Does football cause brain damage? Med J Aust. May 21 2012;196(9):547-549.

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38 Perrine Figure 1. The distribution of pathological tau accumulation in 4 stages. 50-µm tissue sections were stained using the CP-13 antibody for phosphorylated tau. McKee et al., The spectrum of disease in chronic traumatic encephalopathy, Brain 2013: 136; 43–64, by permission of Oxford University.

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Disclosure- Conflict of Interest

None of the authors has a conflict of interest.