Chronic traumatic encephalopathy (CTE) …

Neurobehavioral & Cognitive Disorders

Updated 08.07.2025
Released 11.01.1994
Expires For CME 08.07.2028

Chronic traumatic encephalopathy

Authors: Minzae Kim, Katherine Turk MD, Andrew E Budson MD

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Editor: Howard S Kirshner MD

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Chronic traumatic encephalopathy

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Introduction

Overview

Chronic traumatic encephalopathy refers to a specific pathology found in the brains of some people with a history of repetitive head impacts or traumatic brain injury. Although first recognized as a clinical entity in the early 20th century, it has only recently become more commonly studied and diagnosed in the scientific and medical communities over the past 2 decades. This article provides a look into its history and epidemiology as well as a summary of current research into the evaluation, diagnosis, and management of this neurodegenerative disease.

Key points

	• Chronic traumatic encephalopathy is a neuropathological diagnosis associated with repeat exposure to repetitive head impacts; traumatic encephalopathy syndrome is the term used for the clinical presentation associated with disease.
	• Currently, the diagnosis of chronic traumatic encephalopathy can only be confirmed through postmortem neuropathological examination, unlike traumatic encephalopathy syndrome, a clinical diagnosis made during life.
	• The clinical presentation of chronic traumatic encephalopathy includes a progressive form of dementia distinct from Alzheimer disease, although it can be mistaken for it.
	• One of few well-established risk factors is a history of either multiple mild or at least one moderate to severe traumatic brain injury; signs and symptoms of disease often begin years or even decades after the last reported head injury.
	• To date, more than 99% of cases of symptomatic former professional American football players tested were confirmed to have chronic traumatic encephalopathy at autopsy.
	• No evidence of chronic traumatic encephalopathy without documented repetitive head trauma was found amongst cases at an all-cause dementia brain bank. In addition, a 32% prevalence of chronic traumatic encephalopathy was found amongst the dementia brain bank cases with history of contact sports participation.
	• There is no cure for chronic traumatic encephalopathy; treatment is symptomatic.
	• Current research is underway to diagnose traumatic encephalopathy syndrome, and subsequently chronic traumatic encephalopathy, in living patients using clinical evaluation criteria and biomarkers, such as serum, cerebrospinal fluid, and imaging studies.

Historical note and terminology

Chronic traumatic encephalopathy was first described in 1928 as the clinical “punch drunk syndrome” (55). It was associated with people who participated in the sport of boxing, also referred to as pugilists (71), particularly athletes who received multiple blows to the head. An associated term “dementia pugilistica” was coined by Millspaugh in 1937 (66). Pathological findings attributable to clinical “punch drunk syndrome” were later published, also using former professional boxers as case studies (23). Although the term “traumatic encephalopathy” began to be used as early as 1934, Critchley is widely credited with popularizing the term “chronic traumatic encephalopathy” in 1957 due to his emphasis on the gradually progressive nature of the disease (26; 41; 19). Although Critchley later introduced the term “chronic progressive traumatic encephalopathy,” the designation “chronic traumatic encephalopathy” was retained as the word “progressive” was deemed misleading, implying that clinical deterioration is always inevitable (43). The prevalence of the disease, once believed to affect only “less-skilled” boxers, was illustrated in 1969, when Roberts found that as many as 17% of retired boxers exhibited symptoms consistent with chronic traumatic encephalopathy (76). Building on these clinical observations, Corsellis and colleagues were among the first to describe the neuropathology of chronic traumatic encephalopathy in 1973 through a case series of 15 retired boxers (25). However, this entity went largely unnoticed by the general public until 2005, when the first reported case was found in a former professional American football player (68). A larger series of chronic traumatic encephalopathy cases among American football players was further expanded by Mez and colleagues in 2017 (65). Since then, chronic traumatic encephalopathy has become the focus of media attention with respect to prevention and management of brain injury in sports, particularly American football (44). The scientific community has likewise developed a renewed interest in the study of chronic traumatic encephalopathy, and multiple studies are currently underway to better understand this disease. The neuropathology of chronic traumatic encephalopathy has been confirmed as distinct from other forms of neurodegenerative disease, and the search continues for in vivo diagnostic and therapeutic options.

Clinical manifestations

Presentation and course

At present, the primary risk factor for the diagnosis of chronic traumatic encephalopathy is a history of substantial exposure to repetitive head injury. Although chronic traumatic encephalopathy remains a neuropathological diagnosis confirmed exclusively through postmortem evaluation, consensus criteria have been developed to characterize its potential clinical manifestations during life, termed “traumatic encephalopathy syndrome.” In addition to the major diagnostic criteria of repetitive head impacts, the core clinical features for presenting signs and symptoms of traumatic encephalopathy syndrome, according to the National Institute of Neurological Disorders (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome, consist of cognitive impairment (episodic memory or executive dysfunction), neurobehavioral dysregulation, and a progressive course not accounted for by any other condition (45). When comparing 2014 research diagnostic criteria for traumatic encephalopathy syndrome with findings from the DIAGNOSE CTE and Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) studies, the traumatic encephalopathy syndrome criteria demonstrated high sensitivity (0.97) but low specificity (0.21) for predicting the pathological diagnosis of chronic traumatic encephalopathy (45; 64). Retrospective analysis revealed mood changes, such as hopelessness, agitation, and irritability, or behavioral changes in 96% of confirmed cases of neuropathologically mild chronic traumatic encephalopathy, compared with 89% of those with severe chronic traumatic encephalopathy (65). Psychiatric symptoms, such as anxiety, depression, apathy, and paranoia, are categorized as supportive rather than core diagnostic features due to concerns about increasing the risk of false-positive diagnoses. Behavioral dysregulation, such as violent and impulsive actions often characterized by rage, was observed in more than 40% of autopsy-confirmed chronic traumatic encephalopathy cases. Cognitive symptoms were present in 85% of mild cases and 95% of severe cases, whereas dementia was reported in 33% of mild and 85% of severe cases. Thus, cognitive domains, including episodic memory, attention, executive functioning, language, and visuospatial functions, were among the most common clinical problems reported in over 60% of chronic traumatic encephalopathy cases at autopsy. Lastly, motor symptoms, such as tremor, dysarthria, and dyscoordination, were present in 48% of mild cases and 75% of severe cases of confirmed chronic traumatic encephalopathy. Following the diagnostic criteria for traumatic encephalopathy syndrome, individual functional dependence can be graded based on the presence and severity of dementia using the following categories: independent, subtle/mild functional limitation, mild, moderate, and severe. Table 1 lists the most commonly described symptoms at initial presentation for chronic traumatic encephalopathy of any stage.

Table 1. Most Common Initial Presenting Clinical Features Among Symptomatic Subjects

•·Memory impairment (84.8%)
•·Executive dysfunction (78.8%)
•·Attention and concentration difficulties (72.7%)
•·Sadness or depression (63.6%)
•·Hopelessness (63.6%)
•·Explosivity (57.6%)
•·Language impairment (57.6%)
•·Visuospatial difficulties (54.5%)
•·“Out of control” (51.5%)
•·Physically violent (51.5%)
•·Verbally violent (48.5%)
•·Impulse and control problems (45.5%)
•·Suicidal ideation or attempts (30.3%)

% Indicates the percentage of symptomatic individuals with autopsy proven CTE endorsing each feature at initial presentation.

Adapted from (84).

Time course and prognosis. Repetitive head impacts refers to repeated instances of either subconcussive or concussive head injuries due to traumatic brain injuries and is thought to initiate a cascade of neurobiological events leading to the clinical symptoms of traumatic encephalopathy syndrome, which may culminate in the neuropathology of chronic traumatic encephalopathy (88). Retrospective analysis revealed progressive decline comparable to other neurodegenerative disorders, occurring in 85% and 100% of confirmed cases of mild and severe chronic traumatic encephalopathy, respectively (65). Based on an analysis of 68 brains of male subjects with evidence of chronic traumatic encephalopathy, McKee and colleagues developed the first of two systematic staging criterions for chronic traumatic encephalopathy, outlining its progression from early-stage symptoms, like headaches and confusion, to advanced stages, characterized by widespread tau pathology, brain atrophy, cognitive impairment, and motor impairment (62). Retrospective analysis revealed 28% of confirmed cases presented with behavioral and mood disturbances as the major complaint, 32% presented with cognitive difficulty in the absence of mood changes, and 40% presented with both behavioral and cognitive complaints. However, the presence of chronic traumatic encephalopathy in younger patients with primarily mood and behavioral symptoms suggests a more slow-moving or even static process than the progressive cognitive symptoms noted in patients who are older at initial presentation (03; 65). Given the estimated progression between subsequent stages of chronic traumatic encephalopathy of 11 to 14 years, ranging from stage I to IV from mild to severe, this discrepancy may represent at least two distinct subtypes of chronic traumatic encephalopathy, which also makes accurate diagnosis difficult in living patients. Alosco and colleagues reported that a younger age of exposure to football significantly predicted an earlier onset of both behavioral and cognitive symptoms (03). In a postmortem study of 152 contact sports players younger than 30 years of age at death, 63 showed chronic traumatic encephalopathy pathology, correlating with career length, older age, and playing at a higher level. In these subjects, neurobehavioral dysregulation, apathy, and depression were prevalent, with suicide being the most common cause of death (58). Cortical-sparing chronic traumatic encephalopathy, a subtype of high stage chronic traumatic encephalopathy that was proposed in 2024, is characterized by lower amounts of tau inclusions in the cortex and increased tauopathy in the medial temporal lobe and brainstem, which was found to be significantly associated with less severe levels of cognitive impairment (01). The most common cause of death among individuals with mild chronic traumatic encephalopathy pathology (stages I and II) was found to be suicide (27%), frequently associated with changes in mood, whereas those with severe chronic traumatic encephalopathy pathology (Stages III and IV) most commonly passed from dementia-related and parkinsonian neurodegenerative conditions (47%) (65).

The proposed traumatic encephalopathy syndrome criteria were updated in 2021 by a group of 20 field experts who performed an extensive literature review and application of previously published criteria for chronic traumatic encephalopathy to achieve consensus on core clinical features, supportive symptoms, and level of certainty regarding underlying chronic traumatic encephalopathy pathology (Table 2).

Table 2. Research Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES)

	(1) Substantial exposure to repetitive head impacts, including:
		(a) Involvement in high-exposure contact or collision sports
			(i) For American football, minimum 2 years (preferably 5) at the high school level or above
			(ii) Minimum of 5 years for other high contact sports, such as boxing, ice hockey, soccer, rugby, martial arts
		(b) Military service involving repetitive head impacts
		(c) Other exposure to multiple head impacts (eg, domestic violence, head banging, vocational activities)
	(2) One or both core clinical features, including:
		(a) Cognitive impairment (all four required)
			(i) As reported by self, informant, or clinician’s report
			(ii) Representing a significant decline from baseline level of function
			(iii) Deficits in episodic memory and/or executive function
			(iv) Substantiated by impaired performance on formal neuropsychological testing (if available)
		(b) Neurobehavioral dysregulation (all three required)
			(i) As reported by self, informant, or clinician’s report
			(ii) Representing a significant change from baseline level of function
			(iii) Symptoms and/or observed behaviors representing poor regulation or control of emotions and/or behavior, including (but not limited to) explosiveness, impulsivity, rage, violent outbursts, short fuse, or emotional lability, preferably substantiated by standardized measures
	(3) Progressive course is a required core clinical feature
	(4) Not fully accounted for by other disorders
Adapted from (17; 45)

Diagnostic evaluation with biomarkers is an area of active research, with several possible candidates in early development. Tau-specific PET scanning, which detects the deposition of hyperphosphorylated tau (p-tau) as neurofibrillary tangles, has been previously studied as a potential marker for diagnosis in living patients (61). However, this approach cannot reliably detect chronic traumatic encephalopathy or show any significant differences from control subjects, possibly due to this method being specifically designed to detect tau associated with Alzheimer disease (50; 53). Cerebrospinal fluid analysis for total tau, p-tau, and amyloid levels may provide supportive data for patients with suspected chronic traumatic encephalopathy potentially allowing for a clinical distinction between chronic traumatic encephalopathy and Alzheimer disease (87). Additional CSF biomarkers, including neurofilament light protein and glial fibrillary acidic protein, are under investigation as are serum studies for related proteins. A study of postmortem brain tissue found increased levels of the protein CCL2 in cases of confirmed chronic traumatic encephalopathy pathology, but not in confirmed Alzheimer disease cases, suggesting a potential future therapeutic target (21). Supportive data, including structural imaging studies (MRI and CT) with evidence of cortical atrophy and septal abnormalities, have also been evaluated (65). One study found that up to 94% of retired football players had evidence of cavum septum pellucidum, versus only 18% of control patients (32). However, this finding likely represents a marker of prior head trauma that is unlikely to be related in any direct way to chronic traumatic encephalopathy pathology.

Co-occurrence of neuropathology. Chronic traumatic encephalopathy pathology can be found alongside that of other neurodegenerative diseases commonly seen in older individuals (60). The chronic traumatic encephalopathy brain bank of the Veterans Affairs-Boston University-Concussion Legacy Foundation (VA-BU-CLF) reported 142 confirmed cases of chronic traumatic encephalopathy, of which 15 also had Alzheimer disease, another 15 had motor neuron disease, 10 had Lewy body disease, and four had frontotemporal lobar degeneration (60). Seven of the cases showed evidence of at least two other comorbid pathologies, whereas just 89 of the 142 showed pure chronic traumatic encephalopathy pathology. TDP-43 is also commonly found in cases of chronic traumatic encephalopathy, though its pattern of accumulation appears to be variable (52; 80; 60). One theory is that TDP-43 deposition follows a staged progression similar to p-tau and spreads from the subcortical white matter through the medial temporal lobe to involve larger cortical structures in late-stage chronic traumatic encephalopathy (62). This was later supported by the observed and almost universal finding of TDP-43 in cases of stage IV chronic traumatic encephalopathy (60). TDP-43 has also been implicated in frontotemporal lobar degeneration and several types of motor neuron disease, suggesting a class of neurodegenerative diseases known as TDP-43 proteinopathies (42). However, the exact relationship between chronic traumatic encephalopathy and other neurodegenerative disease pathologies is unknown. Though the likelihood of development of Alzheimer disease increases as individuals age, the abnormal beta-amyloid (Aβ) plaques associated with Alzheimer disease are felt to arise earlier in people with repetitive head injury (82). In addition, the presence of Alzheimer pathology, indicated by a positive Aβ-PET scan, may contribute to cognitive deficits in traumatic encephalopathy syndrome (TES) patients that more closely resemble the presentation of Alzheimer disease, in comparison to traumatic encephalopathy syndrome patients with negative Aβ-PET (10). In about one third of cases of comorbid chronic traumatic encephalopathy and motor neuron disease pathology, patients were reported to present with cognitive and behavioral changes many years before onset of motor symptoms (60). Thus, chronic traumatic encephalopathy is commonly found in concert with evidence of other neurodegenerative conditions, though investigation is underway to determine whether associations exist between these diseases.

Risk factors. Understanding whether there is a genetic predisposition for chronic traumatic encephalopathy is an active area of investigation. The APOEε4 allele on chromosome 19 confers higher risk of Alzheimer disease development and has also been associated with greater cognitive impairment in former boxers and American football players (78). In a cohort of 68 confirmed chronic traumatic encephalopathy cases, the carrier frequency of APOEε4 did not differ from that found in the general population, but there was a higher rate of homozygotes in cases of pure chronic traumatic encephalopathy without comorbid neurodegenerative disease (84). Subsequently, in 294 subjects with confirmed chronic traumatic encephalopathy, the presence of APOEε4 correlated with both chronic traumatic encephalopathy staging and increased p-tau accumulation in the dorsolateral frontal lobe (11).

A few nonheritable chronic traumatic encephalopathy risk factors have also been identified, including age at first exposure to repetitive head injury and cumulative exposure. A study of 214 former American football players revealed twice the risk of behavioral changes (such as executive dysfunction and apathy), and three times the risk of clinical depression in those who began playing prior to age 12 compared to those who began later in life (03). Another study found changes in white matter integrity in boys aged 8 to 13 years after a single season of tackle football (12). These findings suggest that exposure to repetitive head injury during critical periods of neural development could result in long-term detriment. Specifically, the cumulative length of exposure to repetitive head trauma has been demonstrated as the primary risk factor for chronic traumatic encephalopathy. In a study of postmortem tissue from 580 American football players exposed to repetitive impacts, length of football play was significantly predictive of chronic traumatic encephalopathy pathology, corresponding to higher odds of greater chronic traumatic encephalopathy severity at autopsy (27). This finding is supported by a postmortem study of 631 American football players, in which cumulative exposure duration correlated with chronic traumatic encephalopathy severity, whereas playing position didn’t (54; 29). In a cohort of 31 retired rugby players, career length had a significant dose-response relation with chronic traumatic encephalopathy diagnosis at autopsy, whereas presence of loss of consciousness did not significantly correlate with chronic traumatic encephalopathy pathology (85). Outside of the context of contact sports, repeated blast exposure during military service has been shown to be a risk factor for veterans in addition to non-military law enforcement personnel (75). A postmortem investigation of blast-exposed veterans found chronic traumatic encephalopathy pathology identical to that seen in athletes with history of sports-related concussions (74). Chronic traumatic encephalopathy was observed more frequently among individuals with a history of blast exposure compared to those without, reflecting a relative risk of 1.71, though the association did not reach statistical significance (74).

Although a retrospective neuropathological study of cases did not find any evidence to link chronic traumatic encephalopathy and domestic abuse (28), several cases of chronic traumatic encephalopathy in victims of domestic abuse have been reported since 1990 (77; 86). This is consistent with prior findings indicating that head injuries are implicated in approximately 6% of documented domestic assault cases.

By contrast, cognitive reserve, or the capacity to preserve cognitive function in the presence of neuropathological damage (70), has been observed as a protective factor. In a study of cognitive reserve in former football players with confirmed late-stage (III or IV) chronic traumatic encephalopathy, those who attained professional, technical, or managerial post-football careers manifested cognitive and behavioral symptoms later than those who served in sales, service, construction, or other occupations requiring less than a college education (03b). Interestingly, level of education itself was not significantly correlated with age of symptom onset.

Prognosis and complications

Chronic traumatic encephalopathy is a progressive, irreversible neurodegenerative disease. As such, the prognosis is poor. Clinically, symptoms generally progress over years to decades depending on initial presentation. Current treatments are aimed toward symptom management and do not alter the time course significantly. For patients who came to autopsy and presented with mood or behavioral symptoms, death commonly occurred via suicide, whereas patients who presented with cognitive symptoms often succumbed to complications of dementia.

Clinical vignette

A former professional NFL player started to play football at 12 years of age, including 4 years in high school, 4 years of Division I college football, and 5 years of professional football. His wife described him, in his thirties, as a bigger-than-life, charismatic personality who was very confident, caring, and giving. His family history consisted of depression in his mother and Alzheimer dementia late in life in his father.

In his mid-to-late 40s, he began to have a short fuse, with his mood changing “on a dime.” He would lose his temper over small things like someone cutting him off on the road or misplacing an object at home. He had a road-rage incident wherein he was riding a bike and someone cut him off, and he became physically aggressive, leading to an altercation with the police. All of this was unusual for him.

He had daily headaches from his 30s until his death in his 60s and was regularly taking ibuprofen. His memory worsened, and he began to use sticky notes all over the house on every surface to remind him to go to an appointment or to turn the stove off. Despite these notes, he still often forgot to turn the stove off.

His speech was generally fluent, and he understood others well, but in his 50s he began to pause in conversation, searching for the appropriate word. He was still able to do the taxes and remember to take his car to get an oil change until his death. He began shopping inappropriately in the last 4 to 5 years of his life, frequently buying expensive new vehicles impulsively, without consulting his wife.

He had a minor elective foot surgery in his 50s, and then became apathetic, refusing to shower and shave. He became obsessive about the temperature of the house to keep the pipes from freezing and would also become overly protective about his wife’s safety, calling her when she was out at night multiple times asking her to come home immediately, which was unlike him as a younger man.

He expressed suicidal ideation passively in his 60s. He had no tremor or gait difficulty and remained physically active until his death. He died by self-inflicted gunshot wound to the chest at 66 years of age. Autopsy of his brain at Boston University revealed stage II chronic traumatic encephalopathy.

Biological basis

Etiology and pathogenesis

Currently, chronic traumatic encephalopathy can only be diagnosed postmortem. The inability to diagnose chronic traumatic encephalopathy in living patients, unlike other neurodegenerative diseases, is primarily due to the lack of an optimal tau PET radiotracer with high affinity for the 3R/4R neurofibrillary tangles characteristic of chronic traumatic encephalopathy (02). Furthermore, amyloid PET scans are unable to detect tau deposition in perivascular regions, a hallmark of chronic traumatic encephalopathy pathology, necessitating histological examination for definitive diagnosis. Corsellis first analyzed the brains of 15 deceased former professional boxers with reported dementia in 1973, describing both gross structural changes and microscopic neuropathology (25). More than 3 decades passed before the landmark discovery of similar pathology in a former professional American football player by Omalu and colleagues (68). Finally, the National Institute of Neurological Disorders and Stroke, in association with the National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB), published reliable, consensus-based neuropathological criteria for the diagnosis of chronic traumatic encephalopathy, which includes the pathognomonic irregular, perivascular distribution of hyperphosphorylated tau (p-tau) at the depths of cerebral sulci (60).

Another supportive but not necessary finding is deposition of TDP-43 within the medial temporal lobes, amygdala, and hippocampus. The presence of TDP-43 in the hippocampus, along with hippocampal sclerosis, has been found to be associated with a longer duration of exposure to repetitive head impacts, which is considered the significant risk factor for chronic traumatic encephalopathy (67). In a postmortem investigation, chronic traumatic encephalopathy pathology was significantly correlated with hippocampal sclerosis and TDP-43 inclusions (79). Gross abnormalities that may be present along with multifocal cortical atrophy are third ventricular dilatation, abnormalities of the septum, including fenestration or cavum septum pellucidum or cavum vergae, and cerebral contusions or other signs of traumatic brain injury. Furthermore, ongoing research has focused on understanding neuropathological correlates of various clinical features (09). For instance, one study determined that severity of p-tau inclusions in the frontal cortex correlated with higher measures of neurobehavioral dysregulation, whereas p-tau severity in cortical regions and the amygdala correlated with impairments in cognition and activities of daily living (08). Another study found evidence of TDP-43 pathology in retinas of eight athletes with autopsy-confirmed stage IV chronic traumatic encephalopathy, possibly contributing to visuospatial deficits in those subjects (73).

Multiple studies have purported to identify chronic traumatic encephalopathy pathology in the brains of donors with no apparent history of traumatic brain injury (60). On further review, the pathology described in these brains was more consistent with 4R immunoreactive “thorn-shaped astrocytes” in the subpial, periventricular, and perivascular white matter, also known as age-related tau astrogliopathy (ARTAG). This pathology also commonly occurs in normal aging and other neurodegenerative diseases, and it can be confused with chronic traumatic encephalopathy pathology. Although the presence of ARTAG is considered supportive evidence, the absence of any pathognomonic lesions (such as perivascular tau) greatly reduces the likelihood of and does not meet neuropathological criteria for chronic traumatic encephalopathy.

Table 3 provides the full criteria recommended by NINDS-NIBIB. Chronic traumatic encephalopathy is classified from stage I (mild) to stage IV (severe) based on the distribution of p-tau; extent of neurofibrillary tangles, neurites, and astrocytic tangles; anatomical involvement beyond the cortex; and other macroscopic changes, such as brain atrophy and secondary pathologies like TDP-43 (62; 14). Through collateral information obtained postmortem, each stage may present with an array of clinical signs and symptoms (65). Based on these clinicopathological correlations, researchers developed potential clinical criteria for the diagnosis of chronic traumatic encephalopathy in living patients, though the validity of this scheme remains under investigation (57).

Table 3. Preliminary NINDS Pathologic Criteria for Chronic Traumatic Encephalopathy Diagnosis

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 neuropathological 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 AD
	(2) In the hippocampus, pretangles, NFTs or extracellular tangles preferentially affecting CA2 and pretangles and prominent proximal dendritic swellings in CA4. These regional p-tau pathologies differ from the preferential involvement of CA1 and subiculum found in AD
	(3) Abnormal p-tau immunoreactive neuronal and astrocytic aggregates in subcortical nuclei, including the mammillary bodies and other hypothalamic nuclei, amygdala, nucleus accumbens, thalamus, midbrain tegmentum, and isodendritic core (nucleus basalis of Meynert, raphe nuclei, substantia nigra and locus coeruleus)
	(4) P-Tau immunoreactive thorny astrocytes at the glial limitans most commonly found in the subpial and periventricular regions
	(5) P-Tau immunoreactive large grain-like and dot-like 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 dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala
Age-related p-tau astrogliopathy that may be present; non-diagnostic and non-supportive:
	(1) Patches of thorn-shaped astrocytes in subcortical white matter
	(2) Subependymal, periventricular, and perivascular thorn-shaped astrocytes in the mediobasal regions
	(3) Thorn-shaped astrocytes in amygdala or hippocampus
Adapted from (14).

Epidemiology

The true incidence and prevalence of chronic traumatic encephalopathy within the general population is unknown. Among patients with a history of contact sports involvement at the professional level, the reported rate varies from 17% to 99%, depending on the series and sports studied (49; 65). Although the definitive diagnosis of chronic traumatic encephalopathy can only be performed via postmortem analysis, a cross-sectional survey documented that 108 of 2913 (28%) living former American football players self-reported chronic traumatic encephalopathy diagnosed by clinicians (33), despite the fact that chronic traumatic encephalopathy cannot be diagnosed during life. Most of the reported data suffer from some degree of ascertainment or selection bias, given that symptomatic individuals were more likely to be recruited for such studies. People with a variety of sources of repetitive head injury have been found to have chronic traumatic encephalopathy at autopsy, including players of soccer, ice hockey, rugby, wrestling, and American football as well as boxers and victims of domestic violence (68; 69; 62; 72; 63; 18). Chronic traumatic encephalopathy also has been found in the brains of deceased military veterans, both with and without a history of contact sports participation (59). Bieniek and colleagues applied the 2015 NINDS-NIBIB consensus guidelines to 1,721 brains at the Mayo Clinic Brain Bank to estimate chronic traumatic encephalopathy prevalence (15). They found chronic traumatic encephalopathy in 32% of cases with history of contact sports, compared to no chronic traumatic encephalopathy in 195 cases with either no reported head trauma or a single traumatic brain injury. However, these cases were also selected from a brain bank designated for symptomatic individuals and, thus, were susceptible to selection bias as well.

The literature regarding concussion prevalence estimates that around 3.8 million sports-related concussions occur per year in the United States alone, with many going unreported (24; 40). Furthermore, the rate of asymptomatic or subconcussive head trauma appears to be exponentially higher than that of symptomatic concussions (12). Through sensory arrays implanted into helmets, one study estimated that the average college football player incurs about 415 head impacts per season (56).

In a cohort of over 2.5 million post-9/11 military veterans, 17.5% reported at least one occurrence of mild traumatic brain injury (38). Posttraumatic stress disorder affects about 23% of Iraq War veterans (31). A 2008 study showed that nearly half of veterans returning from the war in Iraq who suffered loss of consciousness as a result of traumatic brain injury also fulfilled diagnoses of posttraumatic stress disorder, compared to only 9.1% of Iraq war veterans without traumatic brain injury (37). Unfortunately, symptoms such as irritability, memory and concentration difficulties, sleep disturbances, and headaches are common to chronic traumatic encephalopathy as well as posttraumatic stress disorder and postconcussion syndrome (47). What is unknown is whether some of these same posttraumatic stress disorder symptoms could be present or exacerbated in some patients by indolent, underlying chronic traumatic encephalopathy pathology.

Although the age of initial presentation for chronic traumatic encephalopathy is estimated to be between 30 and 65 years, chronic traumatic encephalopathy pathology has been seen in patients as young as 18 years (58). Like other neurodegenerative diseases, chronic traumatic encephalopathy is purported to begin with deposition of p-tau years or even decades before symptoms of traumatic encephalopathy syndrome arise. More inclusive prospective studies are needed to define the true epidemiology of chronic traumatic encephalopathy.

Diagnostic workup

Clinical evaluation. Patients with suspected chronic traumatic encephalopathy should be evaluated for the presence of mood and behavioral symptoms as well as difficulty with memory and cognition. Age of onset and interval progression of symptoms should be elicited as chronic traumatic encephalopathy is associated with functional decline analogous to other neurodegenerative disorders. Clinicians should inquire about history of contact sports (age of first exposure, years played, amateur or professional), military history (deployment to active combat zone), domestic violence, motor vehicle collisions, and other sources of head trauma with or without a diagnosis of concussion. A detailed neurologic examination should include a comprehensive mental status examination and motor, coordination, and gait evaluations as well as surveillance for signs of parkinsonism or motor neuron disease, both of which have been reported in patients with history of repetitive head injury (45).

Biomarkers. Investigation continues into the use of biomarkers for the diagnosis of chronic traumatic encephalopathy in living patients. Given that chronic traumatic encephalopathy is a disease of abnormal tau protein accumulation, serum evaluation for total tau (t-tau) has been investigated. One study showed elevated levels only in former professional American football players (07). However, elevated serum t-tau levels did not correlate with abnormal clinical function and were also found in brain diseases such as stroke, Alzheimer disease, and frontotemporal lobar degeneration (06; 83). An immunoassay of vitreous humor biomarkers reported significantly elevated levels of t-tau in patients with co-occurring Alzheimer disease and chronic traumatic encephalopathy pathology, compared to subjects with Alzheimer disease or chronic traumatic encephalopathy alone (89). Autoradiography and in vitro binding studies using 3H-MK-6240 PET imaging on frozen temporal and frontal cortex tissue found that 3H-MK-6240 can bind to tau aggregates characteristic of chronic traumatic encephalopathy, but with low-to-intermediate intensity and wide variability of cortical uptake location across the cases (04). In addition, findings indicated that all six chronic traumatic encephalopathy stage III cases studied had Braak NFT (neurofibrillary tangle) stage III but no neuritic plaques.

Obtaining a lumbar puncture for analysis of CSF for markers of acute brain injury may also include glial fibrillary acid protein (GFAP) and neurofilament light protein, all of which have been found at elevated levels in rugby players after head injury (48). In some cases, neurofilament light protein and GFAP remained elevated long after normalization of other CSF proteins, possibly indicative of continuing neurodegeneration. NfL levels in vitreous humor have also been shown to be significantly increased in high chronic traumatic encephalopathy compared to low chronic traumatic encephalopathy, as well as low chronic traumatic encephalopathy compared to controls (89). An analysis of postmortem CSF samples obtained from participants with confirmed chronic traumatic encephalopathy showed elevated levels of p-tau231 and reduced levels of Aβ1-42 compared to controls and participants with confirmed Alzheimer disease (35; 87).

One study found increased levels of a protein called eotaxin-1 (CCL11) in cases of confirmed chronic traumatic encephalopathy compared to nonathlete controls and cases of Alzheimer disease (22). A subsequent investigation of immune markers across various tauopathies found that CCL21 was most specifically associated with chronic traumatic encephalopathy-confirmed tissue, with CCL21 also significantly elevated in CSF analysis of chronic traumatic encephalopathy cases compared to Alzheimer disease cases (20). Markers of vascular injury, including ICAM1 and CRP, have also been demonstrated to significantly increase with chronic traumatic encephalopathy pathology (46). Noninvasive testing may include the use of tau-specific tracers for PET, first developed to aid in diagnosis of Alzheimer disease (50). Although a number of tracers have been developed and validated, the studies have only applied to murine models and postmortem cases of Alzheimer disease (36).

One study did show high signals after injection of the PET ligand 2-(1-{6-[(2-[F-8]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) in the amygdala and subcortical regions of five symptomatic retired professional American football players compared to healthy controls, although autopsy confirmation of chronic traumatic encephalopathy has yet to be obtained for these patients (81). Additionally, FDDNP is only relatively specific in binding capacity, having an affinity for protein motifs exhibiting a beta-pleated sheet pattern as found in both tau and amyloid neuroaggregates. The quest for a reliable diagnostic evaluation for chronic traumatic encephalopathy involving the use of fluid and imaging biomarkers is an area of burgeoning research, though it is a slow process because autopsy specimen analysis remains the only validated method of definitive diagnosis.

Management

Currently, there is no cure for chronic traumatic encephalopathy, as is the case with all other neurodegenerative disorders. Clinicians should aim to mitigate symptoms with both pharmacologic and nonpharmacologic means (18). For mood and behavioral symptoms, psychotherapy may provide some benefit, and selective serotonin reuptake inhibitors should be considered for symptoms of depression and anxiety. One may also consider atypical antipsychotic medication for patients with uncontrolled rage or violent tendencies, though this class of medication does carry the risk of increased mortality among patients with dementia. Treatment of cognitive difficulty may include off-label use of cholinesterase inhibitors, such as rivastigmine, galantamine, and donepezil (13) for all phases of memory loss and memantine for the attention and awareness difficulty associated with moderate to severe dementia. A multidisciplinary approach to treatment should include a neurologist, psychiatrist, psychologist, and social worker to assist with the evolving needs of patients and their families. Although no clinical trials are currently underway for the treatment of chronic traumatic encephalopathy due to lack of validated diagnostic biomarkers, animal models have shown promise for kinase inhibitors and immunotherapy, though demonstrating poor translational efficiency (16), and clinical trials are on the horizon. Possible nonpharmacologic treatment and alternative therapy options include mind-body practices, such as Mindfulness-based Stress Reduction (MBSR) and Mindfulness-based Cognitive Therapy (MBCT), and physical therapy with rehabilitation exercises (51; 39).

Outcomes

As serum biomarker targets become available, specific treatments will be able to mitigate symptoms and possibly delay disease progression. The current research into potential Alzheimer disease treatments provides a model that will eventually lead to similar treatments for other neurodegenerative diseases, including chronic traumatic encephalopathy. However, current pharmacologic and nonpharmacologic treatments improve symptoms and may delay functional decline but do not affect overall outcome. The existing evidence supporting the benefits of pharmacological treatment for chronic traumatic encephalopathy remains limited (30). Similarly, nonpharmacological interventions of chronic traumatic encephalopathy have demonstrated benefits in managing mood and cognitive symptoms commonly associated with the condition; however, the evidence remains nonspecific to individuals diagnosed with chronic traumatic encephalopathy (51).

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Minzae Kim

Ms. Kim of Boston University Chobanian and Avedisian School of Medicine has no relevant financial relationships to disclose.
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Katherine Turk MD

Dr. Turk of the Boston VA Healthcare System and Boston University School of Medicine received research funding from VoxNeuro, Inc. as an investigator.
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Andrew E Budson MD

Dr. Budson of the Boston VA Healthcare System and Boston University School of Medicine received honorariums from AbbVie and Eli Lilly as a consultant and grant support from Eisai and NovoNordisk as principal investigator.
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Editor

Howard S Kirshner MD

Dr. Kirshner of Vanderbilt University School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Jason L Weller MD
Guneet S Bindra BS

Patient Profile

Age range of presentation: 13 to 65+ years
Sex preponderance: Female = male

(However, studies have a historical male bias due to limited female involvement in contact sports prior to 1972.)
Heredity: Heritability still under investigation
Population groups selectively affected: No current information on specific groups
Occupation groups selectively affected: Contact sports athletes: American football, boxing, ice hockey, soccer, wrestling, mixed martial arts

Military veterans

ICD & OMIM codes

ICD-10: Organic personality disorder due to brain disease, damage and dysfunction: F07.0

Postencephalitic syndrome: F07.1

Postconcussional syndrome: F07.2

Other organic personality and behavioural disorders due to brain disease, damage and dysfunction: F07.8

Unspecified organic personality and behavioural disorder due to brain disease, damage and dysfunction: F07.9
ICD-11: Other specified concussion: NA07.0Y

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Chronic traumatic encephalopathy

Associated Disorders

Alzheimer disease
Amyotrophic lateral sclerosis
Parkinson disease
Lewy body disease

Differential Diagnosis

Alzheimer disease
Fronto-temporal dementia
Lewy body disease
Amyotrophic lateral sclerosis with dementia
Posttraumatic stress disorder
- Chronic postconcussion syndrome

Also Relevant

Amyotrophic lateral sclerosis
Chronic subdural hematoma
Frontotemporal dementia
Headache attributed to head trauma
Memory loss
- Minor closed head injury
- Posttraumatic epilepsy
- Posttraumatic movement disorders
- Posttraumatic sleep disturbance
- Severe closed head injury
- Sexual dysfunction in neurologic disorders
- Sports activities: neurologic complications

Clinical Categories

Neurobehavioral & Cognitive Disorders

Chronic traumatic encephalopathy (CTE) …

Chronic traumatic encephalopathy

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Most Common Initial Presenting Clinical Features Among Symptomatic Subjects

Table 2. Research Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES)

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 3. Preliminary NINDS Pathologic Criteria for Chronic Traumatic Encephalopathy Diagnosis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Cryptococcal meningitis

GM2 gangliosidoses

Developmental delay in children: evaluation and management

Levacetylleucine

Whipple disease

Mucopolysaccharidoses

Primary CNS angiitis

Cortical blindness

Chronic traumatic encephalopathy

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Most Common Initial Presenting Clinical Features Among Symptomatic Subjects

Table 2. Research Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES)

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 3. Preliminary NINDS Pathologic Criteria for Chronic Traumatic Encephalopathy Diagnosis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Cryptococcal meningitis

GM2 gangliosidoses

Developmental delay in children: evaluation and management

Levacetylleucine

Whipple disease

Mucopolysaccharidoses

Primary CNS angiitis

Cortical blindness

This is an article preview.
Start a Free Account
to access the full version.