Clinical manifestations

Presentation and course

At present, the only definitive risk factor for the diagnosis of chronic traumatic encephalopathy is a history of repetitive head injury. The diagnostic criteria for presenting signs and symptoms consist of mood and behavioral changes, cognitive difficulties, motor dysfunction, and dementia (35). Retrospective analysis revealed mood changes in 96% of confirmed cases of neuropathologically mild chronic traumatic encephalopathy, compared with 89% of those with severe chronic traumatic encephalopathy (33). 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. 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. 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 (48).

Time course and prognosis. Retrospective analysis revealed progressive decline comparable to other neurodegenerative disorders in 68% of confirmed chronic traumatic encephalopathy cases (35). 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 (34; 35). Given the estimated progression between subsequent stages of chronic traumatic encephalopathy of 11 to 14 years, this discrepancy may represent at least 2 distinct subtypes of chronic traumatic encephalopathy, which also makes accurate diagnosis difficult in living patients and has led to the development of a classification system based on the presenting symptoms (31; 35). Barry Jordan proposed in 2013 a set of clinical criteria to associate symptomatology with the likelihood of chronic traumatic encephalopathy, creating categories of definite (pathology-proven), probable, possible, and improbable (19). These categories were further expanded to include subtypes of behavior or mood, cognitive, mixed, and dementia presentations as well as to account for future diagnostic biomarker evaluation (35). Average age of onset appears to have 2 distinct peaks: 34.5 years for behavioral or mood variant, and 58.5 years for the cognitive variant. Although true prevalence is unknown, 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.

Despite the classification of chronic traumatic encephalopathy as a neuropathological diagnosis possible only via postmortem analysis, a survey reported a clinicians diagnosis of chronic traumatic encephalopathy in living former football players in 108 of 3913 (2.8%) respondents (14). To delineate between the clinical presentation and neuropathological findings, the term traumatic encephalopathy syndrome was introduced to describe the clinical research criteria associated with these subtypes (35). Although the proposed traumatic encephalopathy syndrome criteria also require a history of traumatic brain injury, they allow for a diagnosis to be made in the absence of neuropathology. The 5 required criteria, core and supportive clinical features, and classification scheme are outlined in Table 2. These criteria were recently 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. The currently-accepted criteria still include supportive features such as delayed onset, psychiatric symptoms, and presence or absence of parkinsonism, but these are no longer required for diagnosis. Additionally, imaging and fluid biomarkers were not included with the current criteria with the expectation that these will be incorporated as more evidence becomes available.

Table 2. Research Diagnostic Criteria for Traumatic Encephalopathy Syndrome

	(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
		(b) Military service involving repetitive head impacts
		(c) Other exposure to multiple head impacts
	(2) One or both core clinical features, including:
		(a) Cognitive impairment (all 4 required)
			(i) As reported by self, informant, or clinicians 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 3 required)
			(i) As reported by self, informant, or clinicians 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 (21).

Diagnostic evaluation with biomarkers is an area of active research, with several possible candidates in early development. Of these, neuroimaging with amyloid- and tau-specific PET scanning appears to hold the most promise for accurate diagnosis in living patients (10; 49; 37), with the expectation that the amyloid would be negative and p-tau positive in most cases. A case-control study utilizing tau- and amyloid-specific PET scans of 26 symptomatic former National Football League players and 31 healthy, age-matched controls showed elevated standard uptake value ratios of p-tau in the study group, suggesting that these scans may aid in diagnosis (47). However, standard cognitive screening tests did not show significant differences between the 2 groups. Furthermore, 2 related studies analyzing tau-PET imaging in both postmortem, pathology-proven chronic traumatic encephalopathy and living patients who matched criteria for traumatic encephalopathy syndrome failed to show significantly elevated levels of p-tau compared to controls (24; 26). Cerebrospinal fluid analysis for total tau, p-tau, and amyloid levels is useful in ruling out the diagnosis of Alzheimer disease when advanced imaging is either contraindicated or prohibited by cost and may provide supportive data for patients with suspected chronic traumatic encephalopathy (36). 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 (08). Supportive data, including structural imaging studies (MRI and CT) with evidence of cortical atrophy and septal abnormalities, have also been evaluated (35). One study found that up to 94% of retired football players had evidence of cavum septum pellucidum, versus only 18% of control patients (13). 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 (31). 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 4 had frontotemporal lobar degeneration (30). Seven of the cases showed evidence of at least 2 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 (43). 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 (31). This is supported by the observed and almost universal finding of TDP-43 in cases of stage IV chronic traumatic encephalopathy (30). TDP-43 has also been implicated in both sporadic and familial forms of motor neuron disease and frontotemporal lobar degeneration, suggesting a class of neurodegenerative diseases known at TDP-43 proteinopathies (25). 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 (46). 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 (30). 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 been associated with greater cognitive impairment in former boxers and American football players (34). 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 (31; 48). 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 3 times the risk of clinical depression in those who began playing prior to age 12 compared to those who began later in life (01). Another study found changes in white matter integrity in boys aged 8 to 13 years after a single season of tackle football (04). These findings suggest that exposure to repetitive head injury during critical periods of neural development could result in long-term detriment. Cognitive reserve, by contrast, 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 (02). Interestingly, level of education itself did not significantly affect age of symptom onset.

Prognosis and complications

Chronic traumatic encephalopathy is classified as a neurodegenerative disease, a group of disorders that includes Alzheimer disease, frontotemporal dementia, Parkinson disease, amyotrophic lateral sclerosis, and Lewy body disease. As such, the prognosis for all of these diseases is poor. Clinically, symptoms generally progress over years to decades depending on initial presentation. Treatments are aimed toward symptom management and do not alter the time course significantly. For patients who presented with mood or behavioral symptoms, death commonly occurred via suicide, and 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 wifes 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. Corsellis first analyzed the brains of 15 deceased former professional boxers with reported dementia in 1973, describing both gross structural changes and microscopic neuropathology (11). More than 3 decades passed before the landmark discovery of similar pathology in a former professional American football player by Omalu and colleagues (39). 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 (28).

Another supportive but not necessary finding is deposition of a 43 kilodalton TAR DNA-binding protein (TDP-43) within the medial temporal lobes, amygdala, and hippocampus. 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.

Table 3 provides the full criteria recommended by NINDS-NIBIB. Chronic traumatic encephalopathy is classified from stage I (early) to stage IV (late) based on the amount and distribution of p-tau (31). Through collateral information obtained postmortem, each stage may present with an array of clinical signs and symptoms (33). 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 (35).

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 (28).

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 (42; 33). 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 (39; 40; 07; 31; 41; 32). Chronic traumatic encephalopathy also has been found in the brains of deceased military veterans, both with and without a history of contact sports participation (29). 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 (05). 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 between 2 and 4 million reported sports-related concussions per year in the United States alone (22). Furthermore, the rate of asymptomatic or subconcussive head trauma appears to be exponentially higher than that of symptomatic concussions (27). Through the use of accelerometers implanted into helmets, 1 study estimated that the average high school football player incurs 652 head strikes of more than 15G acceleration, none of which resulted in acute clinical symptoms or a diagnosis of concussion (06).

The reported prevalence of head injuries among active duty military personnel in this century is nearly 25% (38). Posttraumatic stress disorder affects nearly 20% of Gulf War veterans (17). 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 (18). 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 (44). 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 (34). 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.

Prevention

Given that 100% of autopsy-confirmed specimens have the common history of traumatic brain injury, the current recommendation for prevention of chronic traumatic encephalopathy is to avoid activities in which a high likelihood of repetitive head trauma is present. Despite advances in impact detection and improved protective equipment in contact sports, in addition to a more conservative approach to potential head injuries, concussions and subconcussive injuries continue to occur with regularity and are even considered a sanctioned part of most combat sports. Current research will lead to a more comprehensive pre-participation evaluation, including modifiable and nonmodifiable risk factors that may lead to more caution in at-risk individuals.

Differential diagnosis

Chronic traumatic encephalopathy is a unique neuropathological entity with multiple presumed clinical presentations. As such, there is significant overlap of reported symptoms with other neurodegenerative disorders. Loss of short-term memory and functional decline is characteristic of Alzheimer disease (07). Executive dysfunction and impulsivity are suggestive of behavioral-variant frontotemporal dementia, which is also associated with amyotrophic lateral sclerosis in patients found to have a genetic mutation in the Open Reading Frame of Chromosome 9 (C9ORF) (12). Tremor, bradykinesia, and gait instability are hallmarks of Parkinson disease, and the co-occurrence of parkinsonism with dementia is seen in Lewy body disease (as well as late Parkinson disease dementia) (20). Although these conditions should be considered in symptomatic patients with a history of repetitive head injury, chronic traumatic encephalopathy may be more likely in patients who appear to have symptoms consistent with multiple disorders. For instance, patients with Alzheimer dementia may display apathy or agitation but rarely show the emotional volatility and impulsivity reported with chronic traumatic encephalopathy. Moreover, chronic traumatic encephalopathy has not been associated with visual hallucinations or REM sleep behavior disorder, both of which are extremely common with Lewy body disease (20). Lastly, confounding diagnosis is the fact that chronic traumatic encephalopathy neuropathology may coexist with these disorders as well.

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 (23).

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 (03). 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 fronto-temporal lobar degeneration (15).

Obtaining a lumbar puncture for analysis of CSF for markers of acute brain injury may include t-tau, glial fibrillary acid protein (GFAP), and neurofilament light protein, all of which have been found at elevated levels in Olympic boxers within 1 week post-bout (36). In some cases, neurofilament light protein and GFAP remained elevated long after normalization of other CSF proteins, possibly indicative of continuing neurodegeneration.

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 (09). Noninvasive testing includes use of tau-specific tracers for PET, first developed to aid in diagnosis of Alzheimer disease (10). Although a number of tracers have been developed and validated, the studies have only applied to murine models and postmortem cases of Alzheimer disease (49; 16).

One study did show high FDDNP signals in the amygdala and subcortical regions of 5 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 (45), and FDDNP is somewhat nonspecific in its binding. 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 (07). 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 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.

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, pharmacologic and nonpharmacologic treatments improve symptoms and may delay functional decline but do not affect overall outcome.