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 (34). 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 (32). 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
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•·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 (47). |
Time course and prognosis. Retrospective analysis revealed progressive decline comparable to other neurodegenerative disorders in 68% of confirmed chronic traumatic encephalopathy cases (34). 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 (33; 34). Given the estimated progression between subsequent stages of chronic traumatic encephalopathy of 11 to 14 years, this discrepancy may represent at least two 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 (30; 34). 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 (34). Average age of onset appears to have two 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 clinician’s 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 (34). 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 five 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
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(1) Substantial exposure to repetitive head impacts, including: |
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(a) Involvement in high-exposure contact or collision sports |
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(i) For American football, minimum 2 years (preferably 5) at the high school level or above |
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(b) Military service involving repetitive head impacts |
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(c) Other exposure to multiple head impacts |
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(2) One or both core clinical features, including: |
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(a) Cognitive impairment (all four required) |
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(i) As reported by self, informant, or clinician’s report |
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(ii) Representing a significant decline from baseline level of function |
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(iii) Deficits in episodic memory and/or executive function |
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(iv) Substantiated by impaired performance on formal neuropsychological testing (if available) |
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(b) Neurobehavioral dysregulation (all three required) |
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(i) As reported by self, informant, or clinician’s report |
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(ii) Representing a significant change from baseline level of function |
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(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 |
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(3) Progressive course is a required core clinical feature |
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(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; 36), 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 (46). However, standard cognitive screening tests did not show significant differences between the two groups. Furthermore, two 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 (35). 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 (34). 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 (30). 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 (29). 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 (42). 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 (30). This is supported by the observed and almost universal finding of TDP-43 in cases of stage IV chronic traumatic encephalopathy (29). 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 (45). 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 (29). 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 (33). 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 (30; 47). An analysis of 264 subjects with confirmed chronic traumatic encephalopathy showed a significant association between APOEε4 status and chronic traumatic encephalopathy stage in donors older than 65, independent of Aβ status. 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 (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 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.