Chronic Traumatic Encephalopathy

Katherine W. Turk, MD; Andrew E. Budson, MD Dementia p. 187-207 February 2019, Vol.25, No.1 doi: 10.1212/CON.0000000000000686
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KEY POINTS

Chronic traumatic encephalopathy is a pathologically defined neurodegenerative disorder associated with repetitive concussive or subconcussive head injury.

The frequency, severity, and total exposure to head trauma and the exact pathophysiologic mechanism by which blows to the head result in chronic traumatic encephalopathy are active areas of research.

Head injury is an important but nonsufficient risk factor in the development of chronic traumatic encephalopathy; other exposure and genetic risk factors are under investigation.

Currently, no validated clinical diagnostic criteria for chronic traumatic encephalopathy exist, although research diagnostic criteria have been developed.

Concussion is a clinical syndrome of impaired brain function, typically impacting memory and orientation, with or without loss of consciousness that results from head injury.

Chronic traumatic encephalopathy is defined by neuropathology: perivascular aggregation of phosphorylated tau protein within neurons and astrocytes that begins in the depths of sulci and progresses to involve the medial temporal lobes and other parts of the brain.

Chronic traumatic encephalopathy deficits involve progressive cognitive, behavior, and mood changes as well as possible motor deficits.

The most common cognitive difficulties in patients with chronic traumatic encephalopathy involve memory and executive function.

Four traumatic encephalopathy syndrome subtypes have been described: (1) a behavioral/mood variant, occurring in younger patients; (2) a cognitive variant, which occurs later in life; (3) a mixed variant; and (4) a dementia form.

The classification of patients into the diagnostic categories probable, possible, and unlikely chronic traumatic encephalopathy relies, in part, on results of potential research-based biomarker findings, thus diagnoses are for use in research, not clinical settings.

The evaluation for possible chronic traumatic encephalopathy should include asking about a history of repetitive head trauma, with or without concussion, including exposures during contact sports, military service, domestic abuse, assault, and motor vehicle accidents.

The differential diagnosis for chronic traumatic encephalopathy often includes frontotemporal dementia and Alzheimer disease.

No disease-modifying or symptomatic treatments for chronic traumatic encephalopathy are US Food and Drug Administration approved. All medication management is off-label and symptom-based, and can include acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, and memantine.

The incidence and prevalence of chronic traumatic encephalopathy is unknown because of a lack of epidemiologic data. However, the frequency of chronic traumatic encephalopathy is potentially increased within the professional contact sports community and others exposed to head trauma.

The age of clinical onset of traumatic encephalopathy syndrome/chronic traumatic encephalopathy symptoms is delayed by several years or decades following exposure to head injuries and is currently estimated to be between 30 and 65 years of age.

Posttraumatic stress disorder and traumatic brain injury often co-occur in military veterans and may share a common pathophysiology.

Posttraumatic stress disorder, postconcussive disorder, and chronic traumatic encephalopathy share many common symptoms, including difficulty with concentration, changes in mood, memory problems, irritability, and sleep disturbances.

Chronic traumatic encephalopathy frequently involves TDP-43 pathology, but TDP-43 is not necessary for pathologic confirmation.

Chronic traumatic encephalopathy can co-occur pathologically with other neurodegenerative conditions, including motor neuron disease, Alzheimer disease, Lewy body disease, and frontotemporal dementia.

The main genetic risk factor investigated in association with head injury and chronic traumatic encephalopathy is the APOE ε4 allele.

The APOE ε4 allele may lower the threshold for an individual to develop cognitive deficits following repeated head injury.

Nongenetic potential risk factors for chronic traumatic encephalopathy include cognitive reserve, age of first exposure, and cumulative exposure to head injuries.

Serum tau concentration elevations may indicate the existence of prior head injury but have not been found to correlate with cognitive function.

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PURPOSE OF REVIEW: This article provides a discussion on the current state of knowledge of chronic traumatic encephalopathy (CTE), with an emphasis on clinical features and emerging biomarkers of the condition.

RECENT FINDINGS: The results of several large brain bank case series among subjects with a history of contact sports or repetitive head trauma have indicated that a high frequency of CTE may exist in this population. However, the true prevalence of CTE among individuals with a history of head trauma remains unknown, given that individuals who experienced cognitive, behavioral, and mood symptoms during life are more likely to have their brains donated for autopsy at death and epidemiologic studies of the condition are lacking. Neuropathologic consensus criteria have been published. Research-based clinical criteria have been proposed and are beginning to be applied, but the definitive diagnosis of CTE in a living patient remains impossible without effective biomarkers for the condition, which is an active area of study.

SUMMARY: The field of CTE research is rapidly growing and parallels many of the advances seen for other neurodegenerative conditions, such as Alzheimer disease decades ago.

Address correspondence to Dr Katherine W. Turk, VA Boston Healthcare System, 150 S Huntington Ave, 151-C, Jamaica Plain, MA 02130, kturk@bu.edu.

RELATIONSHIP DISCLOSURE: Dr Turk receives research/grant support from the Alzheimer’s Association. Dr Budson has served as a consultant for Axovant Sciences, Inc, and Eli Lilly and Company and has received personal compensation for speaking engagements from Eli Lilly and Company. Dr Budson receives research/grant support from the US Department of Veterans Affairs (I01CX000736) and publishing royalties from Elsevier and Oxford University Press.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Drs Turk and Budson discuss the unlabeled/investigational use of several classes of medications for chronic traumatic encephalopathy, including cholinesterase inhibitors for memory-related issues, selective serotonin reuptake inhibitors for mood and behavioral issues, memantine for attentional issues in those with advanced dementia, and atypical antipsychotics for those who are disinhibited and violent.

INTRODUCTION

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder with unique neuropathologic findings distinct from other degenerative disorders, namely characteristic perivascular accumulations of phosphorylated tau (p-tau) in neurons and astrocytes. As early as 1928, Martland noted a progressive clinical syndrome of behavioral, cognitive, and mood symptoms associated with retired boxers, which he termed punch-drunk syndrome. However, the disorder was not clearly differentiated from other neurodegenerative conditions until 1973, when Corsellis and colleagues described 15 cases with clinical and pathologic features, which he termed dementia pugilistica. CTE is the current term used for this progressive neurodegenerative disorder thought to result from repeated concussive or subconcussive head injury. A 2005 case report described the first neuropathologically confirmed CTE case in a former professional football player (note that in this article, the term football is used to refer to American football), which renewed interest in the disease and has ushered in an exciting period of inquiry into this previously underrecognized condition. Our knowledge of CTE is quickly advancing, yet it is currently in a state of infancy compared to that of other neurodegenerative conditions.

Although a strong association exists between repeated blows to the head and chronic cognitive and behavioral impairment, epidemiologic, cross-sectional, and prospective studies that firmly establish the causal link between repetitive head trauma and the characteristic neuropathology of the disorder are lacking, making the diagnosis of CTE in life challenging. The frequency, severity, and total exposure to head trauma and the exact pathophysiologic mechanism by which blows to the head result in CTE are active areas of research. Exposure to head injuries is thought to be a necessary factor in developing CTE, yet head injuries in isolation are not sufficient to cause the condition, thus a search is under way to define the additional susceptibility factors that increase risk of the disease. Factors under investigation include modifiable lifestyle risk factors; genetics; and quantity, severity, time course, and duration of exposure to head injuries. As a result, CTE is currently defined by its hallmark neuropathology. CTE neuropathology has been recognized in the brains of many contact sport athletes, most notably football players and boxers, but has also been found in other individuals exposed to head trauma, including wrestlers, soccer players, hockey players, and military service members. Most symptoms of CTE are thought to occur years to decades following the initial head trauma. Although CTE is thought to result in characteristic clinical deficits involving cognition, behavior, and mood as well as possible motor deficits, no validated consensus clinical criteria have yet been developed. Research diagnostic criteria have been proposed and are discussed in detail below.

The terminology in the field of head injury has led to confusion. Traumatic brain injury (TBI) and concussion are often defined based on the time course of postconcussive symptoms. The terms mild traumatic brain injury and concussion are used somewhat interchangeably, without clear distinction, with concussion often being preferred by the sports community and mild TBI by the medical community. Concussion is defined as a clinical syndrome of impaired brain function, typically impacting memory and orientation, with or without loss of consciousness, that results from some type of impact to the head. Postconcussive syndrome is a constellation of clinical signs and symptoms that may remain weeks, months, or years following a concussion in a small number of patients. Typical signs and symptoms of postconcussive syndrome include headache, insomnia, vertigo, tinnitus, anxiety, and fatigue, among other symptoms. CTE should not be confused with the postconcussive syndrome that may result from a symptomatic head injury. CTE is a separate long-term consequence of concussive and subconcussive repetitive head impact. Studies have demonstrated that asymptomatic subconcussive impacts are associated with CTE pathology.

PATHOLOGIC CRITERIA

In 2015, the first consensus neuropathologic criteria for the diagnosis of CTE were developed by a panel of seven expert neuropathologists organized by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) (TABLE 9-1). The neuropathologists evaluated 25 cases of various tauopathies, blinded to clinical data, and arrived at an agreed-upon set of criteria to diagnose CTE. The hallmark lesion of CTE, capable of distinguishing the disorder from other tauopathies, was an accumulation of abnormal p-tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci in a patchy, irregular pattern (TABLE 9-1). Pathognomonic accumulation of perivascular tau at the sulcal depths is thus a required element for the diagnosis of CTE. In addition, several supportive neuropathologic criteria may be present in CTE cases but are not necessary for a diagnosis (TABLE 9-1). The supportive features include specific types of p-tau pathologies as well as non–p-tau–related pathologies, such as transactive response DNA-binding protein 43 (TDP-43) neuronal inclusions in the hippocampus, anteromedial temporal cortex, and amygdala. Macroscopic features of CTE include dilation of the third ventricle, septal abnormalities, atrophy of the mammillary bodies, and contusions. Following the development of the NINDS-NIBIB criteria, most cases of CTE in the literature have been diagnosed postmortem using these newly developed pathologic criteria along with standardized clinical case interviews of informants for retrospective evaluation of potential clinical characteristics that may be associated with the pathology to allow clinicopathologic correlation. This association between pathologic findings and reported clinical symptoms led to the development of proposed staging criteria for both neuropathology and clinical features (TABLE 9-2 ).

CLINICAL PRESENTATION

Although CTE is thought to result from the long-term consequences of head injury, the amount and type of head injury required to produce the resulting clinical syndrome and neuropathology are still under investigation. The CTE phenotype varies and can involve a clinical constellation of often-progressive cognitive, behavior, and mood changes as well as possible motor deficits. Informants have reported in retrospective postmortem interviews that up to 43% of patients with CTE had behavior or mood symptoms at initial presentation.

NEUROPSYCHOLOGICAL SYMPTOMS

The cognitive profile of CTE involves impaired memory and executive function. Patients with CTE may also have problems with concentration, judgment, and problem-solving. The clinical features most commonly seen in CTE by order of frequency at time of clinical presentation are listed in TABLE 9-3. The cognitive and behavioral deficits may lead to substance abuse, bankruptcy, and failed relationships.

TIME COURSE AND PROGNOSIS

In a review of 202 published cases of CTE, 68% had a progressive clinical course similar to other degenerative brain diseases. McKee and colleagues estimated the rate of progression between any two successive pathologic stages of CTE to be approximately 11 to 14 years. Although most cases have been described as progressive, cases exist in younger individuals with predominant behavior/mood symptoms that are thought to be more stable than when the disease manifests in older individuals. Since a progressive course is a hallmark of neurodegenerative diseases, this group of younger individuals with a predominantly behavioral/mood presentation presents a diagnostic challenge for clinicians.

DIAGNOSTIC CRITERIA

Currently, no validated clinical diagnostic consensus criteria for CTE exist; however, research diagnostic criteria have been developed by Montenigro and colleagues to better classify the clinical spectrum of symptoms that can be seen with the disorder (TABLE 9-4). Similar to other neurodegenerative conditions, including Alzheimer disease (AD), neuropathologic findings are the gold standard for diagnosis; definitive diagnosis of CTE in a living person is not yet possible. Thus, the research diagnostic criteria use the terms probable, possible, and unlikely CTE. The research diagnostic criteria are meant to build upon prior published diagnostic criteria by Jordan and are based upon literature review of CTE case series as well as the clinical presentation of neuropathologically confirmed cases of CTE. Importantly, these research criteria do not conflate the clinical syndromes being reported with definite, pathologically proven CTE.

The term traumatic encephalopathy syndrome (TES) is used in the research diagnostic criteria to refer to the clinical syndrome associated with repetitive blows to the head. Some individuals with TES may have CTE neuropathologic changes, although others may not; they may, instead, have other pathologies or even predominantly psychiatric conditions without a clear neuropathologic correlate. Importantly, TES criteria do not broadly apply to the acute or postacute signs and symptoms following concussion, postconcussive syndrome, or moderate to severe TBI. The proposed TES diagnostic criteria include five general criteria, three core clinical features, and nine supportive features. The general criteria were selected based on prior literature with the intention of maximizing sensitivity over specificity. Core clinical features were retrospectively reported by family members at a minimal rate of 70% among pathologically confirmed CTE cases. The nine supportive features were selected to increase specificity and were based on clinical features described in the CTE literature.

The research diagnostic criteria describe four TES subtypes: (1) a behavioral/mood variant, occurring in younger patients; (2) a cognitive variant, which occurs later in life; (3) a mixed variant (CASE 9-1); and (4) a TES dementia form. The two main subtypes of TES are the behavioral/mood variant, which had an average age of clinical symptom onset of 34.5 years, and the cognitive variant (CASE 9-2), which had average age of clinical onset of 58.5 years. The relative frequency of the subtypes is not known. In neuropathologically confirmed cases, the initial clinical presentation has been described as mood predominant without cognitive impairment in 28% of cases, cognitive without mood or behavioral difficulties in 32%, and initially mixed between cognitive and mood symptoms in 40%. The current research diagnostic criteria also include a minimum amount of head injury exposure to consider a diagnosis of TES (TABLE 9-5).

CASE 9-1

A former rugby player who began playing at age 16 and continued for more than 20 years committed suicide by firearm at age 46. He had played the equivalent of quarterback in rugby, a sport in which no head protection is used in games. Although he was never diagnosed with a concussion and never missed a game because of head injury, his teammates reported that he was confused on the field many times because of a head injury but kept playing. He had no family history of neurologic or psychiatric disorders.

He developed behavioral symptoms in his early thirties. His personality changed, and he overreacted and became stressed out and anxious about minor things that previously did not bother him. He developed emotional volatility and lost his temper quickly. Subsequently, his memory deteriorated, and he would forget to pick up his daughter from school, which was previously uncharacteristic for him. He developed word-finding difficulties and became much less communicative with family. At one point, he stopped paying the family’s bills and, when confronted by his wife, could not verbalize why he was no longer paying them. He initially was depressed for a week at a time, but his depression gradually increased in frequency and length over the 15 years until his death.

He developed a “short fuse,” began yelling without a trigger, and was very paranoid about his wife’s fidelity, not wanting her to go out without him. He became interested in unusual sexual practices that he had previously never expressed any desire for. He impulsively pushed his wife once, which was completely out of character. He verbalized that he had a baseball bat in the trunk and threatened her.

He had no gait instability, falls, or tremor. He was working part time as a teacher until the months before his death but had stopped cooking several months before he died, a role he had previously maintained within his family. He reported frequent severe headaches starting 6 months before he died. He began using alcohol excessively 2 years before his death, often drinking during the day, which was very unusual for him.

In the months before he died, he told his best friend he wanted to learn how to shoot a gun, which was very surprising because, as a younger person, he had refused to touch a gun. He had previously expressed he was against suicide throughout his life and had never expressed suicidal ideation. After his death, pathologists at Boston University diagnosed stage II chronic traumatic encephalopathy.

COMMENT

This patient meets all five of the general traumatic encephalopathy syndrome (TES) criteria (TABLE 9-4), given a 20-year history of exposure to head injury through rugby. Clinical features were present over 15 years, and he displayed all three core clinical features of TES: cognitive, behavioral, and mood changes. He also had seven of the nine supportive features of TES present: impulsivity, anxiety, paranoia, suicidality, headache, documented decline, and delayed onset. In the absence of an autopsy, a clinician or researcher might consider this a case of possible chronic traumatic encephalopathy, mixed variant, given the presence of both cognitive core features and behavioral and mood core features.

CASE 9-2

A former football player developed cognitive and behavioral changes beginning in his midforties. He had played football in high school, then in college for 4 years, and subsequently for several seasons in the National Football League. Although he never reported a head injury while playing, he did report to his wife that his “bell was rung a bunch” as a professional player. He had no family history of psychiatric or neurologic disorders.

In his midforties, his wife noticed that he began going to the wrong school to pick up his kids and became much more angry and defensive. He became confused about which city they lived in. A previously successful businessman, he began making bad financial decisions. He made impulsive purchases he previously would not have made. He once wrote a check to the bank for 10 times more than he intended, writing the entire check upside down. His wife found the taxes from years prior in his desk drawer, completed but never sent; previously, he never would have forgotten to pay the taxes or a bill.

He became socially withdrawn and angered more easily, yelling at family and friends without a reason. He would also yell in socially inappropriate settings, such as yelling at a teacher in his daughter’s school on parent night when he was in his fifties.

He developed frequent severe headaches in his fifties that worsened over time. He became very anxious and developed nervous, anxious behaviors, including rubbing his hands together frequently until the skin peeled off. At times, he was quite depressed and apathetic, sitting for days at a time at home looking at the wall. Previously social, he withdrew from family and friends. When he did speak, he paused to find words and spoke tangentially and circuitously.

In his fifties and sixties, he would forget conversations. He became paranoid about his wife and her whereabouts. His mood worsened, and he made statements to his wife such as, “You would be better off if I weren’t here.”

Previously an avid golfer, he suddenly stopped playing in his sixties and watched the golf channel for hours, holding his clubs and crying, saying that if he watched some more, he might be able to remember how to play. His gait gradually became unsteady, and he was noted to have a tremor when writing and performing other activities. He developed difficulty swallowing and unintentionally lost weight in the last years of his life. He died at home at age 70, requiring 24-hour care before his death. Autopsy of his brain revealed irregularly distributed phosphorylated tau aggregates at the depth of cerebral sulci in multiple locations throughout the cortex, consistent with stage IV chronic traumatic encephalopathy (FIGURE 9-1, FIGURE 9-2).

COMMENT

The patient in this case meets all five of the general traumatic encephalopathy syndrome (TES) criteria (TABLE 9-4), given a 14-year history of exposure to head injury through football. Clinical features were present over 25 years, and he displayed all three core clinical features of TES: cognitive, behavioral, and mood changes. He also had all nine supportive features of TES: impulsivity, anxiety, apathy, paranoia, suicidality, headache, motor symptoms, documented decline, and delayed onset. In the absence of an autopsy, a clinician or researcher might consider this a case of possible chronic traumatic encephalopathy, cognitive subtype, given the older age at presentation and prominence of cognitive deficits.

The classification of patients into the diagnostic categories probable, possible, and unlikely CTE (TABLE 9-4) relies, in part, on the results of proposed research-based biomarker findings (amyloid and tau positron emission tomography [PET] imaging results or tau CSF levels) and the presence of a cavum septum pellucidum, and/or cortical atrophy as seen on structural imaging studies. TABLE 9-6 provides a full description of proposed CTE biomarkers. Of note, these proposed biomarkers are still under active investigation and are not yet recommended for routine clinical care (refer to the Trends section for information on biomarkers under active investigation). A cavum septum pellucidum, a fluid-filled space between the leaflets of the septum pellucidum (FIGURE 9-3), is present in up to 15% of healthy individuals. A cavum septum pellucidum is thought to be present in increased frequency within the CTE population, although the exact rate is unknown. During head trauma, fluid waves may produce fenestrations within the septum and allow the entry of fluid between the leaflets, creating the cavum (separation) within the structure.

EVALUATION

The evaluation of patients for possible CTE should include questions about a history of repetitive head trauma, with or without concussion, including exposures during contact sports, military service, domestic abuse, assault, and motor vehicle accidents. The clinician should also obtain a history of the behavioral, mood, cognitive, and possible motor symptoms that have been reported in individuals with CTE pathology. As in other neurodegenerative diseases, determining the time course of decline in cognition, behavior, mood, and activities of daily living is important. The neurologic examination should be completed with a focus on the mental status examination as well as motor and gait evaluations. Specifically, clinicians should evaluate for fasciculations or upper motor neuron signs that would suggest motor neuron disease and evaluate for signs of parkinsonism, as both have been associated with head injury.

DIFFERENTIAL DIAGNOSIS

While the pathologic hallmark of CTE is distinct, the clinical presentation of CTE can mimic other disorders and can co-occur with other neurodegenerative pathologies. Individuals with pathologically proven CTE have often been clinically characterized by poor impulse control, executive dysfunction, and a young age of onset, similar to behavioral variant frontotemporal dementia. In addition, motor neuron disease can occur with frontotemporal dementia (often related to C9orf72 mutation) and has been associated with CTE. Despite the overlap in clinical features, patients with CTE have a history of repetitive or subconcussive head injury during contact sports and more memory loss than patients with behavioral variant frontotemporal dementia. AD dementia is often considered as a cause of memory loss and should be included in the differential in cases of possible CTE. Although behavioral changes, often apathy or irritability, may be seen in AD dementia, these problems are distinct from the explosivity and disinhibition typically seen in individuals with CTE pathology. Dementia and parkinsonism can be seen in combination in CTE and dementia with Lewy bodies (DLB). However, parkinsonism tends to be a late feature of CTE, if present. Additionally, prominent disinhibition and explosivity are rare in DLB, while in CTE, these features are early and prominent. The presence of rapid eye movement (REM) sleep behavior disorder strongly suggests DLB rather than CTE.

SYMPTOMATIC TREATMENT

Treatment of CTE is currently supportive, as no medication is US Food and Drug Administration (FDA) approved for the treatment of CTE. Several classes of medications that are commonly used in other patients with cognitive impairment can be trialed on an empiric basis to help with symptom management. Trials of empiric medications may also be reasonable clinically, given the possibility that other neurodegenerative pathologies may coexist, especially among older patients (refer to the section Overlap With Other Neurodegenerative Pathologies). Medications to consider include a trial of acetylcholinesterase inhibitors for memory-related issues, selective serotonin reuptake inhibitors (SSRIs) for depression and anxiety, and memantine for attentional issues in those with advanced dementia; rarely, atypical antipsychotics may be used for those who are disinhibited and violent. However, it is important to note that, as a class, antipsychotics carry an FDA boxed warning of increased mortality in patients with dementia, and thus the decision to use this class should be made on a case-by case-basis after weighing the risks and benefits with the patient and family.

EPIDEMIOLOGY

The true incidence and prevalence of CTE is unknown because of a lack of epidemiologic data, including a dearth of cross-sectional and prospective studies in the general population. However, the incidence of CTE is potentially high within the professional contact sports community and in others exposed to head trauma. CTE has been found in the brains of individuals who engaged in a wide variety of contact sports during life, including boxing, football, wrestling, ice hockey, rugby, soccer, and others. An early study of prevalence of neurologic deficits among professional boxers reported a 17% rate of neurologic diagnoses attributable to the sport, with risk factors including later retirement from boxing, boxing for more than 10 years, and engagement in 150 matches or more. Using the 2015 NINDS-NIBIB consensus pathologic criteria for CTE, 1721 cases in the Mayo Clinic Brain Bank were reviewed for CTE pathology; contact sport athletes had CTE present at a rate of 32%, with no cases of CTE found in 162 control brains without a TBI or contact sport history and no cases of CTE found among 33 individuals with a history of a single TBI. In the largest CTE case series to date, of 202 deceased individuals who had a significant history of repetitive head trauma related to either contact sports or military service, Mez and colleagues reported that CTE was diagnosed in 177 former professional football players (or 87% of the cases) and, more specifically, in 110 out of 111 (99%) of the former National Football League (NFL) players. The authors noted that the study was limited by ascertainment bias since individuals with symptoms consistent with possible CTE were much more likely to participate in the brain donation program, and, therefore, the true frequency of CTE pathology is unknown.

Annually in the United States, approximately 2 million to 4 million individuals experience sports-related concussions, with the number of youth sports–related concussions growing. Additionally, it is thought that the incidence of subconcussive blows to the head is much higher than clinical concussions. Others have reported that in a single season of high school football, a player receives an average of 652 head blows, most of which involve more than 15 g of force. Age of clinical onset of TES/CTE symptoms is thought to be delayed by several years or decades following exposure to head injuries. The current age of onset is estimated to be between 30 and 65 on average, with case reports of tau aggregates already present in the brains of teenage football players. In a retrospective study of causes of mortality in former professional football players, neurodegenerative mortality in former players was 3 times higher than in the general population, and Alzheimer disease–related and amyotrophic lateral sclerosis–related mortality was 4 times higher. Importantly, the retrospective nature of the study, in which cases were evaluated from a period before the establishment of CTE as a pathologic diagnosis, means it is likely that some of the neurodegenerative disease burden in this population may, in fact, be better accounted for by CTE.

CHRONIC TRAUMATIC ENCEPHALOPATHY AMONG VETERANS AND MILITARY SERVICE MEMBERS

Soldiers experience head injuries at a higher rate than the general population, approaching one-fourth of all returning veterans. Posttraumatic stress disorder (PTSD), a common result of combat, has a prevalence similar to TBI, as high as 17% among veterans. Furthermore, recognition of a potential association between PTSD and the long-term effects of TBI is growing; the two have many overlapping symptoms and often co-occur in veterans. In a 2008 survey of more than 2500 American soldiers 3 to 4 months following their return home from yearlong deployments to Iraq, nearly 5% reported head trauma with a loss of consciousness and 10% reported head injuries with resulting altered mental status. Of those who reported loss of consciousness, 43.9% met criteria for PTSD, and 27.3% of those who had altered mental status following a TBI met criteria for PTSD. In contrast, 9.1% of the soldiers without TBI met criteria for PTSD. The exact nature of the complex relationship between head trauma and PTSD requires further study in the veteran population, as it is unclear whether the two disorders share a common pathogenesis.

Similarly, the frequency of CTE in the veteran population is currently unknown. CTE has been reported in association with military combat exposures and in association with veterans who engage in contact sports. In the majority of military CTE case reports, concomitant PTSD is described. It has been recognized, however, that the clinical constellation of symptoms seen in PTSD, postconcussive disorder, and CTE share many common elements, including difficulty with concentration, changes in mood, memory problems, irritability, and sleep disturbances. Thus, it has been hypothesized that some proportion of veterans with PTSD may instead have a diagnosis of CTE. Some case reports exist of behavioral changes before death and tau aggregates at autopsy, allowing postmortem diagnosis of CTE in military service members. However, large-scale investigations into the incidence of CTE in the military veteran population are lacking.

OVERLAP WITH OTHER NEURODEGENERATIVE PATHOLOGIES

Although not an essential component of CTE pathologic diagnostic criteria, CTE frequently occurs with TDP-43 pathology. A variety of diseases that involve abnormal tau accumulation, including frontotemporal dementia, are also associated with TDP-43 accumulation. The range of TDP-43 pathologies seen in CTE is varied and can include accumulation of TDP-43 in neurons colocalizing with p-tau inclusions or in glia. The extent of TDP-43 accumulation in brain structures is also thought to progress with CTE pathologic stages, beginning in the subcortical white matter and fornix in stage I disease; then involving the brainstem, medial temporal lobe, periventricular, and perivascular regions in stage II; accumulating in the cerebral cortex in stage III; and accumulating in structures as widespread as the spinal cord, diencephalon, and basal ganglia in stage IV disease. Also, the frequency with which TDP-43 is observed tends to increase with each stage, such that in stage IV disease nearly all individuals display TDP-43 inclusions. TDP-43 accumulation patterns observed in CTE may also overlap with that of individuals found to have frontotemporal lobar degeneration (FTLD).

CTE is known to co-occur with other neurodegenerative diseases as individuals age. Of 177 neuropathologically confirmed CTE cases in the Veterans Affairs-Boston University-Concussion Legacy Foundation (VA-BU-CLF) CTE Brain Bank, 11 were found to also have pathology consistent with motor neuron disease, 23 had pathology consistent with AD, 34 had pathology consistent with Lewy body disease, 14 had pathology consistent with frontotemporal dementia, and 98 were reported as having CTE alone (FIGURE 9-4). Three cases overlapped between the neurodegenerative diseases, resulting in a total higher than 177 cases.

When CTE occurs with other neurodegenerative diseases, it is unclear if these individuals have developed a mixed-pathology neurodegenerative disorder or whether a synergistic relationship exists between CTE and other pathologies. Older individuals with CTE pathology are more likely to have concurrent amyloid-β plaques consistent with AD and may develop amyloid-β accumulation at a younger age than individuals without head injuries. In one study of a cohort of 114 deceased military veterans and athletes with neuropathologically confirmed CTE, 52% of the cases displayed some degree of amyloid-β deposition. Individuals with CTE and motor neuron disease often display greater accumulations of TDP-43 at earlier CTE disease stages than in cases of CTE without motor neuron disease. About one-third of CTE cases with concomitant motor neuron disease pathology display behavioral and cognitive changes as the presenting symptoms years before the onset of motor changes.

PROSPECTIVE SUSCEPTIBILITY FACTORS

The investigation of genetic and nongenetic risk factors is an important additional area of research that will allow clinicians to understand why some patients with a history of head trauma develop CTE, while others do not.

Genetic Modifiers

The main genetic risk factor investigated in association with head injury and CTE, the APOE ε4 allele, is most well-known for its association with AD. Some association may also exist between APOE ε4 and risk of worse outcomes following recurrent mild TBI. APOE may be expressed by neurons following injury. Boxers who were carriers of the allele were more impaired on scales of motor, cognitive, and psychiatric deficits. Similar results have been found among 53 professional football players who were ε4 allele carriers and showed greater deficits in cognition, processing speed, and attention than did noncarriers. Recent work has suggested that APOE ε4 may be a risk factor for CTE severity, especially earlier in the disease course and at lower levels of head impact exposure. In CTE cohorts without comorbid pathologies, it has been reported that APOE ε4 was overrepresented compared to the general population. The APOE ε4 allele may lower the threshold for an individual to develop cognitive deficits following repeated head injury, although one study found no difference in the frequency of APOE ε4 carriers among a CTE cohort of 68 cases compared to the allele carrier rate in the population at large. The search continues for other heritable risk factors that may explain a genetic predisposition to CTE other than APOE ε4 carrier status.

Nongenetic Risk Factors

Nongenetic potential risk factors are just starting to be investigated and include cognitive reserve, age of first exposure, and cumulative exposure to head injuries. Cognitive reserve in the form of occupational attainment was associated with later symptom onset in a sample of neuropathologically confirmed cases of stage II and stage IV CTE in deceased former football players. However, number of years of education was not associated with CTE symptom onset. The significance of this discrepancy between occupation and years of education as markers of cognitive reserve is still under investigation. Age of first exposure to football or other sources of head injuries may represent a modifier of later neurologic outcomes. It is hypothesized that head impacts may have increased effects on later neurologic outcomes when exposures occur during key periods in brain development. White matter changes have been reported in a group of 8- to-13-year-olds following exposure to repetitive head injuries during a single season of youth football. Similarly, former NFL players who began playing before age 12 showed increased rates of neuropsychological and brain structural changes, including verbal memory losses, executive dysfunction, and alterations of the microstructure of the corpus callosum. More recent work has found that among 214 former football players, those who were playing before age 12 had double the risk of clinical impairments in behavior, including apathy and executive function, and a threefold increased risk of having depression compared to those who began playing at age 12 or older.

TRENDS

Tau imaging and nonimaging CSF biomarkers are important areas of inquiry within the CTE field as they are potential avenues for the definitive diagnosis of patients with CTE. The use of these techniques is currently strictly for research settings.

Tau Imaging

PET imaging using tau-specific tracers is being developed with the intent to diagnose CTE during life. Tau-specific radioligands were first developed in association with the imaging of AD patients. Several tracers have been developed specifically for aggregated tau. These tracers have been investigated and validated mainly in animal models of AD and in postmortem AD cases that showed increased tau ligand binding in the cortex of patients with AD compared to healthy age-matched controls. Tau PET investigations of retired athletes who have sustained head injuries are on the horizon. An important area of investigation will be a potential tracer’s ability to sensitively and specifically bind the p-tau aggregates seen in CTE versus those in other neurodegenerative diseases that involve tau.

Other Biomarkers

Other potential non-PET biomarkers of CTE are under active investigation given some of the limitations of PET imaging, including radiation, expense, and limited availability. Some researchers have considered using CSF as a possible biomarker. Neurofilament light polypeptide and tau protein in the CSF have been found to be elevated immediately after boxing matches, and these elevations normalize in the following days and weeks after rest from head injury. However, CSF techniques require a lumbar puncture, and therefore serum biomarkers are also under active investigation. A study evaluating total tau (t-tau) plasma levels reported that all former NFL players had a concentration greater than or equal to 3.56 pg/mL, indicating that t-tau elevations may be a promising biomarker for the presence of remote head injuries. While t-tau serum elevations were seen exclusively in former players, levels did not correlate with cognitive testing, and t-tau elevations are seen in other neurodegenerative and cerebrovascular conditions, limiting its role in diagnosis. T-tau is, therefore, likely a general marker of brain injury that occurs with a variety of disorders, including AD, frontotemporal degeneration, and stroke.

CONCLUSION

The science of CTE is advancing rapidly as we learn more each year about the ongoing, often lifelong, impacts of head injuries in our patients. It has been established in the past decade that some amount of repetitive head injuries combined with unknown genetic, exposure, and other susceptibility factors ultimately leads to CTE, a neurodegenerative condition marked by perivascular accumulations of tau at the depths of the sulci. The exact clinical features and premorbid hallmarks of CTE are under investigation, yet at the same time we are seeing patients and caregivers of patients with extensive contact sport or military service histories who wonder if changes in behavior are related to prior head injuries. Research in AD and other neurodegenerative conditions will continue to guide the way in CTE research as we seek to diagnose patients during life, perhaps in the future using validated clinical consensus criteria and biomarkers being developed, such as tau PET imaging. In the future, studies of the long-term effects of head injuries in military veterans and other specific populations will be important to advancing the scientific understanding of this important condition.

KEY POINTS

  • Chronic traumatic encephalopathy is a pathologically defined neurodegenerative disorder associated with repetitive concussive or subconcussive head injury.
  • The frequency, severity, and total exposure to head trauma and the exact pathophysiologic mechanism by which blows to the head result in chronic traumatic encephalopathy are active areas of research.
  • Head injury is an important but nonsufficient risk factor in the development of chronic traumatic encephalopathy; other exposure and genetic risk factors are under investigation.
  • Currently, no validated clinical diagnostic criteria for chronic traumatic encephalopathy exist, although research diagnostic criteria have been developed.
  • Concussion is a clinical syndrome of impaired brain function, typically impacting memory and orientation, with or without loss of consciousness that results from head injury.
  • Chronic traumatic encephalopathy is defined by neuropathology: perivascular aggregation of phosphorylated tau protein within neurons and astrocytes that begins in the depths of sulci and progresses to involve the medial temporal lobes and other parts of the brain.
  • Chronic traumatic encephalopathy deficits involve progressive cognitive, behavior, and mood changes as well as possible motor deficits.
  • The most common cognitive difficulties in patients with chronic traumatic encephalopathy involve memory and executive function.
  • Four traumatic encephalopathy syndrome subtypes have been described: (1) a behavioral/mood variant, occurring in younger patients; (2) a cognitive variant, which occurs later in life; (3) a mixed variant; and (4) a dementia form.
  • The classification of patients into the diagnostic categories probable, possible, and unlikely chronic traumatic encephalopathy relies, in part, on results of potential research-based biomarker findings, thus diagnoses are for use in research, not clinical settings.
  • The evaluation for possible chronic traumatic encephalopathy should include asking about a history of repetitive head trauma, with or without concussion, including exposures during contact sports, military service, domestic abuse, assault, and motor vehicle accidents.
  • The differential diagnosis for chronic traumatic encephalopathy often includes frontotemporal dementia and Alzheimer disease.
  • No disease-modifying or symptomatic treatments for chronic traumatic encephalopathy are US Food and Drug Administration approved. All medication management is off-label and symptom-based, and can include acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, and memantine.
  • The incidence and prevalence of chronic traumatic encephalopathy is unknown because of a lack of epidemiologic data. However, the frequency of chronic traumatic encephalopathy is potentially increased within the professional contact sports community and others exposed to head trauma.
  • The age of clinical onset of traumatic encephalopathy syndrome/chronic traumatic encephalopathy symptoms is delayed by several years or decades following exposure to head injuries and is currently estimated to be between 30 and 65 years of age.
  • Posttraumatic stress disorder and traumatic brain injury often co-occur in military veterans and may share a common pathophysiology.
  • Posttraumatic stress disorder, postconcussive disorder, and chronic traumatic encephalopathy share many common symptoms, including difficulty with concentration, changes in mood, memory problems, irritability, and sleep disturbances.
  • Chronic traumatic encephalopathy frequently involves TDP-43 pathology, but TDP-43 is not necessary for pathologic confirmation.
  • Chronic traumatic encephalopathy can co-occur pathologically with other neurodegenerative conditions, including motor neuron disease, Alzheimer disease, Lewy body disease, and frontotemporal dementia.
  • The main genetic risk factor investigated in association with head injury and chronic traumatic encephalopathy is the APOE ε4 allele.
  • The APOE ε4 allele may lower the threshold for an individual to develop cognitive deficits following repeated head injury.
  • Nongenetic potential risk factors for chronic traumatic encephalopathy include cognitive reserve, age of first exposure, and cumulative exposure to head injuries.
  • Serum tau concentration elevations may indicate the existence of prior head injury but have not been found to correlate with cognitive function.

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