Chronic traumatic encephalopathy in athletes

Introduction

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease caused by repeated minor traumatic brain injuries. Most documented cases of CTE have occurred in athletes involved in contact (high-impact) sports, such as American football, boxing, hockey, and rugby, which are often associated with minor brain injuries [1][2]. The problem of sports-related injuries to the central nervous system (CNS) has been discussed for several decades, however with gradual data acquisition and increase in prevalence, CTE-specific studies have been initiated relatively recently [3].

According to present knowledge, neurological symptoms of CTE are largely similar to those of some neurodegenerative diseases [2]. This challenges medical and athletic communities to address the differential diagnosis of genetically based and traumatic degenerations, their combinations and relative effects. The genetic determination of CTE severity, including genetic disposition to primary degenerative disorders, is also important.

For a scientific literature review, in 2022, a total of 1141 publications were retrieved from the PUBMED database using the search term "chronic traumatic encephalopathy", increasing from 147 in 2013. The search term "chronic traumatic encephalopathy in sports" produced 504 and 69 hits, respectively. These data demonstrate evidence of increasing interest in the problem over the last decade.

Epidemiology

It is estimated that approximately 1.6 to 3.8 million sports-related minor traumatic brain injuries occur annually, and the incidence of sports-related injuries accounts for 20% of all brain injuries, with half of them reported in children and adolescents [4-6].

According to several studies, the incidence rate of sports-related brain injuries ranges from 3.5 in Italy (Servadei et al., 2002) to 31.5 in the United States (Selassie et al., 2013) per 100,000 population; however, the studies only included athletes who sought medical care. Theadom et al. (2014) reported the incidence rate of brain injuries during a sports-related activity of 170 per 100,000 of the New Zealand population. The analysis group also included athletes who did not seek medical treatment for their injuries [6-9].

Broglio et al. (2013) demonstrated that American football practices accounted for 24 head impacts (>14g) per athlete per session [10].

Theories of Pathogenesis

Some people who suffer from frequent repeated minor traumatic brain injuries are more susceptible to developing CTE symptoms and experience early onset and rapid progression of the disease [1]. This fact gives rise to studying physiological aspects of the individual response to chronic injuries.

According to Mez et al. (2017), among 202 deceased former football players in the United States, 87% had abnormal tau metabolism in the CNS. Out of them, 99% were former U.S. National Football League (NFL) players. The disease severity was correlated with the level of play: moderate changes were found among university athletes, while NFL players experienced the most severe brain injuries [11].

In a retrospective cohort study of 3,493 NFL players, Lehman et al. (2012) concluded that the neurodegenerative mortality was 3 times higher than that in the general U.S. population, and 4 times higher than that in patients with amyotrophic lateral sclerosis and Alzheimer's disease [12]. Other authors have reported that former NFL players over 50 years of age are 5 times more likely to be diagnosed with dementia than the general population [13].

According to Casson et al. (2010), who examined clinical data from U.S. NFL players over the two study periods, there were 0.38 documented concussions per NFL game in 2002‒2007, i.e. 7.6% lower than 0.42 in the earlier period of 1996‒2001. The most common symptoms of cerebral concussion were headaches and dizziness, and short-term memory problems were also reported. Most concussed players (83.5%) returned to play in less than 7 days, and the percentage of players with loss of consciousness decreased to 57.4% between 2002 and 2007. The proportion of players who returned to play in less than 7 days was 8% lower in 2002–2007 than in 1996–2001, and 25% lower for those with loss of consciousness [14].

Currently, a pathological study is the most reliable procedure to make a definitive diagnosis of CTE, and establishing the lifetime criteria for this disease is one of the major challenges for sports neurology. Microscopically, CTE is mainly characterized by neurofibrillary tangles, transactive response DNA binding protein 43 (TDP43), and reactive astrocytes and microglia [15].

Among them, particular attention should be given to the misfolding mechanism of tau protein, since due to the disturbed tau distribution, CTE may be linked to primary neurodegenerative diseases (Alzheimer's disease, frontotemporal dementia) [1, 2].

Physiological tau binds to tubulin and stabilizes microtubule fibrils in neurons, thereby facilitating axon development. A brain injury may lead to tau dissociation and hyperphosphorylation. Hyperphosphorylated tau binds to normal proteins, which results in pathological aggregation. The hyperphosphorylated protein has less affinity for microtubules and travels through axons to the neuron body, and loses its solubility property, which results in decreased tau excretion from the nerve cell. Hence, the abnormal hyperphosphorylation of tau promotes its oligomerization [16-18]. The dysregulation of the tau kinase/phosphatase system is responsible for the slow dephosphorylation kinetics, and tau oligomers are ultimately modified into neurofibrillary tangles leading to axonal neurodegeneration and nerve cell death [15].

Concussion

A concussion is a complex pathophysiological process characterized by traumatically induced disturbance of brain functions without morphological changes visible by standard brain imaging. According to current diagnostic criteria, concussed people may not experience loss of consciousness. Symptoms develop rapidly, persist briefly, and resolve spontaneously. In most cases, a concussion can affect muscle coordination, memory, and concentration, and less often – voluntary motor control. These changes are exclusively functional and reversible [19].

The genetic modulators associated with the clinical features of concussion are of some interest, and the significance of Apolipoprotein (Apo) E4, ApoE promoter gene, and its exon encoding tau synthesis has been widely studied; however, no clear patterns have been identified so far [20][21].

The concussion symptom complex develops through microstructural pathophysiological responses. Traumatic injuries are thought to be related to abnormal ion exchange with massive sodium and calcium influx, potassium efflux, and excessive glutamate release through the damaged cell membranes. These changes then trigger voltage-gated ion channels, creating a lower cortical activity and causing acute symptoms of concussion. In an effort to restore ionic homeostasis, ATP-dependent ionic pumps overdrive. This causes relative depletion of neuronal energy reserves and an increase in ADP levels. This increased demand for energy may persist for 7‒10 days in a setting of reduced cerebral blood flow, cytoskeletal damage, altered neurotransmission, and other mechanisms of axonal dysfunction. There is a risk of repeated brain injury, behavioral impairment, and learning deficits [22].

The published sports medicine literature reports a number of concussion severity grading systems. Among them, three classification systems, i.e. proposed by Cantu (Cantu, 1986), the American Academy of Neurology (1997), and the Colorado Medical Society (1990), are currently most widely used in clinical practice. They suggest three grades of concussion severity [23-26].

Mild concussions (grade 1) are the most common type among athletes. Colorado guidelines define a grade 1 concussion as no loss of consciousness, and the main signs are short-term confusion and feeling dazed. According to Cantu's definition, a mild concussion is one without loss of consciousness, with confusion alone or a brief (less than 30 minutes) period of amnesia. With the grading criteria issued by the American Academy of Neurology, patients with a grade 1 concussion do not lose consciousness, and their cognitive impairment resolves in less than 15 minutes. This type of concussion is frequently experienced by athletes playing sports like football or soccer with an incidence rate of one player per session. Diagnosis can only be made with a thorough examination.

If a head injury is accompanied by significant disorientation, confusion, memory problems, dizziness, headache, and neurological symptoms lasting for more than 15 minutes, the concussion may not be qualified as mild. It should also be recognized that loss of consciousness may not correlate with concussion severity. In their study, Ommaya and Gennarelli (1974) suggested that the absence of loss of consciousness combined with gross mnestic disorders may be explained by irritation of subcortical and cortical structures with no significant effect on the activating reticular formation of the brainstem [27][28].

Based on the Colorado classification, a moderate, or grade 2, concussion, is accompanied by initial or delayed amnesia, although there is no loss of consciousness. Cantu defines a moderate concussion as less than 5 minutes of unconsciousness or post-traumatic amnesia lasting more than 30 minutes but less than 24 hours. According to the American Academy of Neurology classification, patients with a moderate concussion may stay conscious, and the primary sign is the altered mental status lasting for more than 15 minutes.

The loss of consciousness is the main criterion for a severe concussion, or grade 3 concussion, based on the Colorado and American Academy of Neurology grading systems. Cantu defines a severe concussion as a traumatic brain injury, characterized by loss of consciousness lasting more than 5 minutes or post-traumatic amnesia for more than one day. This type of concussion is a good reason to visit the nearest emergency room to have CT imaging and neurosurgical assessment. The possibility of concomitant cervical spine injury must always be considered in an unconscious patient and transport performed with cervical immobilization and maintenance of an adequate airway [27].

All efforts should be made to accurately assess the athlete's neurological status. There are three targets to be pursued: to diagnose the presence of a brain injury, assess the need for transportation to medical services for further examination, and explore a return to sport. Obviously, the detection of a potentially life-threatening or neurologically significant injury is of critical importance. Due to the risk of post-concussion syndrome, those athletes with mild brain injuries should be cautiously observed and must not return to play until the neurological symptoms resolve completely.

An athlete who experienced a head impact or acceleration/deceleration injury has to be removed for a thorough examination. Consciousness, coordination, orientation, and post-traumatic amnesia must be evaluated. A grade 1 concussion should be typically monitored for 20 to 30 minutes. Once symptoms have resolved completely, the affected athlete may return to play. The athlete should stop competition and see a physician if any persistent symptoms, such as headache, dizziness, or confusion, occur. With a grade 2 concussion, an athlete should be immediately suspended from play and examined by a physician. In a grade 3 concussion, consciousness or orientation may be significantly or permanently altered, and other neurological abnormalities occur. Transport to a hospital for emergency evaluation should be undertaken immediately [27].

Returning to Sports After Concussion

There are no consensus criteria for returning to sports after a concussion. The guidelines recommend that anyone suspected of a concussion should not return to sport within 24 hours. An athlete with spontaneous and induced clinical symptoms should be definitely removed from the competition. Exercise adaptation should be gradually increased within 24 hours of the concussion, starting with light aerobic activity to full-contact training. If post-concussion symptoms occur, it is essential to wait until they resolve and then follow a gradual 24-hour athletic adaptation. If new symptoms appear, a doctor should be seen immediately.

The return to sport after a concussion is based on the empirical five-stage system. The first stage involves 5-10-minute light anaerobic exercises that cause the athlete’s heart rate to go up. The next stage implies moderate-intensity activities, e.g. trunk or head movements, and weight training. In the third stage, heavier but non-contact physical activities, such as running, cycling, and weight training, are allowed. With the fourth stage, supervised contact training may be initiated. Finally, the athlete gets ready to return to conventional full-contact competitions [19].

Types of Traumatic Encephalopathy

Currently, there are two types of CTE-associated neurological disorders: young-onset with behavioral and mental disorders and late-onset symptoms, which generally constitute cognitive and motor deficits [29].

The differential diagnostic criteria for primary mental illnesses and chronic brain disorders have been described. Mental illnesses are characterized by depression, brief periods of mania, a psychotic disorder with delusions and hallucinations, non-significant cognitive deficits, and limited neurological symptoms. chronic brain disorders are mostly characterized by apathy in depression-free patients, impulsive behavior without mania symptoms, aggression without psychosis, behavioral maladaptation with normal ideation, cognitive deficits, and other focal neurological symptoms [30].

CTE and Other Degenerations

Phenotypically, CTE is similar to some genetically determined primary degenerations, post-concussion syndrome, and the so-called vascular dementia. However, the listed disorders have a number of pathogenetic differences. CTE is characterized by the onset at 8-10 years of chronic trauma injuries, slow progression, certain neuroimaging patterns (fenestration of the septum pellucidum, enlargement of the lateral and third cerebral ventricles, frontal and temporal atrophy, and atrophic mamillary bodies, thinned corpus callosum and third ventricular floor). Neurofibrillary tangles are localized in the second and third superficial layers of the cerebral cortex, focal or diffused in the cortical sulcular projection, and prevail in the frontal and temporal regions. The target cells are neurons and astrocytes. The micromorphology identifies tau oligomers consisting of 3–4 monomers. TDP-43 deposits are found in the frontal and temporal cortex, basal ganglia, diencephalon, and brainstem. Clinically, this disease is characterized by headaches, cognitive, motor, and Parkinsonian symptoms, as well as mood swings, behavioral changes, and pseudobulbar signs.

Alzheimer's disease and CTE have been recognized as sharing similar phenotypes. Alzheimer's disease is genetically determined. It is pathogenetically associated with dystrophic changes in medial temporal regions and diffuse cortical atrophy. The micromorphology is characterized by chaotic aggregates of tau protein to form neurofibrillary tangles in hippocampal cortex layers III and IV and to a lesser extent – in the limbic and convexital cortex. Alzheimer's disease typically destroys neurons. Extracellular deposits of pathologic amyloid-beta (Aβ) protein, degenerating axon bundles, and cerebrospinal fluid (CSF) neurofilament light have been recognized as biomarkers of Alzheimer's disease. Similar to CTE, Alzheimer's disease is associated with oligomeric tau complexes (up to 3‒4 monomers). TDP-43 deposits may also be distributed across the hippocampus. The most common clinical signs of Alzheimer's disease include memory loss and other cognitive difficulties. The disease is often accompanied by behavioral symptoms.

Post-concussion syndrome occurs immediately after the injury and even if the symptoms continue for a long time, they never worsen. The syndrome is characterized by headaches, memory problems, difficulty concentrating, personality disorder, and depression. Brain MRI usually remains unremarkable. Focal microscopic hemorrhages (diffuse axonal damage) may sometimes occur in brains as shown by diffusion-tensor MRI.

Patients with frontotemporal dementia experience a rapid progression; however, no direct association has been found with a brain injury. Frontotemporal dementia is characterized by cognitive and behavioral disorders. On autopsy, patients show gross atrophy of the frontal and temporal cortex. Neurons are targeted in frontotemporal dementia. Similar to CTE and Alzheimer’s disease, tau oligomers and TDP-43 deposits have been found in frontotemporal dementia by cortical micromorphology.

Parkinson's disease is a slowly progressive disorder with no association with CNS injury. The pathogenetic hallmarks of Parkinson's disease include the selective death of substantia nigra neurons, the brainstem, limbic, and cortical deposits of alpha-Synuclein aggregates and Lewy bodies. Changes in blood chemistry markers associated with other neurodegenerative diseases, such as Alzheimer's disease (e.g. tau oligomerization) may occur. Parkinson's symptoms may include hypokinesia, hypomimia, muscle hypertonicity, tremor, and non-motor signs, such as cognitive impairment and vegetative disorders.

The brain gross morphology remains unchanged in mental disorders, while no specific protein metabolic imbalance has been described. The underlying pathophysiology is based on the affected neurotransmitter metabolism. The primary clinical patterns of mental disorders include behavioral disorders and bipolarities.

Vascular dementia is a gradual mental decline. Patients with acute cerebrovascular accident typically present with focal neurologic deficits. Multiple small (lacunar) infarctions are common. Specific proteins never aggregate in pathological complexes.

Thus, a number of genetically-based neurodegenerative diseases could be symptomatically (and sometimes pathophysiologically, as with e.g. pathological tau deposits) similar to CTE. This suggests the presence of chronic brain degeneration caused by multiple repeated head injuries [1].

Clinical Diagnosis

The diagnostic algorithm is based on medical history, clinical data, neurological symptoms, and neuroimaging findings. There are five major diagnostic signs:

I. Medical history (multiple head impacts or body injuries with a second-impact transient concussion):

1) Mild head injury or concussion defined by the International Conference on Concussion in Sport criteria (Zurich, 2012). A sports-related concussion is a complex pathophysiological process affecting the brain and induced by biomechanical forces. It may be caused either by a direct blow to the head, face, neck or elsewhere on the body with an impulsive force transmitted to the head. Symptoms develop acutely and largely reflect a functional disturbance rather than a structural injury. At least four prior concussions must be reported [21].

2) Clinical signs and symptoms of a moderate/severe traumatic brain injury involve at least 30 minutes of unconsciousness, 24 hours of post-traumatic confusion and disorientation, more than 24 hours of post-traumatic amnesia, and a Glasgow Coma Scale score of 13 or less. At least two prior moderate to severe brain injuries must be reported.

3) Asymptomatic post-concussion injuries that are defined as head or body injuries induced by traumatic forces, however insufficient to develop clinical symptoms.

II. Absence of other neurological disorders (including residual symptoms of a single brain injury or persistent post-concussion syndrome); however, other neurodegenerative comorbidities may present.

III. Clinical signs must be evident for at least 12 months. For successful neurology treatment, the healthcare professional should keep in mind that if left untreated, symptoms could get worse over time or remain unchanged.

IV. At least one of the major clinical criteria (see below).

V. At least two additional clinical criteria (see below).

All major clinical criteria confine to pathologies of the higher nervous system. This group of symptoms can be divided into three subgroups: cognitive, behavioral, and emotional-volitional (mood disorders, depression).

The additional clinical criteria include impulsive behavior, anxiety disorder, motivational and emotional-volitional decline, paranoid syndrome, suicidal ideation, chronic headaches (at least once a month for at least six months), motor symptoms (dysarthria, dysgraphia, bradykinesia), and symptom worsening for at least one year [31].

If a concussed affected athlete continues playing sports, the onset of CTE symptoms may concur with an active traumatic injury. In some cases, the clinical features of prolonged or persistent post-concussion syndrome could not be differentiated from traumatic encephalopathy, and the resolution of post-concussion syndrome may overlap with the onset of CTE.

Based on these clinical features, four subtypes of CTE can be distinguished:

1) behavioral/mood variant without cognitive changes;

2) cognitive variant without behavioral and mood changes;

3) mixed variant of cognitive and mood/behavioral disturbances;

4) dementia (clinical presentation not distinguishable from that of dementia due to Alzheimer's disease or another neurodegenerative disease).

The published literature has identified CTE-specific biomarkers useful to support a diagnosis of CTE, including as follows:

1) a cavity or fenestration of the septum pellucidum on the brain imaging;

2) normal CSF Aβ levels;

3) increased ratios of CSF phosphorylated/non-phosphorylated tau fractions and phosphorylated fraction/total tau;

4) no obvious signs of Aβ deposits on positron emission tomography (PET);

5) characteristic tau deposits;

6) cortical hypotrophy on MRI or spiral CT, including generalized brain gray matter atrophy not specific for the age category.

The diagnosis of CTE is considered probable if it is clinically consistent with any subtype of progressive CTE and does not meet the diagnostic criteria of another disorder with at least one positive biomarker. CTE may be possibly diagnosed if it is clinically consistent with any subtype of progressive CTE with no or negative biomarkers available (except for PET findings suggestive of tau aggregates). Improbable CTE is stated for any neurological process that does not meet the CTE diagnostic criteria and/or is inconsistent with PET findings of tau aggregates [31].

Brain Imaging

Although the diagnosis of CTE can be only made postmortem, there are neuroimaging biomarkers that identify the major pathological features and may improve in vivo diagnosis. MRI and fludeoxyglucose positron emission tomography (FDG-PET) can detect structural and functional neurodegenerative changes, respectively, while radiotracers specific for tau ([ 18F]flortaucipir) and Aβ ([ 18F]florbetapir) may be useful in detecting the molecular pathology in CTE and excluding underlying dementias such as Alzheimer's disease [32].

In their studies, Little et al. (2014), Orrison et al. (2009), Gardner et al. (2016), and Koerte et al. (2015) showed that the patients at risk of CTE had a higher incidence and increased dimensions of the septum pellucidum, and more severe cortical atrophy compared to a control group of elderly subjects [33-36]. According to Gardner et al. (2015), Bang et al. (2016), Provenzano et al. (2010), and Peskind E.R. (2011), high-risk patients demonstrate a profile of brain FDG-PET hypometabolism [37-40]. A recent study by Stern et al. (2019) used [ 18F] PET to measure tau and Aβ deposition in 26 former professional American football players experiencing CTE symptoms. Their findings were compared to [ 18F] PET images of 31 controls. The group of former players showed higher tau levels in the frontal temporal (bilateral) and parietal (left) lobes [41]. Lesman-Segev et al. (2019) reported that in contrast to Alzheimer's disease, [ 18F] PET may be a useful tool to diagnose late-stage CTE [32].

Barrio et al. (2015) compared [18F] PET findings from former American football players with CTE symptoms (14 individuals) to those from healthy controls (28 individuals) and Alzheimer's patients (24 individuals). Based on [ 18F] PET, Barrio et al. (2015) have identified 4 CTE-specific patterns of tau distribution. The T1 pattern is predominantly subcortical in the brainstem (midbrain) with localized involvement of the medial temporal lobe areas. The T2 pattern shows PET signal in all subcortical areas, medial temporal lobe areas, and parts of the frontal cortex. The T3 pattern includes all affected areas in the T2 pattern plus additional cortical areas (posterior cingulate gyrus, lateral temporal lobe, and parietal lobe). The T4 pattern T4 shows extensive areas of tau deposits throughout the white and gray matter areas [42].

The PET signal patterns have been based on the results from the pathology study performed by McKee et al. (2013). The study analyzed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of CTE in 68 subjects. Tauopathies have been described by 4 stages. Stages I-II included mild cases, whereas stages III-IV correlated with severe CTE. TDP-43 aggregates were also detected in more than 80% of the analyzed cases [43].

To measure brain matter atrophy, researchers focus on magnetic resonance brain volumetry. Meysami et al. (2019) analyzed 40 patients aged 67.7±14.5 years with a history of repeated brain injuries. Volumetric results were compared with reference values for this age category. The most severe brain hypotrophy affected the ventral diencephalon and putamen, and to a lesser extent – the temporal lobes (hippocampus) and brainstem. The correlation analysis between volumetry findings and cognitive symptoms has demonstrated a significant direct relationship [44].

The study by Misquitta et al. (2018) included 53 retired Canadian Football League players and 25 age/education-matched healthy controls. Compared to controls, former athletes with a history of multiple concussions had more significant bilateral hypotrophy of the hippocampus accounting for impaired verbal memory [45].

Diffusion-tensor MRI, functional MRI, magnetic resonance spectroscopy, and single-photon emission computed tomography (SPECT) are considered very promising for CTE studies [46].

Prevention and Treatment

The primary approach to prevent CTE is to develop interventions that reduce the incidence of head injuries among athletes.

There are currently no standardized protocols for CTE treatment. The main therapeutic strategies are based on the pathogenesis of the disease. Promising candidate treatments include kinase inhibitors that catalyze tau phosphorylation, phosphorylation state-specific antibody therapy, and mechanisms promoting antibody transport across the blood-brain barrier [47].

The role of substances affecting the function of mitochondrial chains (pyrimidine) is currently under investigation [48]. Modulation of arachidonic acid metabolism as one of the main links in CTE pathogenesis is a promising method [49][50].

Conclusion

CTE resulting from repeated traumatic brain injuries more frequently occurs in contact sports and represents a complex of neurodegenerations associated with cognitive, emotional, behavioral, and even motor disorders.

The clinical features of CTE may include symptoms specific to other neurodegenerative diseases, which often makes the differential diagnosis difficult. As evidenced by numerous publications, the identified radiological patterns may not be considered absolutely reliable. Sports-related injury prevention is constantly improving, but the incidence of mild traumatic brain injuries remains high. Recent years have been remarkable for significant advances in the treatment of traumatic encephalopathy, but a consensus algorithm has yet to be developed.

Although this problem has been studied for decades, it remains a major challenge for sports and medical communities.