Chronic traumatic encephalopathy is a progressive neurodegenerative disease occurring in retired sportspersons who have received several head blows with concussions during their games. The clinical symptoms start with mood disorders and with a progressive evolution into dementia and Parkinsonism. The disease is due to a progressive accumulation of hyperphosphorilated tau in neurons as neurofibrillary tangles, abnormal neurites and inclusions in astrocytes around small vessels. There is a tendency of the lesions to occur in clusters at the sulcal depths of the cerebral cortex. Chronic traumatic encephalopathy has to be differentiated from Alzheimer’s disease, in which head trauma can also increase the illness symptoms. Recently, new tracers in positron emission topography of the brain have been used for a better evaluation of chronic traumatic encephalopathy. There is actually no treatment that allows to cure or to slowdown the evolution of chronic traumatic encephalopathy. However, new treatment studies are recently conducted and in progress.

Keywords: chronic traumatic encephalopathy, traumatic brain injury, alzheimer’s disease, positron emission tomography

Chronic traumatic encephalopathy is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depth of one or more cortical sulci.¹ Extensive exposure of boxers to repeated neurotraumata has led in 1928 to the term called “punch drunk syndrome”. This terminology was replaced by the less derisive term “dementia pugilistica” in 1937.²

However, the observation of the occurrence a similar clinical presentation in American football players has now led to the more commonly used term of chronic traumatic encephalopathy (CTE). It is now understood that exposure to traumatic brain injury (TBI) from any sport increases the risk of developing a progressive neurodegenerative disease. The true prevalence of CTE among individuals with a history of head trauma remains unknown.³ The incidence of dementia pugilistica is estimated to occur in approximately 20% of retired boxers.⁴ There is some evidence that a single moderate or severe TBI can also induce progressive neuropathological changes.⁵ The diagnosis of CTE can only be made conclusively by post-mortem neuropathological examination.⁶

 CTE is characterized by the build-up of hyperphosphorilated tau (p-tau) neurofibrillary tangles, abnormal neurites and inclusions in astrocytes around small vessels with a tendency to occur in clusters at the sulcal depths of the cerebral cortex. The tau epitope in CTE maps to the filamentous tau inclusions in Alzheimer’s disease (AD). Also, the abnormal tau proteins isolated from the CTE brains are indistinguishable from the six abnormally phosphorylated brain tau isoforms in AD.⁷ However more recently, a different conformation of beta-helix creating hydrophobic cavities with additional cores, that are absent in the tau filaments in AD brains, has been observed.⁸

A four pathological stage scheme, characterizing the severity of p-tau varying from mild (stage 1) to severe (stage 4) was proposed for CTE by McKee and colleagues in 2013. They found a predilection for p-tau pathology in the dorsolateral frontal cortex, the superior temporal cortex, the entorhinal cortex, the amygdala and the locus coeruleus. The lowest CTE stages involved only the frontal cortex and the locus coeruleus.⁹ In the medial temporal lobes the different tau profiles across the CTE stages, proffering CA3 tau pathology and dystrophic neuritis clusters, were as the markers for the transition between early (II) and late (III/, IV) stages.¹⁰ Also the substantia nigra can be involved in the late stages.¹¹

The association of a cavum septi pellucidi and dementia in old boxers was first described by Ferguson and Mawdsley in 1965. The significance and the epidemiology of the cavum septi pellucidi were however recently questioned.¹² White matter rarefaction, arteriosclerosis and tau with dementia in CTE were more frequently observed among older patients who had many years of their sports activities.¹³

Cantu has proposed 3 grades of cerebral contusion. In grade 1 there is no loss of consciousness, less than 30 minutes post-traumatic amnesia and post-concussion symptoms for less than 24 hours. In grade 2 there is a loss of consciousness of less than 1 minute, post-traumatic amnesia of more than 30 minutes and post-concussion signs between day 1 and day 7. Grade 3 is characterized by a loss of consciousness of more than 1 minute or post-traumatic amnesia of more than 24 hours or post-concussion signs of more than 7 days.¹⁴

The short-term sequels of acute severe brain injury include subdural haematoma and other catastrophic injuries, whereas mild TBI or concussion causes functional disturbances and axonal injury rather than gross structural brain damage. Following concussion, symptoms such as dizziness, nausea, reduced attention, amnesia and headache tend to develop acutely but usually resolve within a week or two. The developing brains in children and adolescents are more susceptible to concussion than the adult ones.¹⁵

Many studies show a significant association between cumulative exposure to repetitive head trauma, judged by the length of the sportive career, and the risk for severity of CTE.¹⁶ There is also a significant relationship with the length of the sport activities and the age of death.¹⁷ TBI significantly increases the risk of developing AD and Parkinson’s disease. Evidence for a possible role in TBI as a risk factor for sporadic amyotrophic sclerosis has been provided by studies of professional players of European football.¹⁸

A minority of younger patients who do not experience the latency phase with symptoms of CTE may be clinically diagnosed as post-concussion syndrome.¹⁹ In mild CTE behavioural or mood symptoms or both are present in 96%, cognitive symptoms in 85% and signs of dementia in 33%. In severe CTE pathology 89% had behavioural or mood disorders or both, 95% cognitive symptoms and 85% signs of dementia.²⁰

CTE manifests itself in four stages. In stage 1 the patients are asymptomatic or have mild memory and depressive symptoms. In stage 2 symptoms include behavioural outbursts and severe depression. Stage 3 is characterized by cognitive deficits including memory loss and executive dysfunction. In stage 4 advance language deficits, psychotic symptoms, profound cognitive deficits and motor features are observed.²¹

Computed tomography of the brain does not allow the diagnosis of CTE.²² Magnetic resonance imaging shows a significant increase of prevalence of cavum septum pellucidum and cavum vergae among boxers.²³ This is associated with lower regional brain volumes in a cohort of exposed boxers to repetitive head trauma.²⁴ The extend of the cavum septum pelucidi is more pronounced in the posterior parts of the brain, probably due to the sudden increase of the intracranial pressure during the blows, that forces cerebrospinal fluid through small defects in the septal leaflets.²⁵ Brain diffusion constant increases and diffusion anisotropy significantly decreases in the corpus callosum and the internal capsule of boxers.²⁶

Positron emission tomography (PET) of the brain with fluorodeoxyglucose, tau and amyloid radiotracers, are powerful modalities in the diagnosis of TBI-related conditions and CTE.²⁷ Mildly elevated tau-PET binding is observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with the CTE pathology stages III-IV.²⁸ Former national football league players with cognitive and neuropsychiatric symptoms have higher tau levels measured by PET in brain regions that are affected by CTE than in controls.²⁹ A consistent increase of tau is mainly observed in the hippocampi, the amygdalae and the brainstem.³⁰ Also a close correlation is found between psychosis and tau binding capacity in the white matter.³¹

 Guidelines have been published by the International Concussion in Sport Group, the American Academy of Neurology, the National Athletic Trainers Association and the 2013 Team Physician Consensus Statement Update.³² Also a more recent 2017 Berlin Concussion in Sport Group Consensus Statement in collision sports has been published.³³ However most of these guidelines are based on those proposed by Cantu. He classified the guiding prevention principles for TBI as dependent from the grade of severity and the recurrence rate of the concussion. For grade 1 one week is needed for a first contusion, two weeks for the second one and termination of the sport season after the third one. For grade 2 one week is needed for a first contusion, one month for the second one and termination of season after the third one. For grade 3 one month is needed for the first one, while for the second and the third contusion the season should be terminated.¹⁴

Factors associated with delayed return to rugby play were young age, initial loss of consciousness, Cantu grade 3 and post-concussive syndrome of more than 5 days.³⁴ A protective effect of helmets in collusion sports reduces concussions by head contact.³⁵ The helmet-to-helmet impact is 30% less in high safety-rated ones compared to the lowest safety-rated ones in the American National Football League.³⁶

Data are insufficient to show that any intervention enhances recovery or diminishes long-term post-concussion sequels.³⁷ However some symptomatic treatments can be tried such as central cholinesterase inhibitors for cognitive disturbances and dementia, dopamine and associated drugs for Parkinsonism symptoms and antipsychotics for psychosis and behavioural disturbances.³⁸ Even acupuncture and music therapy are considered to be helpful to combat the early neuropsychiatric symptoms of CTE.³⁹

During the recent years much advances have been made concerning the diagnostic mechanisms and the neuroimaging in CTE. Mainly the recent PET techniques with new tracers have contributed to a better understanding of TBI.

As CTE is characterized by accumulation of p-tau there is a growing interest in clinical trials with new tau-directed therapies. These treatments are hypothesised to have disease-modifying effects by reducing the concentrations of toxic forms of tau in the brain or by compensating for the loss of tau function.⁴⁰ Also a series of candidate treatments, including kinase inhibitors, antibody therapy and anti-inflammatory drugs are evaluated in preclinical animal models of CTE.⁴¹

However there are some dough’s that the pathogenesis of CTE is correlated solely to the repeated concussive injuries alone. The causes can be multivariate. In particular it is known that TBI is promoting the severity of AD.^41,42 There are still major concerns about the traditional guidelines to be used for return to sport participation after concussion, who are inconsistently applied, in particular in boxing. Only a few athletic commissions require either formal consultation with a neurological specialist or formal neuropsychological testing prior to the return to the competition.⁴³

Although there are many advances during the recent years in the understanding of CTE, still some clear prevention and treatment modalities are missing.

None.

The authors declare no conflicts of interest.

The authors have nothing to declare in relation to this article. No funding was received for the publication of this article.

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