Keywords
traumatic brain injuries - brain concussion - chronic traumatic encephalopathy - tauopathies
Palavras-chave
lesões cerebrais traumáticas - concussão cerebral - encefalopatia traumática crônica
- tauopatias
Introduction
Traumatic brain injury is a proven risk factor for neurodegenerative diseases, including
chronic traumatic encephalopathy (CTE).[1] Chronic traumatic encephalopathy was first described in boxers under the name “punch-drunk
syndrome”, in 1928, by the pathologist and examiner Harrison Martland,[2] later renamed as “pugilistic dementia” (Millspaugh, 1937),[3] and, finally, as CTE (Critchley, 1957).[4] It is characterized as a neurodegenerative tauopathy caused by repetitive and cumulative
head trauma or traumatic brain injury (TBI).[5]
[6]
[7] Besides the classical description in boxers, other sport activities, such as muay
thay, Chinese boxing, mixed martial arts, wrestling, hurdling, lacrosse, rugby, field
hockey, and soccer and football, in particular, have been described as potential causes
of TBIs and, consequently, risk factors for the development of CTE.[6]
[8]
[9]
Epidemiological studies show that trauma is one of the main causes of morbidity and
mortality, ranking third in general mortality in Brazil, with greater severity when
considering TBI, whether from contact and collision sports or accidents. Traumatic
brain injury can be related with intracranial hemorrhages, hematomas, carotid or vertebral
dissection, concussions, and diffuse axonal lesions.[10]
Between 1965 and 2019, research from Europe, the United States, New Zealand, and Australia
has found that up to one third of all causes of TBI are sport-related. Furthermore,
the occurrence of trauma ranged from 3.5 to 31.5 per 100,000 in studies analyzing
those individuals who attended hospitals after TBI, whereas, in the community, it
ranged 170 per 100,000, according to the population of the countries.[11] In time, it is important to highlight that concussion is very common when related
with contact and collision sports, such as in the United States, where 1.6 to 3.8
million sports-related concussions occur annually.[12]
Chronic traumatic encephalopathy is a neurodegenerative syndrome caused by single,
episodic, or repetitive blunt force impacts to the head and transfer of acceleration/deceleration
forces to the brain. It presents itself clinically as a syndrome composed of mood
disorders and behavioral/cognitive impairment, with or without a sensory-motor disease.[13] Furthermore, it is related to the widespread deposition of hyperphosphorylated tau
protein (p-tau) in the form of neurofibrillary tangles (NFTs)[14] in the sulci and perivascular spaces[12] with preferential involvement of the superficial cortical layers and a propensity
for sulcal depths.[6]
[15]
The occurrence of CTE has demonstrated significant importance within the scientific
context, with regard to its development and specificities inherent to the etiology.
In addition, its health implications with differential value to other diseases evoke
the need for more thorough studies in this matter.
Therefore, this article aims to clarify, through a literature review, the existing
correlation between chronic traumatic encephalopathy and the practice of sports, as
well as its main aspects for a differential diagnosis. Additionally, this paper aims
to establish a threshold that distinguishes CTE from other pathologies that have similar
clinical outcomes.
Material and Methods
This review article was developed based on a data survey found in the literature.
The related bibliographic searches were published in the period between 2000 and 2020
in the following scientific databases: SciELO, PUBMED, and BVS-Bireme.
The descriptors used in the medical subject headings (MeSH) and Descritores em Ciência da Saúde (DeSC) were: chronic traumatic encephalopathy, traumatic brain injury, and trauma in athletes. Their respective correspondents in Brazilian Portuguese were also consulted. Subsequently,
the studies that met the following inclusion criteria were distinguished as such:
electronic bibliographies compatible with the descriptors listed above; chronology
from the year 2000 on; books; full texts and theses; abstracts; original articles,
review articles, and case reports in the aforementioned medical scientific databases.
We decided to exclude studies that did not establish a relationship between CTE and
the practice of sports, and, in order to guarantee an adequate theoretical basis for
the evolution and discussion of the theme, only the studies considered most significant
were analyzed.
From this point, 375 manuscripts were found and, after applying the inclusion criteria,
234 were accounted for. By reading the titles and abstracts, 168 texts were eliminated
and 66 of them were analyzed and read in their entirety. Thus, 35 references were
considered for this review and 8 duplicates were discarded. In the end, 27 sources
were included as proper bibliographic references, which present original scientific
properties as well as relevance to the approach of this work.
Results and Discussion
Given what was analyzed, there was significant correlation between the diagnosis of
CTE and its connection to sports practitioners, or even in cases of repeated traumatic
brain injuries.
Thus, from an analysis of postmortem brains donated and obtained from a cohort of
85 individuals with a history of repetitive mild traumatic brain injury, approved
by the Boston University School of Medicine, it was found that 80 were athletes, and
22 of these were athletes and military veterans. Of these 85, evidence of CTE was
found in 68 individuals. It is worth noting that all (68) those with evidence of CTE
were males aged between 17 to 98 years old, 51 (75%) of whom had the confirmed diagnosis
and 7 (10.3% of all cases with evidence of CTE) had Alzheimer disease ([Table 1]), ranging from focal comorbidity in stages I to III to inclusions and generalized
neuritis in stage IV[14] ([Table 2]).
Table 1
Diagnostic correlation of chronic traumatic encephalopathy with the practice of sports
in identified studies
|
Source
|
Type of study
|
N sample
|
Age group
|
Diagnosis
|
|
McKee et al.[14]
|
Cohort (autopsy)
|
80 athletes (22 of whom were also military veterans)
|
Between 17 and 98 years old (average of 59.5 years old)
|
Of the 68 cases with evidence of CTE: 51 (75%) - CTE; 8 (12%) - Motor neuron disease;
7 (10.3%) - Alzheimer disease; 11 (16%) - Lewy body disease; 4 (6%) - Frontotemporal
lobar degeneration
|
|
McKee et al.[12]
|
Review
|
51, of whom: 46 (90%) were athletes (39 boxers [85%], 5 football players [11%], 1
professional wrestler and 1 soccer player).
|
Between 23 and 91 years old
|
100% - CTE
|
|
Montenigro.[16]
|
Review
|
202 (141 boxers, 54 football players, 5 ice hockey players and 2 professional wrestlers)
|
|
83 - definite CTE, 90 - probable CTE, and 29 - possible CTE.
|
Table 2
Symptomatology characteristic of chronic traumatic encephalopathy according to stages
I to IV of the disease
|
Stages of CTE
|
Symptoms
|
|
I
|
Headache, loss of attention and concentration.[14]
[18]
|
|
II
|
Depression, explosiveness, and short-term memory loss.[14]
[18]
|
|
III
|
Executive dysfunction and cognitive impairment.[14]
[18]
|
|
IV
|
Dementia, difficulty finding words, and aggression.[14]
[18]
|
Abbreviations: CTE, chronic traumatic encephalopathy.
In contrast, in the review study by McKee et al.,[12] it was observed that of 51 neuropathologically confirmed cases of CTE, 46 (90%)
occurred in athletes. The first symptoms were noticed between 25 to 76 years old (M = 42.8,
SD = 12.7). One third were symptomatic at the time of retirement from the sport, and
half were symptomatic within 4 years of cessation of practice ([Table 1]).
Similarly, in another review, 202 cases from 20 publication series, 4 books and 1
medical dissertation[16] were analyzed. The Jordan criteria[17] were considered, which are: definite CTE (any neurological process consistent with
clinical presentation of CTE in conjunction with pathological confirmation), probable
CTE (any neurological process characterized by two or more of the following conditions:
cognitive and/or behavioral impairment; cerebellar dysfunction; pyramidal tract disease
or extrapyramidal disease; clinically distinguishable from any known disease process
consistent with the clinical description of CTE), possible CTE (any neurological process
that is consistent with the clinical description of CTE, but can potentially be explained
by other known neurological disorders).[17] Thus, in this study, 83 of the cases would have definite CTE; 90, probable CTE,
and 29, possible CTE[16] ([Table 1]).
However, Montenegro et al.[16] point out new diagnostic criteria, such as: a behavioral/mood variant, a cognitive
variant, a mixed variant, and dementia (traumatic encephalopathy syndrome). The progressive,
stable, and unknown course modifiers are used to describe the clinical course, and
if specific motor signs are evident, the modifier with motor characteristics will
be added. The selection of the general criteria was based on the literature reviewed
by the authors and was designed to favor sensitivity over specificity.[13]
The noticeable changes triggered by CTE involve a series of clinical, encephalic,
and microscopic manifestations, which are characteristics that can help in differentiating
it from other tauopathies ([Table 3]).
Table 3
Diagnostic characterization of the pathophysiological impairment of chronic traumatic
encephalopathy at the clinical, neuroimaging, and neuropathological levels
|
Level
|
Alterations
|
|
Clinical
|
Memory disorders; behavioral and personality changes; parkinsonism; speech and gait
abnormalities[6]
[12]
[18]
|
|
Neuroimaging
|
Atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies,
and brainstem; ventricular dilatation; and a fenestrated septum pellucidum cavum[6]
[12]
[18]
|
|
Neuropathological
|
Extensive tau-immunoreactive and astrocytic neurofibrillary tangles; and spindle-shaped
neurites throughout the brain[6]
[12]
[18]
|
Pathophysiology
The definitive encephalic lesion, which is established after TBI, is a result of the
different densities between the encephalon and the cranial box, thus, when submitted
to the same inertial forces, they respond unequally. This mismatch of movements can
promote rupture of cerebral veins that flow into the dural sinuses, as well as the
impact and laceration of the parenchyma against the rigid structures of the skull.
In addition to this mechanism, as the central region of the brain is relatively fixed
due to the presence of the brainstem, the peripheral regions of the brain and cerebellum
tend to present a greater amplitude of displacement. Therefore, this difference in
the extent of movements between the central and peripheral regions of the brain generates
stretching of axons and cerebral blood vessels, which can result in anything from
temporary dysfunction to rupture of these structures.[18]
[19]
The alterations are of macro and microscopic character. Macroscopically, modifications
of the septum pellucidum are found, with the presence of fenestrations and a large
cavum, associated with cerebellar atrophy. On the other hand, microscopically, there is
loss of cerebellar Purkinje cells, degeneration, and loss of substantia nigra cells,
presence of neurofibrillary tangles (NFTs), which are aggregates of tau polymers,
neuropil threads and glial tangles (GTs).[10]
[12]
[18]
During a traumatic event, there is a shear deformation in the brain and spinal cord,
causing transitory or permanent lengthening of axons. Traumatic axonal injury's outcomes
are changes in axonal membrane permeability; ionic changes, including great calcium
influx and release of caspases and calpains that can trigger phosphorylation of tau;
unfolding; truncation and aggregation, as well as cytoskeletal breakdown with dissolution
of microtubules and neurofilaments.[6]
[20]
Immediately after a biomechanical injury to the brain, there is an abrupt and indiscriminate
release of neurotransmitters and uncontrolled ion fluxes. In this regard, the binding
of excitatory transmitters, such as glutamate, to the N-methyl-D-aspartate (NMDA)
receptor conditions additional neuronal depolarization with potassium efflux and calcium
influx. These ionic changes promote acute and subacute changes in cellular physiology.[21]
In the acute deformation, the effort to restore the neuronal membrane potential, the
sodium-potassium (Na + - K +) pump, is beyond normal. Therefore, it requires increasing
amounts of adenosine triphosphate (ATP), causing a dramatic jump in glucose metabolism.
This “hypermetabolism” occurs in the scenario of decreased cerebral blood flow, and
the disparity between glucose supply and demand triggers a cellular energy crisis.
The resulting energy shortage is a likely mechanism of post-concussive vulnerability,
making the brain less able to respond adequately to a second injury and, thus, leading
to prolonged deficits.[21]
After the initial period of accelerated glucose utilization, the affected brain enters
a period of depressed metabolism. As such, persistent increases in calcium can impair
mitochondrial oxidative metabolism and worsen the energy crisis. In addition, unchecked
calcium accumulation can also directly activate pathways leading to cell death, and
thus intra-axonal calcium flux disrupts neurofilaments and microtubules, impairing
post-traumatic neural connectivity. There are other changes, such as: lactic acid
generation, decreased intracellular magnesium, free radical production, inflammatory
responses, and altered neurotransmission.[21]
Modifications in neurotransmitters are present in the glutamatergic system through
glutamate and NMDA binding, in which long-term potentiation, a measurement of plasticity
dependent on this receptor, may be persistently impaired in the hippocampus. Meanwhile,
there are impairments to the adrenergic and cholinergic systems, such as early changes
in choline acetyltransferase activity and neuronal loss in the forebrain, a triggering
factor for learning and memory deficits. The loss of hilar neurons, producers of γ-aminobutyric
acid (GABAergic), can compromise the normal inhibition of the hippocampal dentate
granule cells. This loss may predispose the traumatized brain to the subsequent development
of seizures.[20]
Furthermore, nitric oxide (NO) is produced by the increase in intracellular calcium
concentration associated to cellular aggression mechanisms present in trauma. In TBI,
its action may be divided into three phases. First, NO seems to act preserving the
cerebral blood flow (CBF) in its first 30 minutes. In a second phase, there is a depletion
of NO accompanied by a decrease of CBF between 30 minutes and 6 hours. Lastly, NO
increases again after 6 hours. In this last phase, the accumulation of this oxide
affects the endothelium, causing a potent vasodilation and increase in vascular permeability.
The combination of these actions leads to increased CBF, cerebrospinal fluid pressure,
and cerebral edema.[22]
Therefore, repeated injuries in collision and contact sport practitioners over a period
of time can lead to significant anatomical or behavioral impairment. Traumas can be
characterized by concussions, which occasionally lead the brain tissue to a state
of progressive deterioration by overstimulation of the injured brain. Thus, the pathophysiology
has an impact on the possible apparent signs and symptoms that can lead to CTE.[20]
Clinical Aspects
Individuals with CTE may develop a variety of clinical symptoms and secondary illnesses;
and many of these are insidious. These include mood and behavioral impairment, such
as the manifestation of depression, anxiety, apathy, paranoia, psychotic symptoms,
suicidality, explosiveness, violent amnesia, drowsiness, dizziness, altered level
of consciousness, slowness to answer questions or follow directions. There are also
changes in cognition, with impaired memory, executive dysfunction, loss of attention,
and dementia.[12]
[16]
[23]
[24]
Likewise, some physical or somatic signs and symptoms can be observed, such as: blurred
vision, decreased performance, diplopia, fatigue, headache, dizziness, nausea, vomiting,
incoordination, tinnitus, seizures, difficulty speaking (incoherence), stray and glassy
eyes, seeing bright spots, and vertigo.[12]
[16]
[24] Less commonly, eye abnormalities, such as ptosis; and in motor functioning, such
as the appearance of Parkinsonism features: ataxia and dysarthria, dysgraphia, bradykinesia,
tremor, rigidity, gait disturbances, falls, and even Parkinson itself.[12]
[16]
[24]
Following a large systematic review of 47 studies, done by McKee AC et al.,[12] that sought to evaluate the long-term effects of sports-related concussion in 46
retired athletes, the mean age of onset was found to be 42.8 years old. Notwithstanding
one third of the athletes was symptomatic at that time, the onset roughly occurred
around 8 years after retirement. Among the main symptoms noted were major mood disturbances
in 30% of the athletes and movement abnormalities (such as Parkinson and slow gait)
in 42%.[12]
Therefore, there is social instability, irregular behavior, memory loss, and early
symptoms of Parkinson disease in the early affective and psychological disorders.
In the later stages, CTE can be clinically confused with Alzheimer disease or frontotemporal
lobar degeneration (FTD), as well as general cognitive dysfunction progressing to
dementia.[6]
[14]
Diagnosis Criteria
As previously described, CTE is a progressive neurodegeneration characterized by widespread
deposition of hyperphosphorylated tau protein (p-tau) as NFTs, and in late stages
it can be clinically confused with other dementia diseases such as Alzheimer disease
(AD), frontotemporal lobar degeneration (FTD), and Parkinson disease.[23]
[24]
Within the vast information present in the literature, it is important to list the
topics that guide the laboratory diagnosis of CTE: prominent perivascular distribution
of astrocytic tangles (AS) and NFTs; irregular cortical distribution of immunoreactive
NFTs to p-tau and AS with a predilection for the depth of the cerebral sulci; subpial
and periventricular groups of AS in the cerebral cortex, diencephalon, basal ganglia
and brainstem and NFTs located preferentially in superficial layers. Besides the presence
of NFTs in the mamillary body, typical of CTE, likewise in the substantia nigra, in
a severe stage; and absence of β-amyloid peptide deposits. Regarding macroscopy, there
is generalized atrophy of the cerebral cortex, medial temporal lobe, diencephalon
and mamillary bodies with enlarged ventricles.[8]
[25]
Differential Diagnosis
Precisely because it is a dementia, CTE requires differentiation from other syndromes
of the same spectrum, as mentioned above: AD, Parkinson disease, and FTD. In order
to expose such differences, the following milestones for each pathology are found
bellow.
Alzheimer Disease
The criteria for AD were based on the presence of β-amyloid protein plaques and p-tau
ENFs. The nature, pattern, and distribution of p-tau neurofibrillary degeneration
in CTE are distinct from AD, which denotes diffuse cortical presence of NFTs and absence
of pathological perivascular neurofibrillary clustering. Furthermore, there is a widespread
cortical distribution of p-tau pathology without accumulation in the sulcal depths,
and the subpial region in the depth of the sulcus does not demonstrate AEs positive
for p-tau.
Furthermore, there is a notable element of presence of abundant β-amyloid plaques
and intercalated NFTs, along with moderate neurofibrillary alteration in the compact
substantia nigra typical of severe AD; and absence of AEs or NFTs in the mamillary
body in the disease.[14]
[26]
Parkinson Disease and Lewy Body Dementia
The Parkinsonian diagnosis is made based on the presence of positive Lewy bodies with
positive alpha-synuclein predominantly in the brainstem, a laboratory finding absent
in CTE. The existence of these bodies may also signal another type of dementia, the
Lewy body dementia, which evolves intracytoplasmic aggregation of spherical elements
and eosinophilic infiltrate that are, again, elements that are not aggregated to CTE.[14]
[27]
Frontotemporal Lobar Degeneration
The diagnosis of FTD is based on the predominant involvement of the frontal and temporal
cortices and characteristic immunohistochemistry for p-tau and measured by cytoplasmic
and intranuclear neuronal inclusions positive for TAR 43 DNA-binding protein, showing
some relation with CTE and being presented in the scope of differential diagnoses.
Additionally, dystrophic neurites and glial cytoplasmic inclusions are visualized
in the superficial layers of the cerebral cortex and dentate gyrus. The differential
of FTD includes progressive supranuclear palsy, corticobasal degeneration, and Pick
disease, patterns that are absent in CTE.[25]
[27]
Conclusion
In summary, the relationship established between the genesis of CTE and the practice
of sports, especially of contact and collision sports, is clear since repetitive traumas
predispose to an array of metabolic, ionic, cellular, and synaptic disorders that
may provoke the pathophysiological cascade of CTE. Furthermore, similarities and significant
differences have been noted between CTE and other dementia diseases, such as Alzheimer
and Parkinson, aiming to present a differential diagnosis.
