Chronic traumatic encephalopathy

Abstract:

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative
syndrome, which is caused by single, episodic, or repetitive blunt force impacts to the head
and transfer of acceleration deceleration forces to the brain.
CTE presents clinically as a composite syndrome of mood disorders and behavioral
and cognitive impairment, with or without sensorimotor impairment. Symptoms of CTE may
begin with persistent symptoms of acute traumatic brain injury (TBI) following a documented
episode of brain trauma or after a latent period that may range from days to weeks to months
and years, up to 40 years following a documented episode of brain trauma or cessation of
repetitive TBI.
Posttraumatic encephalopathy is distinct from CTE, can be comorbid with CTE, and
is a clinicopathologic syndrome induced by focal and/or diffuse, gross and/or microscopic
destruction of brain tissue following brain trauma. The brain of a CTE sufferer may appear
grossly unremarkable, but shows microscopic evidence of primary and secondary
proteinopathies.
The primary proteinopathy of CTE is tauopathy, while secondary proteinopathies may
include, but are not limited to, amyloidopathy and TDP proteinopathy. Reported prevalence
rates of CTE in cohorts exposed to TBI ranges from 3 to 80% across age groups.Key pointsA panel of expert neuropathologists recently defined chronic traumatic
encephalopathy (CTE) as a unique neurodegenerative tauopathy characterized by a
pathognomonic lesion. The pathognomonic lesion consists of a perivascular accumulation
of abnormally hyperphosphorylated tau in neurons and astrocytes distributed in an
irregular fashion with a propensity for sulcal depths of the cerebral cortex.
The development of research criteria for the clinical diagnosis of CTE, known
as traumatic encephalopathy syndrome, will facilitate clinical research in CTE.
The number of years of exposure to contact sports, not the number of
concussions, is significantly associated with more severe tau pathology in CTE, suggesting
that repetitive head trauma, including subconcussive injury, is the primary stimulus for
disease.
Recent studies in neurodegenerative disease brain bank cohorts suggest that
among amateur athletes, changes of CTE are more common than previously recognized.
The development of in vivo biomarkers for CTE to facilitate the diagnosis of
CTE during life and therapeutic strategies to help individuals with suspected CTE are
critically needed.
IntroductionChronic traumatic encephalopathy (CTE) is defined as a progressive
neurodegenerative syndrome, which is caused by single, episodic, or repetitive blunt force
impacts to the head and transfer of acceleration-deceleration forces to the brain. CTE presents
clinically after a prolonged latent period as a composite syndrome of mood disorders and
behavioral and cognitive impairment, with or without sensorimotor impairment. Although
CTE usually presents clinically after a prolonged latency period, some patients with CTE may
not exhibit the classic prolonged latency period before clinical symptoms begin [1].
The final and definitive diagnosis of CTE remains microscopic tissue examination
with histochemical and immuno-histo-chemical tissue analysis of postmortem whole brains.
However, in vivo premortem presumptive diagnosis of CTE has recently emerged using 2-(1-
{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile-positron
emission tomography (FDDNP-PET) [2]. FDDNP-PET measures both tau tangle and amyloid
plaque deposition in living brains. Premortem clinical diagnosis of CTE in living patients
using radioligands like FDDNP remains a very promising trend in the near future for the
management of CTE.
As part of the CTE spectrum, the spinal medulla may, in addition to the brain, exhibit
distinctive neuropathologic changes of CTE. Since the spinal medulla is part of the central
nervous system, and CTE is a disease of the central nervous system, CTE cases exhibiting
spinal involvement should not be classified as a novel disease that is distinct from CTE. For
such cases the myelopathic component may be emphasized by designating them as chronic
traumatic myeloencephalopathy.
Like other neurodegenerative diseases, CTE exhibits cerebral and spinal
proteinopathies comprising primary and secondary proteinopathies [3]. The primary
proteinopathy of CTE is tauopathy, which may be accompanied by other secondary
proteinopathies including, but not restricted to, amyloidopathy and/or TDP-43 proteinopathy
[1, 4–9].
CTE is a distinct neurodegenerative disease with distinctive histomorphologic and
proteinopathic phenotypes that are distinct from the phenotypes of the most prevalent
neurodegenerative diseases including, but not limited to, Alzheimer’s disease (AD), Lewy
body disease (LBD), frontotemporal lobar degeneration, vascular brain injury, and
cerebrovascular disease [10, 11]. However, similar to other neurodegenerative diseases, CTE
can occur contemporaneously in the same individual with one or more other types of
neurodegenerative diseases [1, 6–9].
CTE is a progressive disease that exhibits cumulative neuropathologic and
proteinopathic changes with advancing age. Advanced or end-stage CTE in elderly patients
can exhibit histomorphologic and proteinopathic phenotypes that resemble AD, and in such
elderly patients it may not be feasible to differentiate CTE from AD with a reasonable degree
of medical certainty [1, 8, 9].
Historically, a minority of doctors and authors, especially doctors and authors who
may work or be associated with sporting organizations, have questioned or denied the
existence of CTE [12–16]. In 1959 and 2006, the medical director of the New York State
Athletic Commission [15, 16] and the Chairman of the Mild Traumatic Brain Injury
Committee of the National Football League (NFL) [17, 18] both respectively published papers
- 3 -and opinions rejecting the notion or hypothesis that blows to the head can cause CTE in
boxers and football players. However, CTE has remained a very well-established concept in
the medical sciences across the centuries. It has become a generally accepted principle in the
medical sciences that trauma to the brain can result in permanent brain damage that can
manifest with a myriad of progressive symptoms.
Over the centuries, CTE has been clearly recognized, described, and named with a
variety of terminologies, which are enumerated in table 1 [19, 20]. The commonality of all
these enumerated terminologies is the causal association of CTE with single, episodic, or
repetitive traumatic brain injury (TBI).
It is pertinent to note that CTE can occur in a variety of human activities and
circumstances in and out of sports, including in the military, whereby the human brain is
exposed to biomechanical loading of kinetic energy and forces in one episode of trauma, in
several (or just a few) episodes of trauma, and/or in numerous repetitive episodes of trauma
over the years. For a single episode of trauma, like in motor vehicle crashes, brain trauma is
more likely to involve severe TBI and posttraumatic encephalopathy (PTE) [21–23], while in
repetitive episodes of trauma, brain trauma is more likely to involve subconcussions and
concussions [24,25].

Chronic Traumatic EncephalopathySymptomatology and Clinimetrics

Symptoms of CTE may begin with persistent symptoms of acute TBI following a
documented episode of brain trauma or after a latent period that may range from days to
weeks to months and years, up to 40 years following a documented episode of brain trauma or
cessation of repetitive TBI [1, 42, 43]. In 1969, The Royal College of Physicians of London
reported that the prevalence of traumatic encephalopathy in ex-professional boxers was 47%
in ex-boxers aged 50 years and over who boxed for more than 10 years. This prevalence rate
dropped to 17% for older professional ex-boxers of the same age who boxed for 6–9 years,
and 13% for those who boxed for less than 5 years. For younger retired professional boxers
30–49 years of age, the prevalence rates for the same durations of professional boxing were
25, 14, and 3% respectively [44, 45]. These reported prevalence rates across
older and younger age groups of retired professional boxers suggest a positive correlation and
association between duration of exposure to repetitive blows to the head and the risk of
developing CTE. These rates also suggest that the prevalence rates of CTE increase with age,
indicating that CTE progresses and advances with age.
In a magnetic resonance imaging (MRI)-based series of professional boxers and
mixed martial arts fighters with a mean age of 27.3 years and a 5.1-year mean of participation
in combat sports, 76% had at least one finding that will be associated with TBI [46]. In a
postmortem series of contact sport athletes, 71% exhibited CTE neuropathologic changes [1].
In another postmortem series of individuals with a history of repetitive mild TBI, 80%
showed CTE neuropathologic changes [8].
CTE symptoms are progressive and multidomain, primarily comprising mood
disorders, behavioral impairment, and cognitive impairment, with or without incapacitating
somatic and physical symptoms including motor dysfunction [1, 20]. The symptom severity
and brain pathology burden of CTE progress and advance with increasing age, and the
neuropathology of end-stage or advanced CTE, especially in the elderly, may resemble and be
indistinct from high AD neuropathologic change [1, 8–10, 47]. Table 2 enumerates the
symptoms and signs of CTE. There is no established and generally accepted threshold for
CTE. Likewise, there are no established and generally accepted risk factors outside the
fundamental risk factor and underlying causal factor, which is exposure to mild, moderate,
and/or severe TBI. Apolipoprotein E-ε4 allele is a risk factor for AD and adverse outcomes
following TBI, and has been suggested to be a risk factor for CTE; however, this risk
quantification for CTE remains to be confirmed across populations [20, 47].
As expected for every disease model, the clinical presentation and symptoms of CTE
exhibit broad variations across CTE sufferers. Several pathologic and clinical grading criteria
and schemes have been proposed for CTE, but these classifications have not been widely
accepted and applied [1, 8, 20].

Chronic Traumatic EncephalopathyNeuropathologic Changes.

The brain of a CTE sufferer may appear grossly unremarkable without any focal or
lobar necrosis, infarct, acute and chronic hemorrhage, or significant cortical atrophy (fig. 2).
Conventional computerized tomography and MRI studies of the brain may appear within
normal limits. Marked symmetrical dilatation of all ventricles (hydrocephalus ex vacuo) is
typically absent as well as any marked atrophy of the subcortical ganglia. The centrum
semiovale does not show any focal gross white matter necrosis or demyelination. However,
typical CTE neuropathologic changes in elderly patients can be accompanied by the
neuropathologic changes of normal aging and other neurodegenerative diseases including AD,
frontotemporal lobar degeneration, Lewy body disease, vascular cognitive impairment, and
cerebrovascular disease [1, 8].
Histologically, the neocortex may show minimal-to-mild neuronal loss and isomorphic
astrogliosis. The centrum semiovale, subcortical white matter and spinal anterior, lateral and
posterior funiculi may show mild patchy-to-diffuse rarefaction, with mild diffuse isomorphic
fibrillary astrogliosis. There is mild diffuse activation of the white matter microglia with
mildly increased numbers of neuropil histiocytes, which may be accentuated perivascularly.
There are increased numbers of pigmentladen histiocytes in the Virchow-Robin spaces, which
may be accompanied by sparse lymphocytic seeding. These neuropathologic changes are
located in a diffuse manner involving all regions of the brain including the brainstem. The
subcortical ganglia, midbrain, pontine and medullary nuclei, and spinal anterior and posterior
horn neurons may also show minimal-to-mild neuronal loss. Hippocampal sclerosis or marked
loss of pyramidal neurons in the stratum pyramidalis of the hippocampus is typically absent.
Essentially, routine hematoxylin and eosin-stained brain sections of the brain
of a CTE sufferer may appear unremarkable with negligible pathologic changes.
Immunohistochemical analysis of the brain with a battery of proteomic antibodies is required
for the diagnosis of CTE [1, 8].
- 7 -Fig. 1. a Gross photograph of a coronal section of the brain of a deceased football
player with CTE.
The brain appears grossly unremarkable without any significant cortical or subcortical
atrophy.Fig. 1. b Photomicrograph of a tau-immunostained section of a brainstem nucleus
from the brain of a deceased NFL player with CTE showing frequent NFTs and NTs. ×100
magnification.The primary proteinopathy of CTE is tauopathy manifested by the presence of
neurofibrillary tangles (NFTs) and neuropil or neuritic threads (NTs) in all regions of the
brain (fig. 1). Neuronal NFTs in CTE may be accompanied by astrocytic NFTs and plaques.
The density of the neuronal NFTs may be sparse, moderate, or frequent in all regions of the
brain, and may exhibit a distinctive skip phenomenon in the neocortex, whereby NFTs are
haphazardly located, being present and absent in adjacent regions of the neocortex within the
same lobe of the brain. Other topographic distributions of NFTs may include perivascular
density accentuation and accentuation in the depths of the sulci. Subpial and periventricular
tangles may also be present. The neocortical NFTs are more superficially located, found
predominantly in laminae II and III. Topographic accentuation of tangle densities may also be
observed in the amygdala, tegmental brainstem nuclei and hypothalamus [1, 8].
Secondary amyloidopathy may accompany the primary tauopathy of CTE in about 20–
30% of cases, but is not a prerequisite or defining proteinopathy of CTE. Diffuse and neuritic
amyloid plaques may be present, but diffuse amyloid plaques are more frequently
encountered. Fully developed AD pathology with frequent neuritic amyloid plaques is more
likely in older and elderly patients who suffer from CTE. With advancing age, advanced or
end-stage CTE may progress and become fully developed AD neuropathologically, especially
in elderly patients. Such a disease model is similar to that of cirrhosis of the liver, which is the
end-stage outcome of many progressive chronic liver diseases. The underlying causes of endstage cirrhosis of the liver may not be distinguishable histologically when cirrhosis is attained.
Likewise, CTE-related end-stage AD neuropathology in a patient may not be distinguishable
from nonCTE-related end-stage AD neuropathology [1, 8].
Cerebral amyloid angiopathy may also accompany CTE changes. Other secondary
proteinopathies, which may accompany tauopathy in CTE may include TDP-43 proteinopathy
and α-synucleinopathy. Secondary α-synucleinopathy is found in a minority of CTE sufferers
- 8 -(about 20%) and is more likely to be found in older and elderly patients, but is not a
prerequisite or defining proteinopathy of CTE.
CTE is not Parkinson’s disease. In CTE, the nigral neurons are damaged by NFTs and
NTs (tauopathy), while in PD the nigral neurons are damaged by Lewy bodies (α-
synucleinopathy) [1, 8].
Secondary TDP-43 proteinopathy, in the form of neuronal, glial, and neuritic
inclusions, is not a prominent feature of CTE and is not a prerequisite proteinopathy for CTE
diagnosis. However, in a minority of CTE sufferers, especially those with prominent clinical
symptoms of motor neuron disease (muscle weakness, atrophy, fasciculations, and muscle
pain), TDP-43 proteinopathy may become very widespread and prominent in the brain and
spinal cord. In such cases, a primary diagnosis of frontotemporal lobar degeneration-TDP or
motor neuron disease may be made, and CTE, if present, will be made as a secondary
diagnosis [1, 8, 10, 48]. When CTE neuropathology occurs with those of other
neurodegenerative diseases in the same brain, the standard of practice for diagnosis is to
enumerate all neurodegenerative disease entities whose distinctive neuropathologies are
present [10].General ConclusionThe past decade has seen a marked rise in scientific research on the long-term effects
of RHI and the development of CTE, yet there remain many knowledge gaps that limit
understanding of this disease. Although there is overwhelming evidence that CTE affects
some professional football players, the risk for CTE in amateur contact sport athletes at the
high school and collegiate levels remains to be determined. Larger, prospective studies are
needed to address CTE risk for the general population and military veterans to define the
parameters of RHI (repetitive head impacts) exposure, gender and genetics that influence
susceptibility.
Furthermore, prospective studies are needed to precisely define the clinical
manifestations of the disease and the role of factors such as cognitive reserve, lifestyle choice,
and comorbid medical conditions in the clinical expression of the disease. In vivo biomarkers
to facilitate the clinical diagnosis of CTE and monitor potential therapies are urgently needed.
Given the millions of people involved in contact sports, as well as military personnel who
experience RHI, CTE is clearly a public health concern.
Although there is intense public pressure to address these concerns immediately and
reduce the dangers of contact sports among amateur and professional athletes as well as to
protect and improve care for military veterans, these solutions will require large-scale,
longitudinal prospective studies as well as diligence and patience.