News
Understanding the Cause of Chronic Traumatic Encephalopathy and Related
Dementias
Maryam Rezaeezadeh Roukerd1,2, Amanda Stump3, Gregory W.J. Hawryluk1,4,5
Traumatic brain injury (TBI) has been long believed to portend an
increased risk for Alzheimer disease. Of great interest, recent
evidence suggests that victims of spinal cord injury (SCI) are also
at risk for delayed dementia, which is not accounted for by
concomitant head injuries.1 The relationship between delayed
Alzheimer disease, dementia pugilistica, chronic traumatic
encephalopathy, and the dementia that can follow SCI is
unclear. It is possible that these dementias that can follow
central nervous system (CNS) injuries may result from the same
or overlapping cellular pathomechanisms.
A very important step forward has been the recognition that the
Alzheimer disease label has been falsely applied to many victims
of dementia after CNS trauma. The histopathology of these de-
mentias is distinct, and the Alzheimer disease label has implied a
false sense of understanding that has likely impeded progress and
curiosity related to this condition.2 Unfortunately, few theories
regarding the etiology of the dementias that follow CNS trauma
have been advanced. We discuss some here, with focus on the
theory we are studying.
CUMULATIVE EFFECTS ON ONGOING SECONDARY INJURY
Secondary injury is now accepted to cause delayed injury to the
CNS long after the initial CNS insult has occurred. Secondary
injury involves complex and highly interrelated cellular and mo-
lecular processes—and frequently positive feedback loops—that
cause further damage to the CNS perhaps for the lifetime of the
individual. There are numerous described secondary injury
mechanisms such as neuroinflammation, mitochondrial dysfunc-
tion, excitotoxicity, cytoskeletal degradation, free radical genera-
tion and lipid peroxidation, ionic dysregulation, and programmed
cell death. It is possible that dementia simply results from
generalized degeneration of the brain as a result of a combination
of these processes. Recent evidence suggests that a combination
of neuroinflammation and excitotoxicity—termed immunoexci-
totoxicity—may contribute to the development of chronic trau-
matic encephalopathy.3
NORMAL AGING IN THE CONTEXT OF DIMINISHED CEREBRAL
RESERVE
The dementia that follows CNS trauma may simply reflect the
degeneration inherent to aging in the context of diminished ce-
rebral reserve resulting from an earlier head trauma. This latter
theory can be likened to post-polio syndrome. It is our view that
this phenomenon likely contributes to the development of delayed
dementia after CNS injury at least in part. The recent observation
of dementia in victims of SCI that is not explained by concomitant
head injury1 is at odds with this theory, however.
192 www.SCIENCEDIRECT.com WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2020.09.120
AMYLOID OVERPRODUCTION AND DEPOSITION
Increased levels of amyloid are seen in the brain following TBI,
and deposition of amyloid plaques is seen after TBI even in
younger patients. This has been a key contributor to the histori-
cally assumed linkage between TBI and Alzheimer disease. Amy-
loid has long been investigated for a possible causative role in the
process of dementia. Studies have found that b-amyloid has
proinflammatory properties and an ability to activate astrocytes. In
turn, this neuroinflammation incites the production and deposi-
tion of b-amyloid protein, which forms a positive feedback loop.4
b-amyloideinduced neuroinflammation has been associated with
neuronal loss and is thus another potential mechanism that could
lead to dementia after CNS injury.
PERSISTENT NEUROINFLAMMATION AND A POTENTIAL
RELATIONSHIP TO CNS AUTOIMMUNITY
Neuroinflammation is believed to persist for a prolonged period
following CNS injuries—perhaps for the lifetime of the individual.
Although neuroinflammation has many beneficial functions after
CNS trauma, it also can cause further injury through the release of
injurious free radicals and other processes. Marked neuro-
inflammation, including microglial and astroglial activation, has
been described decades after acute CNS injury in humans.5
Research to date has revealed that post-traumatic neuro-
degeneration has a strong association with neuroinflammation,
and it is thus possible that neuroinflammation plays a causative
relationship is the development of dementias following CNS
trauma.
In considering the cause of the chronic neuroinflammation that
follows CNS injury, 2 explanations must be considered. First is the
possibility that there is something self-perpetuating about the
immune response to neurotrauma. Another possibility is that this
prolonged immune response is related to CNS autoimmunity. The
latter possibility is supported by the fact that the CNS is normally
immunoprivileged and following brain or spinal cord injury CNS
antigens are spilled into the systemic circulation.6 Indeed, a Food
and Drug Administrationeapproved blood test for concussion is
based upon this phenomenon. Moreover, the bloodeCNS barrier
is disrupted for approximately 14 days after traumatic injury,7
which additionally exposes CNS antigens to the peripheral
immune system. Although research to date has highlighted
beneficial effects of CNS-directed autoimmunity following neu-
rotrauma, deleterious effects are expected, as inflammation typi-
cally acts as a double-edged sword.
Our group explored this latter theory, largely inspired by the
findings of Alan Faden’s group, who discovered inflammation in
the brains of rats following isolated experimental SCI.8
Additionally inspiring was the induction of neuroinflammation
by the practice of “brain blowing” in slaughterhouse workers
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exposed to aerosolized porcine CNS antigens. Investigation by the
Centers for Disease Control and Prevention and the Mayo Clinic
led to the recognition that the aerosolized antigens were
inducing autoimmunity to the nervous system in a dose-
dependent fashion.
Our preliminary work, which seeks to explore the putative role
of CNS-directed autoimmunity in the dementias that follow CNS
trauma, was published recently in the Journal of Neurosurgery.9 Our
laboratory investigation involved inoculation of experimental
animals with allogeneic spinal cord tissue. This non-traumatic
model of CNS-directed autoimmunity helps to exclude another
self-perpetuating mechanism of neuroinflammation following
CNS trauma. Peripheral inoculation with spinal cord tissue was
associated with production of autoantibodies reactive to CNS an-
tigens as well as neuroinflammation, memory deficits, and
neuronal loss. Our findings support the notion that CNS-directed
autoimmunity is a candidate mechanism for dementia that can
follow CNS injuries, although further study will be required to
confirm this finding and to determine if it is amenable to thera-
peutic intervention.
CNS-directed autoimmunity is an attractive theory for what
causes dementia after CNS trauma, as it would tie together many
findings—and in particular the dementia that follows SCI. This
phenomenon also could explain the recently reported trans-
mission of Alzheimer disease through human growth hormone
extracts.10 Much more research is needed in this field, but it is
interesting to consider the possibility that immunosuppressive
therapy could one day benefit victims of CNS trauma or
perhaps even patients undergoing intra-axial neurosurgical
procedures.

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From the 1University of Manitoba, Winnipeg, Manitoba,
Canada; 2Department of Veterinary Medicine, Section of
Physiology and Pharmacology, Shahid Bahonar University of
Kerman, Kerman, Iran; 3University of Utah, Salt Lake City,
Utah; 4Uniformed Services University, Bethesda, Maryland;
and 5Brain Trauma Foundation, New York, New York, USA
1878-8750/$ - see front matter ª 2020 Elsevier Inc. All
rights reserved.
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