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Understanding CTE – causes and the ‘science’ behind it…

August 16, 2012

Found a few publications this morning as I was trying to understand the depositing of the Tau protein better — in a less clinical way.  There are two articles listed here with excerpts.  Once I got past the ‘technical’ and just tried to understand the ‘big picture’ I found myself understanding CTE a bit better.


Repeated blows to the head — from football tackles, blasts from a circus cannon or some other trauma — put the brain at risk for CTE. Although typically associated with concussions or serious head injuries, brains of football players with CTE but without any concussive history demonstrate that repeated, less severe “subconcussive” injuries provide sufficient trigger for this disease. While individual trauma may produce short-term symptoms, the effects of CTE manifest years after the injuries as the disease progresses and the brain breaks down. Yet many athletes with recurrent head injuries evade CTE; it appears repeated head trauma are necessary, but not sufficient, to trigger CTE. Researchers believe that the nature of the head trauma — and the severity, frequency, and age of the recipient — may play a role in whether or not CTE develops. But, for now, why the disease overtakes some and spares others remains a mystery.

The answer hides somewhere amidst tangled neurons and wasted brain tissue. During autopsy, scientists diagnose CTE through the pattern of brain decay and the buildup of tau protein. Normally, the tau protein stabilizes the brain cell skeleton. In both CTE and Alzheimer’s, two distinct diseases, enzymes cause the protein to release from the skeleton and cluster in cells to form neurofibrillary tangles (NFTs). Researchers remain uncertain about the tangles’ exact effect on the brain, says Dr. Brandon Gavett, a neuropsychologist at the University of Colorado-Colorado Springs. Unlike Alzheimer’s, which is characterized by the even spread of NFTs, in CTE, NFTs cluster around blood vessels and dead tissue. According to Gavett, some researchers hypothesize that damage to blood vessels during head trauma may cause the brain to wither and form NFTs but thus far no mechanism of disease has been proven.

Brain damage associated with CTE triggers crippling psychological effects. Because the disease can only be diagnosed by autopsy, the changes in behavior and mood must be pieced together by interviews with family members after the afflicted person’s death. Family members report that their loved ones exhibited problems with learning, remembering new information, and organization. Judgement and impulse control also frequently gave way to aggressive behavior and problems with addiction. Additionally, those affected by CTE frequently became depressed, agitated, and — in what ultimately takes the lives of many with CTE — suicidal. On top of these emotional changes, difficulty with balance, gait, and speech similar to Parkinson’s disease often accompany CTE.

Despite the wealth of symptoms identified, these psychological factors need to be integrated with genetic susceptibility, chemical analysis of blood and cerebrospinal fluid, and brain imaging in order to accurately diagnose CTE in living patients. Possible chemical markers and genetic predispositions for CTE have been identified from research on Alzheimer’s disease, and pilot studies show promise for diagnostic MRI and MRS scans as brain imaging technology improves. Late last year, Boston University CSTE began a study of NFL players and non-contact athletes to begin integrating these parts and develop methods to diagnose CTE before death. Some knowledge needed for such a diagnosis still evades researchers, but scientific advancement creeps closer to this goal every day.

Full article


Here is another article that somehow made sense to me. If anyone has the ability to talk through this and help me better understand what this all means, please let me know 😉  If you can get past the ‘technical’ and medical terminology there are some fascinating thoughts and findings that don’t make the mainstream news (probably because it is not an easy read).


CTE is a potential late effect of repeated head injuries

CTE is not thought to be a long-term sequela following a specific head trauma. Rather, its clinical symptoms emerge later in life, usually after an athlete retires from his or her sport. Like most other neurodegenerative diseases that cause dementia, CTE has an insidious onset and gradual course. Based on a recent review of neuropathologically-confirmed CTE in athletes [11,] the mean age of onset is 42.8 years (SD = 12.7; range = 25 – 76 years). On average, onset occurs approximately 8 years after retirement (SD = 10.7), although approximately one-third of athletes were reportedly symptomatic at the time of retirement. In athletes, the course appears to be considerably protracted (mean duration = 17.5 years, SD = 12.1), especially in boxers. The average duration of the disease in boxers is 20 years (SD = 11.7) and 6 years in American football players (SD = 2.9) [11.] If the affected individual does not die of other causes, full-blown clinical dementia may occur late in the course of the disease.

Gross Pathology

Neuropathological studies of athletes with a history of repeated mild head injuries have produced a number of consistent findings that, together, make CTE a distinctive disorder. Upon gross examination, there is often anterior cavum septum pellucidum and, usually, posterior fenestrations. These changes may be caused by the force of the head impact being transmitted through the ventricular system, thereby affecting the integrity of the intervening tissue. Enlargement of the lateral and third ventricles is also a common feature seen in CTE; the third ventricle may be disproportionately widened. Additional gross features include atrophy of the frontal and temporal cortices, atrophy of the medial temporal lobe, thinning of the hypothalamic floor, shrinkage of the mammillary bodies, pallor of the substantia nigra, and hippocampal sclerosis. Atrophy of the cerebrum, diencephalon, basal ganglia, brainstem, and cerebellum, may result in an overall reduction in brain mass [11].

Microscopic Neuropathology


Microscopically, CTE is characterized by an abundance of neurofibrillary inclusions, in the form of neurofibrillary tangles (NFTs), neuropil threads (NTs), and glial tangles (GTs). The main protein composing NFTs is the microtubule-associated protein tau, and NFTs are aggregates of filamentous tau polymers. While CTE shares many microscopic similarities with Alzheimer’s disease (AD) and other tauopathies, it has several distinguishing features. First, the distribution of tau pathology is unique; it is most commonly found in the more superficial cortical laminae (II and III), whereas tau NFTs in AD are preferentially distributed in large projection neurons in layers III and V. Further, the regional tau pathology is extremely irregular, largely confined to uneven foci in the frontal, temporal, and insular cortices, unlike the more uniform cortical NFT distribution seen in AD. Tau NFTs, NTs and GTs are found throughout the medial temporal lobe, often in densities greater than those found in severe AD, and are also prominent in the diencephalon, basal ganglia, and brainstem. NTs and GTs are also found in the subcortical white matter. Finally, NFTs in CTE are most dense at the depths of cortical sulci, and are typically perivascular, which might indicate that disruptions of the cerebral microvasculature and the blood brain barrier that occur at the time of the traumatic injury play a critical role in the formation of NFTs [11.]

Although the precise pathological mechanisms that tie repeated mild head injuries to NFT formation are not known, they may involve a series of diffuse axonal injuries (DAI) set in motion by the initial trauma and aggravated by subsequent mild traumatic injuries. During a traumatic brain injury, the brain and spinal cord undergo shear deformation producing a transient elongation or stretch of axons. Traumatic axonal injury results in alterations in axonal membrane permeability, ionic shifts including massive influx of calcium, and release of caspases and calpains that might trigger tau phosphorylation, misfolding, truncation, and aggregation, as well as breakdown of the cytoskeleton with dissolution of microtubules and neurofilaments [15, 18, 19].

There is also increasing evidence that tau phosphorylation, truncation, aggregation, and polymerization into filaments represents a toxic gain of function and continued accumulation of tau leads to neurodegeneration. This is supported by tau’s involvement in some genetic forms of frontotemporal degeneration [20] and by work that shows that plasmids containing human tau cDNA constructs microinjected into lamprey neurons in situ produce tau filaments that accumulate and lead to neuronal degeneration [21, 22.] However, it is also possible that the intracellular NFTs, in and of themselves, are byproducts, rather than the cause, of cellular injury, and that NFT formation indicates neurons that survived the initial injury and sequestered the abnormally phosphorylated, truncated and folded tau [23.] How a neurodegeneration that starts multifocally around small blood vessels or in the depths of cortical sulci ultimately spreads to involve large regions of brain as a systemic degeneration such as CTE may be explained by a possible tau toxic factor or trans-cellular propagation by the misfolded tau protein [24].


Beta-amyloid (Aβ) deposits are found in 40–45% of individuals with CTE; this is in contrast to the extensive Aβ deposits that characterize nearly all cases of AD. While neuritic plaques are typically abundant in AD and are essential to the diagnosis, Aβ plaques in CTE, when they occur, are less dense and predominantly diffuse [11.] Despite the relatively minor role Aβ plaques appear to play in the neuropathological manifestation of CTE, the role of Aβ in the pathogenesis of CTE has yet to be elucidated. It is known that acute head injuries cause an up-regulation of amyloid precursor protein (APP) production, and that Aβ plaques may be found in up to 30% of patients who die within hours following TBI [25, 26, 27.] DAI, often a consequence of mild TBI, is thought to influence changes in Aβ following head injury. Interruption of axonal transport causes an accumulation of multiple proteins in the axon, including APP, in varicosities along the length of the axon or at disconnected axon terminals, termed axonal bulbs [28.] Although the axonal pathology in TBI is diffuse in that it affects widespread regions of the brain, typically the axonal swellings are found in multifocal regions of the subcortical and deep white matter, including the brainstem. Due to the rapid and abundant accumulation of APP in damaged axons after TBI, APP immunostaining is used for the pathological assessment of DAI in humans. Accordingly, this large reservoir of APP in injured axons might be aberrantly cleaved to rapidly form Aβ after TBI [25, 29, 30.] However, it remains unclear whether the large quantities of APP and Aβ found in damaged axons after TBI play any mechanistic role in either neurodegeneration or neuroprotection [28, 31, 32.] Moreover, it is unknown how long the increased APP and Aβ lasts or what mechanisms may result in variable clearance.


Recently, in addition to severe tau neurofibrillary pathology, we found a widespread TDP-43 proteinopathy in over 80% of our cases of CTE [13.] Moreover, in 3 athletes with CTE who developed a progressive motor neuron disease several years prior to death, there were extensive TDP-43 immunoreactive inclusions in the anterior horns of the spinal cord, in addition to tau immunoreactive GT, neurites, and, occasionally, extensive NFTs. These findings suggest that a distinctive, widespread TDP-43 proteinopathy is also associated with CTE and that, in some individuals, the TDP-43 proteinopathy extends to involve the spinal cord and is clinically manifest as motor neuron disease with a presentation that may appear similar to amyotrophic lateral sclerosis [13.] The shared presence of two aggregated phosphorylated proteins associated with neurodegeneration in the great majority of cases of CTE suggests that a common stimulus, such as repetitive axonal injury, provokes the pathological accumulation of both proteins [33.] Recent studies in vitro and in vivo suggest that over-expression of wild-type human TDP-43 and its dislocation from the neuronal nucleus to the cytoplasm are associated with neurodegeneration and cell death [34, 35, 36.] By virtue of its capacity to bind to neurofilament mRNA and stabilize the mRNA transcript, TDP-43 plays a critical role in mediating the response of the neuronal cytoskeleton to axonal injury. TDP-43 is intrinsically prone to aggregation, and its expression is upregulated following experimental axotomy in spinal motor neurons of the mouse [37.] Traumatic axonal injury may also accelerate TDP-43 accumulation, aggregation, and dislocation to the cytoplasm, thereby enhancing its neurotoxicity.

Immunoexcitotoxicity as a possible central mechanism for CTE. He describes a cascade of events that begin with an initial head trauma, which “primes” the microglia for subsequent injuries. When the homeostasis of the brain is disturbed, some of the microglia undergo changes to set them in a partially activated state. When these microglia become fully activated by continued head trauma, they release toxic levels of cytokines, chemokines, immune mediators, and excitotoxins like glutamate, aspartate, and quinolinic acid. These excitotoxins inhibit phosphatases, which results in hyperphosphorylated tau and eventually neurotubule dysfunction and neurofibrillary tangle deposition in particular areas of the brain [10]. There is also an apparent synergy between the proinflammatory cytokines and glutamate receptors that worsen neurodegeneration in injured brain tissue. This combination also increases the reactive oxygen and nitrogen intermediates that interfere with glutamate clearance keeping the injury response high. Priming can also occur from insults to the brain like systemic infections, environmental toxins, and latent viral infections in the brain (cytomegalovirus and herpes simplex virus) [10].The microglia, however, have a dual function allowing them to switch between being neurodestructive and neuroreparative. During acute injury the microglia are responsible for containing the damage with inflammation, cleaning up debris, and repairing the surrounding damaged tissue [10]. However, if the individual experiences a second brain trauma or multiple continuous traumas, the microglia may never have the chance to switch from proinflammatory to reparative mode [10]. Such repetitive trauma may place the brain in a state of continuous hyperreactivity leading to progressive and prolonged neuronal injury. This would support the evidence that repeated mTBI results in a higher incidence of prolonged neurological damage than single-event injury [10].

Full publication


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