The development of chronic traumatic encephalopathy (CTE) as a consequence of repeated, minor impact head injury has only recently been described. Although the final pathological manifestation closely resembles that of sporadic Alzheimer's disease, there are some differences, especially the predominance of tau pathology over amyloid accumulation in affected regions of the brain. Anatomical differences in the distribution of pathology are explained by the diffuse nature of traumatic brain injury (TBI) vs a spontaneous development as with Alzheimer's dementia.
A central mechanism responsible for this pathological and clinical picture has not been forthcoming, but in this paper, we present a central mechanism that may explain most of the features of the disorder, especially the pathogenesis of hyperphosphorylated tau proteins.
The interaction between glutamate receptors and specific cytokine receptors has been shown to result in a hyper-reactive response of the microglia that was primed by the initial traumatic head injury or other events. The microglia, which are derived embryologically from macrophage/monocytes, constitute the main cells of the brain's innate immune system. With disturbances of brain homeostasis, some of the microglia undergo a partial activation state in which the mRNAs needed for generating potentially destructive elements are activated, but without an increase in the neuroactive proteins actually involved in neurodegeneration. That is, they are on alert, but not fully active. When previously primed microglia are activated to a fully activated state, they pour out very high levels of neurodestructive elements, far beyond initially activated, unprimed microglia. Priming can occur not only from the initial impact, but also from systemic infections, certain toxic environmental exposures (including mercury, pesticide/herbicides), and latent virus infections within the brain. The latter may include cytomegalovirus and herpes simplex viruses.
Once primed, subsequent injuries can result in a hyperactive response of the microglia, resulting in a several fold higher release of immune cytokines, chemokines, and other immune mediators, as well as a massive release of the excitotoxins—glutamate, aspartate, and quniolinic acid. Crosstalk between proinflammatory cytokines and glutamate receptors accelerate and worsen neurodegeneration in the affected areas of the traumatized brain, a process the lead author named immunoexcitotoxicity. The frontal lobes, hippocampus, and parietal lobes show the greatest sensitivity to trauma-induced immunoexcitotoxicity, all areas involved in learning and memory as well as control of behaviors, such as suicidal impulses, depression, and addictions.
Both inflammatory cytokines and excitotoxins can dramatically increase the generation of reactive oxygen and reactive nitrogen intermediates and an array of lipid peroxidation products, both of which interfere with glutamate clearance, thus magnifying immunoexcitotoxicity over a prolonged period. This accounts for the observed high levels of oxidative stress seen with brain injury as well as energy depletion, since immunoexcitotoxicity initiates mitochondrial dysfunction.
We know that microglial cells have various modes of activity—some of which are mainly reparative and some potentially neurodestructive, and that they switch between these various phenotypes during various phases of brain pathology. During the reparative mode, microglia act as phagocytic cells, cleaning up the debris from the injured neurites and secrete neurotropic substances, such as brain-derived neurotropic factor, so as to enhance repair of the damage. Repeated trauma to the brain may prevent the normal microglial switching from a proinflammatory mode to a reparative mode, resulting in chronic microglial immunoexcitotoxic activity and subsequent progressive neurodegeneration. This has been demonstrated in a number of brain pathologies. And, as demonstrated, several studies have shown that high levels of glutamate and quniolinic acid released from both activated microglia and astrocytes can significantly increase the deposition of hyperphosphorylated tau protein resulting in the observed neurofibrillary tangle accumulation seen with CTE.
An integral part of this process is the effects of brain aging on the immunoexcitotoxic process. It is known that as the brain ages, microglia become spontaneously primed. Under nonpathological conditions, these aging microglia are primed in a non-neurodestructive mode. That is, they do not cause progressive brain degeneration. Yet, in the face of systemic infections, environmental toxic exposure, brain trauma, or pre-existing brain pathology, the primed microglia switch to become neurodestructive and may remain so for very prolonged periods. The neuronal destruction seen with subsequent activation of primed microglia in the aged brain is much more intense and prolonged than in the younger brain. This explains the progressive nature of CTE and why it seems to worsen as the person ages.
This priming and switching process intrinsic to microglia is highly dependent on a number of conditions, including status of brain antioxidant defenses, general health of the individual, presence of systemic inflammation, exposure to neurotoxic environmental elements, and genetic-related susceptibility to immunoexcitotoxicity. This explains why not all athletes are affected and provides a simple mechanism to explain the ongoing pathology being observed in the smaller number subjected to repeated minor head injuries. Also, of importance would be the efficiency of glutamate removal systems, glutathione levels, and dietary habits of the person. All of these factors help explain the observed differences in vulnerability.
Taken together, there is convincing evidence that TBI, especially repetitive injury, initiates the activation of innate brain immunity, which leads to transient immunoexcitotoxicity. Under normal conditions, this rapidly reverses as microglia assume a reparative phenotype. Preexisting brain pathology, even occult, or previous priming of microglia places the injured brain in a state of extended hyper-reactivity, which can lead to a prolonged cascade of immunoexcitotoxic events, eventually culminating in progressive neurodegeneration. As the brain ages, it becomes more vulnerable for a number of reasons, including progressive microglial activation and priming, attenuation of mitochondrial function, higher levels of inflammation, neuronal and glial dystrophy, reduced brain magnesium, periodic infections, and a lifetime of exposure to a number of environmental toxins and events. Compelling evidence suggest that immunoexcitotoxicity can lead to hyperphosphorylation of tau, increase the generation of neurotoxic levels of Aß oligomers, suppression of mitochondrial migration to the synapse as well as depress mitochondrial function, an increase in the generation of reactive oxygen species/reactive nitrogen species and lipid peroxidation products, all of which lead to synaptic and dendritic loss, pathophysiological events commonly seen in CTE.
With better methods of activated microglial scanning, we may be better able to demonstrate the dynamics of this process and design ways to reduce destructive microglial activation, neuroinflammation and immunoexcitotoxicity reactions without interfering with normal brain function, as has been the problem with previous studies using glutamate blockers. It may also be possible to promote switching of the microglia to a reparative phenotype.