Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013 (Naghavi et al., 2015). Injuries accounted for 9% of the world’s deaths in 2000 and 12% of the world’s burden of disease and will surpass many diseases as a major cause of death and disability by the year 2020 (Hyder et al., 2007). At present, the drain on economic resources in America stands at approximately 77 billion US dollars (Coronado et al., 2012). Traumatic brain injury (TBI) may be defined as ‘an alteration in brain function and consciousness which results in impaired cognitive and physical functioning caused by an external force’. The Glasgow Coma Scale (GCS), the most commonly used system for classifying TBI severity, grades a person’s level of consciousness on a scale of 3–15 based on verbal, motor, and eye opening reactions to stimuli. Brain injuries can be classified into mild, moderate, and severe categories. In general, it is agreed that a TBI with a GCS of 13 or higher is mild, 9–12 is moderate, and 8 or lower is severe (Flierl et al., 2009). Further, TBI can be classified as focal or diffuse type. Focal TBI occurs in localized area and causes damage to the underlying brain tissues and vessels, producing skull fractures or hematomas. Extradural and subdural hematomas are commonly seen after TBI, as are hematomas within the brain parenchyma. Focal injuries of this type usually occur in the orbitofrontal, temporal polar, and occipital regions. However, diffuse TBI is widespread throughout the brain. Diffuse TBI mainly involves axonal injury, also called diffuse axonal injury (DAI), brain swelling, and hypoxia. In addition to immediate complications, even managed at the time, TBI involves a complex and chronic disease process with short- as well as long-term consequences, including an increased risk for patients to develop neurodegenerative disorders such as Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS) in later stages of life.
TBI: a chronic disease process
Brain injury leads to tissue deformation at the time of injury, damages blood vessels, shears axons, and produces cellular damage (Prins et al., 2013). TBI initiates a process that induces molecular, biochemical, and cellular changes, which in turn contribute to ongoing neuronal damage and death over time. This continuing damage is known as secondary injury and triggered multiple and multidirectional events, including, but not limited to, excitotoxicity oxidative stress, apoptosis, inflammation edema, cerebral metabolic, and mitochondrial dysfunction (MacFarlane and Glenn, 2015), as shown in Figure 1. These secondary events presented after TBI leads to the other, and the result is greater damage than the initial insult (Gupta and Kanungo, 2013; Gupta and Prasad, 2014, 2015).
Secondary mechanisms associated with TBI
The initial surge of glutamate at the time of injury leads to excitotoxicity that involves the activation of complex biochemical and cellular pathways that produce prolonged depolarization of neurons by activating N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors, leading to the influx of calcium and other ions into the cell (Luo et al., 2011; Gupta and Prasad, 2013). Swelling occurs because of the osmotic shift of water, and strident sodium ion influx depolarizes the neuronal membrane, which leads to the development of cytotoxic edema. Aquaporin 4 (AQP4) is known to predominantly contribute to cytotoxic edema. TBI stimulates nuclear translocation of several transcriptional factors, including Foxo3a in astrocytes, and subsequently augments their binding to AQP4 promoter in pericontusional cortex. The nuclear accumulation of Foxo3a is augmented by a decrease in phosphorylation at its Ser256 residue because of the inactivation of Akt after TBI. The depletion of Foxo3a in mice rescues cytotoxic edema by preventing the induction of AQP4 and attenuates memory impairment after TBI in mice (Kapoor et al., 2013).
The increased calcium influx leads to the activation of several cellular pathways, including the calcium-dependent enzymes nitric oxide synthases (NOS) and phospholipases, which cause the production of free nitrogen radicals and reactive oxygen species (ROS); this leads to further excitotoxic damage (Xiong et al., 2001). The mechanisms of secondary injury after TBI also include an inflammatory response. The immediate response of the brain to an insult is characterized by the activation of microglia in the brain parenchyma (Hinson et al., 2015), accompanied by the infiltration of activated leucocytes from the periphery (Lee et al., 2014) through a disrupted blood-brain barrier (BBB) or transendothelial migration and diapedesis. The inflammatory response in the brain after TBI is dependent on the increased release of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and IL-6 and an increased expression of adhesion molecules such as intercellular adhesion molecule-1 (Hang et al., 2005). Further, ROS are highly reactive molecules implicated in the pathology of TBI through a mechanism known as oxidative stress (Rodriguez-Rodriguez et al., 2014). There are two main families of free radicals: ROS and reactive nitrogen species. The production of O2- is a consequence of normal metabolism, and this species is a precursor to hydrogen peroxide (H2O2), which can generate hydroxyl radicals (·OH) via the Fenton reaction. The ·OH is one of the most reactive chemical species. The reaction of O2- with nitric oxide (NO·) produces peroxynitrite (ONOO-). After brain injury, the levels of ROS production overwhelm scavenging systems and result in oxidative damage (Slemmer et al., 2008). Moreover, TBI-induced intracellular Ca2+ accumulation can activate numerous enzymes, including xanthine dehydrogenase, phospholipase A2, and NOS, which increase O2- and NO· production (Shohami et al., 1997), which can cause widespread oxidative damage because of their ability to induce pathological changes in lipids, proteins, DNA, membrane structures, and mitochondria (Massaad and Klann, 2011). The ROS-induced lipid peroxidation of the cell membranes results in membrane disintegration and increased microvascular permeability (Cristofori et al., 2001).
In addition, ROS can promote inner mitochondrial membrane permeability that forces the rupture of the outer membrane and the release of cytochrome c through the mitochondrial permeability transition. The intracellular cytochrome c then causes the formation of the ‘apoptosome complex’ (Apaf-1, dATP, and caspase-9), which in turn activates a family of cysteine proteases known as caspases3 (Cheng et al., 2012). Caspases play a crucial role in mediating apoptosis, probably by cleaving multiple cellular proteins ultimately causing cell death. Alternatively, a caspase-activating complex is initiated by the binding of ‘death factors’ such as Fas ligand to cell surface receptors belonging to the TNF/nerve growth factor receptor super family (Qiu et al., 2002). Akt, a well-known prosurvival protein, promotes survival and growth in response to activation by extracellular signals. However, TBI induces the expression of GADD34 by stimulating the binding of a stress-inducible transcription factor, ATF4, to the GADD34 promoter. GADD34 then binds with TRAF6 and prevents its interaction with Akt. This event leads to the retention of Akt in the cytosol and prevents phosphorylation at the T308 position and, thus, ceases Akt activation (Farook et al., 2013). However, neuronal death is heterogeneous and exhibits morphological characteristics that may represent a continuum between necrosis and apoptosis (Elmore, 2007). It is now clear that after TBI, both apoptosis and necrosis are observed, affecting astrocytes and oligodendroglial cells as well as neurons (Raghupathi, 2004). However, detailed mechanism about molecular responses after TBI is far from clear, and more research for step-by-step proceedings after TBI may help to develop future interventions to reduce secondary injury.
TBI: a risk factor for neurodegenerative diseases
Research from past decade has drawn much attention of the long-term pathological consequences of TBI. The varying degree of injury is associated with the progressive atrophy of gray and white matter structures that may persist months to years after injury. In addition, several reports link single or repetitive injury with AD, CTE, and ALS, which results in the gradual degeneration of brain cells and gradual loss of brain functions.
TBI and AD
AD is a progressive, neurodegenerative disease characterized by deteriorating cognitive abilities, dementia, and memory loss (Bettcher and Kramer, 2014). Cognitive deficits that can follow TBI include impaired attention; disrupted insight, judgment, and thought; reduced processing speed; distractibility; and deficits in executive functions such as abstract reasoning, planning, problem solving, and multitasking (Tsaousides and Gordon, 2009). Memory loss, the most common and devastating cognitive impairment among TBI patients, occurs in 20%–79% of people with closed head injury, depending on severity (Hall et al., 2005). Evidences from humans (DeKosky et al., 2007) and experimental animal models (Yoshiyama et al., 2005) have revealed abnormal accumulations of extracellular senile plaques and intracellular neurofibrillary tangles (NFTs).
Underlying mechanisms for TBI-induced formation of NFTs and Aβ plaques
Senile plaques are formed of aggregates of amyloid beta (Aβ) peptides, whereas NFTs are composed of bundles of paired helical filaments, which are made up of aberrantly phosphorylated tau microtubule-associated proteins. A recent study has shown that long-term survivors of just a single moderate-to-severe TBI exhibited abundant and widely distributed NFTs and Aβ plaques in approximately one-third of the cases, but this was exceptionally rare in uninjured controls (Johnson et al., 2012). Surprisingly, the plaques found in TBI patients are strikingly similar to those observed in the early stages of AD (Ikonomovic et al., 2004). Such findings demonstrate the long-term consequences of a single TBI event (Jordan, 2014).
Moreover, secondary neuronal injury in chronic neurodegenerative diseases or acute brain injury is mainly mediated by neuroinflammatory responses (Chen et al., 2014). The early phase of microglial activation in response to brain injury is accompanied by increased levels of IL-10 and TGF-β, which are generally regarded as anti-inflammatory cytokines that are capable of mediating neural protection and regeneration. Anti-inflammatory microglia with phagocytic properties have the potential to clear Aβ species and β-amyloid plaques; remarkably, Aβ-containing microglia have been found in association with plaques after TBI (Breunig et al., 2013). Glial activation results in the upregulation of APP as well as other inflammatory mediators that contribute to a cycle of Aβ deposition and microglial activation, which ultimately result in chronic neuropathology. Postcontusion axonal injury and impaired axonal transport are being speculated as a trigger that initiates a disease process and responsible for long-term symptoms (Johnson et al., 2013).
Axonal swelling observed after TBI has been ascribed to cytoskeletal alteration and interruption of protein transport (Tang-Schomer et al., 2012). TBI also induces α-synuclein, APP, BACE1, tau, ApoE4, PS1, and caspase-3, which in turn may involve in APP processing contributing to AD (Breunig et al., 2013). Moreover, studies in various animal models indicate that the expression of amyloidogenic β- and γ-secretases and their substrate APP is increased after TBI, suggesting that Aβ peptides are generated de novo after TBI (Chow et al., 2010; Haass et al., 2012). Interestingly, recent studies have shown that the intracerebral infusion of brain extracts containing aggregated Aβ can initiate Aβ deposition in brains of APP transgenic mice (Bolmont et al., 2007; Rosen et al., 2012). In addition, these Aβ peptides can spread from the site of injection to other brain regions as these Aβ accumulations can migrate between axonally interconnected areas (Jucker and Walker, 2011). Thus, amyloid pathology, spreading from the site of the TBI to other areas, potentially suggests a mechanism for the secondary injury to the areas that were not directly subjected to the TBI but show AD-type pathological lesions.
After TBI, hypoxia and hypertension are common (Frugier et al., 2010; Huang et al., 2010). Hypoxia facilitates the pathogenesis of AD by accelerating the accumulation of Aβ and by increasing the hyperphosphorylation of tau, leading to the chronic process of neurodegeneration (Zhang and Le, 2010). Hypoxia markedly increases Aβ deposition and potentiates memory deficits in AD (Sun et al., 2006). Accumulating evidences show that stroke and ischemic attacks significantly increase the risk of AD because of the drive in cerebral Aβ accumulation and related to apoptotic events in the brain (Wen et al., 2004; Tesco et al., 2007).
TBI also affects the ubiquitin-proteasome system as a significant reduction in the level of free ubiquitin protein is reported after TBI (Staal et al., 2009). In the ubiquitin-proteasome pathway (UPP), abnormal proteins to be degraded are first conjugated by polyubiquitin chains and then degraded by proteasomes (Lecker et al., 2006). The UPP has been linked to several neurodegenerative diseases (Schwartz and Ciechanover, 1999). Recent reports suggest the link between the dysregulation of the ubiquitin-protease system and an accumulation of Aβ levels in TBI (Magnoni and Brody, 2010); however, our understanding about involvement of these processes is far from clear.
TBI and CTE
Symptoms associated with CTE
Also called dementia pugilistica, CTE primarily affects individuals with a history of repetitive closed head injury, most often occurring to career boxers (Corsellis, 1989). Although CTE is a manifestation of repetitive trauma, few reports suggest that single TBI is sufficient to induce CTE (Blaylock and Maroon, 2011). However, this theory needs more speculations to go strong. In general, CTE leads to cognitive, behavioral, and physical impairments and has recently been linked to other contact sports, including American football and ice hockey as well as military service (McKee and Robinson, 2014). The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss, and heightened suicidality (Stein et al., 2014). The symptoms progress slowly over decades to include cognitive deficits and dementia.
CTE contributes to tauopathy and neurological diseases associated with protein aggregation
Repeated traumatic injury, even with mild impact, can damage axons and cause changes in membrane permeability and ionic shifts, leading to the large influx of calcium (Giza and Hovda, 2001). The subsequent release of caspases and calpains would trigger tau phosphorylation, misfolding, shortening, and aggregation as well as cytoskeleton failure with the dissolution of neurofilaments and microtubules. Head injury in the acute setting activates microglia that release toxic levels of cytokines, chemokines, immune mediators, and excitotoxins such as glutamate, aspartate, and quinolinic acid. These excitotoxins inhibit phosphatases, which results in hyperphosphorylated tau and eventually neurotubule dysfunction and NFT deposition in particular areas of the brain (Saulle and Greenwald, 2012). Moreover, the pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes. CTE is distinguished from other neurodegenerative disorders by a distinctive topographic and cellular pattern of tau neurofibrillary pathology. The hyperphosphorylated tau abnormalities begin focally as perivascular NFTs and neurites at the depths of the cerebral sulci and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon, and brainstem (McKee et al., 2009). CTE has been categorized into stages I–IV based on the increased severity of protein deposition, cerebral atrophy, and behavioral sequel (McKee et al., 2013), as shown in Table 1. Compared with AD, the size of individual NFTs in CTE is generally larger, and the neurites are less threadlike and more dotlike and spindle shaped. The tendency of the phosphorylated tau (p-tau) neurofibrillary pathology in CTE to be around BBB and irregularly concentrated at the sulcal depths was also noticed (Blaylock and Maroon, 2011).
β-Amyloid aggregates are only found in 40%–50% of CTE cases, are significantly associated with age at death, and are not a characteristic of early CTE. In CTE, β-amyloid is found predominantly as diffuse plaques in low densities (McKee et al., 2009). α-Synuclein-positive Lewy bodies are found in approximately 20% of CTE cases and are significantly associated with the age of the subject at death (Uryu et al., 2007). Further, McKee et al. (2010) have found widespread TAR DNA-binding protein (TDP-43) inclusions in 10 of 12 cases of CTE. In early stages, the inclusions consist of neuritic threads and dotlike inclusions typically found in subpial, perivascular, and periventricular regions. The TDP-43 inclusions in CTE partially colocalize with p-tau inclusions in neurons. TDP-43 binds to many cellular transcripts, including tau and α-synuclein, and its dysregulation may underlie some of the pathologies seen with these proteins (McKee et al., 2010). However, much research is needed to understand the role of TDP-43 in pathology of CTE.
TBI and ALS
ALS, often referred to as Lou Gehrig disease or Charcot disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. ALS is the most common motor neuron disease affecting approximately 0.8–8.5 people per 100 000 worldwide (Roman, 1996). The disorder causes muscle weakness and atrophy throughout the body because of the degeneration of the upper and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and the muscles responsible for eye movement are usually spared until the final stages of the disorder (Kiernan et al., 2011). Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing, sight, touch, smell, and taste. Cognitive function is generally spared for most people, although some (approximately 5%) may develop frontotemporal dementia (Achi and Rudnicki, 2012). A higher proportion of people (30%–50%) also have more subtle cognitive changes, which may be unnoticed but are revealed by detailed neuropsychological testing. ALS coexists in individuals who also experience dementia, degenerative muscle disorder, and degenerative bone disorder as part of a syndrome called multisystem proteinopathy.
Risk factors associated with TBI-induced ALS
Many risk factors have been considered as possible triggers of the neurodegenerative sequel in ALS, including a history of trauma to the brain and spinal cord (Chen et al., 2007). It is shown that initial lesions to the motor cortex may be a contributing initiating factor in some patients with ALS or determine the site of onset in individuals predisposed to ALS (Rosenbohm et al., 2014). Further, epidemiological research has identified an increased risk of ALS in individuals likely to suffer head trauma, such as football players, soccer players, and military veterans (Chio et al., 2005). Recent literature points toward a trend between brain trauma and ALS development. Case studies of patients suffering traumatic axonopathy to the lower motor neurons are vulnerable to later developed ALS (Riggs, 1985). Riggs has proposed several hypothetical mechanisms that could explain traumatic axonopathy, increasing the risk of ALS. Recently, it was shown that some professional athletes (football and boxing) who have had repeated head injuries and developed what is called CTE may develop ALS (McKee et al., 2010). This study, based on the examination of the brain and spinal cord at autopsy, indicated that some pathological features of CTE in the brain can extend to the spinal cord. The author suggested that traumatic axonal injury may induce caspase death cascade, impaired axonal transport, impairment of retrograde transport, and separation of the axon from its target (Riggs, 1993). Further, lower motor neurons in ALS show axonal swelling and protein aggregates relatively early in disease progression.
The accumulation of neurofilaments and the disruption of retrograde transport may suggest a potential mechanisms initiating ALS. Moreover, it is estimated that 90%–95% of ALS cases are sporadic, and gene mutations in copper/zinc superoxide dismutase 1, senataxin, and dynactin account for some familial forms of the disease (Shi et al., 2010). In addition, motor neurons in sporadic ALS often have ubiquitin- and TDP-43-immunoreactive inclusion bodies that appear either as rounded hyaline inclusions or as skein like inclusions (Leigh et al., 1991; Nonaka et al., 2009). It was also suggested that people with a genetic predisposition to neurotrophin deficiency may show increased vulnerability of motor neurons after trauma and consequently increased risk of ALS (Riggs, 1995).
Many studies support the hypothesis that the survivors of TBI have a major risk of developing neurodegenerative diseases; however, it is a complex issue and requires extensive investigation for a better understanding. Axonal damage and impaired axonal transport due to TBI can induce both rapid and long-term accumulation of several key axonal proteins, including APP, α-synuclein, p-tau, TDP-43, and related peptides that normally do not encounter such high concentration in axons. This serves as a platform for increased processing and accumulation of Aβ plaques, NFTs, or other bodies/inclusions in brain. Persistent accumulation of such malfunctioning peptides in axons due to impaired transport after TBI suggests a continuing pathological process. In addition, very little is known about what type, frequency, or amount of trauma is necessary to induce the accumulation of these pathological proteins. Moreover, there is clearly a need for improved accuracy of clinical diagnostic criteria in the differential diagnosis of TBI-induced neurodegenerative diseases, which need new prospective longitudinal studies on specific biomarkers and also well-standardized criteria to diagnose them neuropathologically. Studies in both experimental models and human TBI patients will be required to identify the key components of the molecular cascades mechanism underlying the observed pathological protein dynamics and elucidate the reasons why TBI increases the risk of neurodegeneration (Johnson et al., 2012).
Bolmont, T., Clavaguera, F., Meyer-Luehmann, M., Herzig, M.C., Radde, R., Staufenbiel, M., Lewis, J., Hutton, M., Tolnay, M., and Jucker, M. (2007). Induction of tau pathology by intracerebral infusion of amyloid-beta-containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am. J. Pathol. 171, 2012–2020.Google Scholar
Chen, Y., Garcia, G.E., Huang, W., and Constantini, S. (2014). The involvement of secondary neuronal damage in the development of neuropsychiatric disorders following brain insults. Front. Neurol. 5, 22.CrossrefGoogle Scholar
Cheng, G., Kong, R.H., Zhang, L.M., and Zhang, J.N. (2012). Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br. J. Pharmacol. 167, 699–719.Google Scholar
Chio, A., Benzi, G., Dossena, M., Mutani, R., and Mora, G. (2005). Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128, 472–476.Google Scholar
Coronado, V.G., McGuire, L.C., Sarmiento, K., Bell, J., Lionbarger, M.R., Jones, C.D., Geller, A.I., Khoury, N., and Xu, L. (2012). Trends in traumatic brain injury in the U.S. and the public health response: 1995–2009. J. Safety Res. 43, 299–307.CrossrefGoogle Scholar
Corsellis, J.A. (1989). Boxing and the brain. Br Med J. 298, 105–109.Google Scholar
Cristofori, L., Tavazzi, B., Gambin, R., Vagnozzi, R., Vivenza, C., Amorini, A.M., Pierro, D. Di., Fazzina, G., and Lazzarino, G. (2001). Early onset of lipid peroxidation after human traumatic brain injury: a fatal limitation for the free radical scavenger pharmacological therapy? J. Investig. Med. 49, 450–458.Google Scholar
DeKosky, S.T., Abrahamson, E.E., Ciallella, J.R., Paljug, W.R., Wisniewski, S.R., Clark, R.S., and Ikonomovic, M.D. (2007). Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch. Neurol. 64, 541–544.CrossrefGoogle Scholar
Farook, J.M., Shields, J., Tawfik, A., Markand, S., Sen, T., Smith, S.B., Brann, D., Dhandapani, K.M., and Sen, N. (2013). GADD34 induces cell death through inactivation of Akt following traumatic brain injury. Cell Death Dis. 4, e754.Google Scholar
Flierl, M.A., Stahel, P.F., Beauchamp, K.M., Morgan, S.J., Smith, W.R., and Shohami, E. (2009). Mouse closed head injury model induced by a weight-drop device. Nat. Protoc. 4, 1328–1337.CrossrefGoogle Scholar
Frugier, T., Morganti-Kossmann, M.C., O’Reilly, D., and McLean, C.A. (2010). In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. J. Neurotrauma 27, 497–507.CrossrefGoogle Scholar
Giza, C.C. and Hovda, D.A. (2001). The neurometabolic cascade of concussion. J. Athl. Train. 36, 228–235.Google Scholar
Gupta, R.K. and Prasad, S. (2013). Early down regulation of the glial Kir4.1 and GLT-1 expression in pericontusional cortex of the old male mice subjected to traumatic brain injury. Biogerontology 14, 531–541.Google Scholar
Gupta, R.K. and Prasad, S. (2014). Differential regulation of GLT-1/EAAT2 gene expression by NF-κB and N-myc in male mouse brain during postnatal development. Neurochem. Res. 39, 150–160.CrossrefGoogle Scholar
Gupta, R.K. and Prasad, S. (2015). Age-dependent alterations in the interactions of NF-κB and N-myc with GLT-1/EAAT2 promoter in the pericontusional cortex of mice subjected to traumatic brain injury. Mol. Neurobiol. doi: 10.1007/s12035-015-9287-y.CrossrefGoogle Scholar
Haass, C., Kaether, C., Thinakaran, G., and Sisodia, S. (2012). Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2, a006270.Google Scholar
Hang, C.H., Shi, J.X., Li, J.S., Wu, W., and Yin, H.X. (2005). Concomitant upregulation of nuclear factor-kB activity, proinflammatory cytokines and ICAM-1 in the injured brain after cortical contusion trauma in a rat model. Neurol. India 53, 312–317.Google Scholar
Hinson, H.E., Rowell, S., and Schreiber, M. (2015). Clinical evidence of inflammation driving secondary brain injury: a systematic review. J. Trauma Acute Care Surg. 78, 184–191.Google Scholar
Huang, R.Q., Cheng, H.L., Zhao, X.D., Dai, W., Zhuang, Z., Wu, Y., Liu, Y., and Shi, J.X. (2010). Preliminary study on the effect of trauma-induced secondary cellular hypoxia in brain injury. Neurosci. Lett. 473, 22–27.Google Scholar
Hyder, A.A., Wunderlich, C.A., Puvanachandra, P., Gururaj, G., and Kobusingye, O.C. (2007). The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 22, 341–353.Google Scholar
Ikonomovic, M.D., Uryu, K., Abrahamson, E.E., Ciallella, J.R., Trojanowski, J.Q., Lee, V.M., Clark, R.S., Marion, D.W., Wisniewski, S.R., and DeKosky, S.T. (2004). Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp. Neurol. 190, 192–203.Google Scholar
Johnson, V.E., Stewart, W., and Smith, D.H. (2012). Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol. 22, 142–149.CrossrefGoogle Scholar
Johnson, V.E., Stewart, W., and Smith, D.H. (2013). Axonal pathology in traumatic brain injury. Exp. Neurol. 246, 35–43.Google Scholar
Jordan, B.D. (2014). Chronic traumatic encephalopathy and other long-term sequelae. Continuum 20, 1588–1604.Google Scholar
Kapoor, S., Kim, S.M., Farook, J.M., Mir, S., Saha, R., and Sen, N. (2013). Foxo3a transcriptionally upregulates AQP4 and induces cerebral edema following traumatic brain injury. J. Neurosci. 33, 17398–17403.Google Scholar
Kiernan, M.C., Vucic, S., Cheah, B.C., Turner, M.R., Eisen, A., Hardiman, O., Burrell, J.R., and Zoing, M.C. (2011). Amyotrophic lateral sclerosis. Lancet 377, 942–955.Google Scholar
Lee, J., Costantini, T.W., D’Mello, R., Eliceiri, B.P., Coimbra R., and Bansal, V. (2014). Altering leukocyte recruitment following traumatic brain injury with ghrelin therapy. J. Trauma Acute Care Surg. 77, 709–715.Google Scholar
Leigh, P.N., Whitwell, H., Garofalo, O., Buller, J., Swash, M., Martin, J.E., Gallo, J.M., Weller, R.O., and Anderton, B.H. (1991). Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 114, 775–788.Google Scholar
Luo, P., Fei, F., Zhang, L., Qu, Y., and Fei, Z. (2011). The role of glutamate receptors in traumatic brain injury: implications for postsynaptic density in pathophysiology. Brain Res. Bull. 85, 313–320.CrossrefGoogle Scholar
Magnoni, S. and Brody, D.L. (2010). New perspectives on amyloid-beta dynamics after acute brain injury: moving between experimental approaches and studies in the human brain. Arch. Neurol. 67, 1068–1073.CrossrefGoogle Scholar
Massaad, C.A. and Klann, E. (2011). Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid. Redox Signal 14, 2013–2054.Google Scholar
McKee, A.C., Cantu, R.C., Nowinski, C.J., Hedley-Whyte, E.T., Gavett, B.E., Budson, A.E., Santini, V.E., Lee, H.S., Kubilus, C.A., and Stern, R.A. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp. Neurol. 68, 709–735.Google Scholar
McKee, A.C., Gavett, B.E., Stern, R.A., Nowinski, C.J., Cantu, R.C., Kowall, N.W., Perl, D.P., Hedley-Whyte, E.T., Price, B., Sullivan, C., et al. (2010). TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69, 918–929.Google Scholar
McKee, A.C., Stern, R.A., Nowinski, C.J., Stein, T.D., Alvarez, V.E., Daneshvar, D.H., Lee, H.S., Wojtowicz, S.M., Hall, G., Baugh, C.M., et al.(2013). The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64.Google Scholar
Naghavi, M., Wang, H., Lozano, R., Davis, A., Liang, X., Zhou, M., Vollset, S.E., Ozgoren, A.A., Abdalla, S., Abd-Allah, F., et al. (2015). Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117–171.Google Scholar
Nonaka, T., Arai, T., Buratti, E., Baralle, F.E., Akiyama, H., and Hasegawa, M. (2009). Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells. FEBS Lett. 583, 394–400.Google Scholar
Prins, M., Greco, T., Alexander, D., and Giza, C.C. (2013). The pathophysiology of traumatic brain injury at a glance. Dis. Model Mech. 6, 1307–1315.Google Scholar
Qiu, J., Whalen, M.J., Lowenstein, P., Fiskum, G., Fahy, B., Darwish, R., Aarabi, B., Yuan, J., and Moskowitz, M.A. (2002). Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J. Neurosci. 22, 3504–3511.Google Scholar
Riggs, J.E. (1993). Antecedent trauma and amyotrophic lateral sclerosis in young adult men. Mil. Med. 158, 55–57.Google Scholar
Roman, G.C. (1996). Neuroepidemiology of amyotrophic lateral sclerosis: clues to aetiology and pathogenesis. J. Neurol. Neurosurg. Psychiatry 61, 131–137.Google Scholar
Rosen, R.F., Fritz, J.J., Dooyema, J., Cintron, A.F., Hamaguchi, T., Lah, J.J., LeVine, H., 3rd, Jucker, M., and Walker, L.C. (2012). Exogenous seeding of cerebral beta-amyloid deposition in betaAPP-transgenic rats. J. Neurochem. 120, 660–666.Google Scholar
Rosenbohm, A., Kassubek, J., Weydt, P., Marroquin, N., Volk, A.E., Kubisch, C., Huppertz, H.J., Weber, M., Andersen, P.M., Weishaupt, J.H., et al. (2014). Can lesions to the motor cortex induce amyotrophic lateral sclerosis? J. Neurol. 261, 283–290.Google Scholar
Saulle, M. and Greenwald, B.D. (2012). Chronic traumatic encephalopathy: a review. Rehabil. Res. Pract. Article ID 816069, 9 pages.Google Scholar
Shi, P., Strom, A.L., Gal, J., and Zhu, H. (2010). Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport. Biochim. Biophys. Acta. 1802, 707–716.Google Scholar
Shohami, E., Beit-Yannai, E., Horowitz, M., and Kohen, R. (1997). Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional outcome. J. Cereb. Blood Flow Metab. 17, 1007–1019.Google Scholar
Slemmer, J.E., Shacka, J.J., Sweeney, M.I., and Weber, J.T. (2008). Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. Curr. Med. Chem. 15, 404–414.CrossrefGoogle Scholar
Staal, J.A., Dickson, T.C., Chung, R.S., and Vickers, J.C. (2009). Disruption of the ubiquitin proteasome system following axonal stretch injury accelerates progression to secondary axotomy. J. Neurotrauma 26, 781–788.CrossrefGoogle Scholar
Stein, T.D., Alvarez, V.E., and McKee, A.C. (2014). Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res. Ther. 6, 4.CrossrefGoogle Scholar
Sun, X., He, G., Qing, H., Zhou, W., Dobie, F., Cai, F., Staufenbiel, M., Huang, L.E., and Song, W. (2006). Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc. Natl. Acad. Sci. USA 103, 18727–18732.Google Scholar
Tang-Schomer, M.D., Johnson, V.E., Baas, P.W., Stewart, W., and Smith, D.H. (2012). Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury. Exp. Neurol. 233, 364–372.Google Scholar
Tesco, G., Koh, Y.H., Kang, E.L., Cameron, A.N., Das, S., Sena-Esteves, M., Hiltunen, M., Yang, S.H., Zhong, Z., Shen, Y., et al. (2007). Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54, 721–737.Google Scholar
Uryu, K., Chen, X.H., Martinez, D., Browne, K.D., Johnson, V.E., Graham, D.I., Lee, V.M., Trojanowski, J.Q., and Smith, D.H. (2007). Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp. Neurol. 208, 185–192.CrossrefGoogle Scholar
Wen, Y., Onyewuchi, O., Yang, S., Liu, R., and Simpkins, J.W. (2004). Increased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res. 1009, 1–8.Google Scholar
Yoshiyama, Y., Uryu, K., Higuchi, M., Longhi, L., Hoover, R., Fujimoto, S., McIntosh, T., Lee, V.M., and Trojanowski, J.Q. (2005). Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model. J. Neurotrauma. 22, 1134–1141.CrossrefGoogle Scholar
Zhang, X. and Le, W. (2010). Pathological role of hypoxia in Alzheimer’s disease. Exp. Neurol. 223, 299–303.Google Scholar
About the article
Published Online: 2015-08-26
Published in Print: 2016-01-01