Post-traumatic neurodegeneration and chronic traumatic encephalopathy

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Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world. Concussive and subconcussive forms of closed-head injury due to impact or blast neurotrauma represent the most common types of TBI in civilian and military settings. It is becoming increasingly evident that TBI can lead to persistent, long-term debilitating effects, and in some cases, progressive neurodegeneration and chronic traumatic encephalopathy (CTE). The epidemiological literature suggests that a single moderate-to-severe TBI may be associated with accelerated neurodegeneration and increased risk of Alzheimer's disease, Parkinson's disease, or motor neuron disease. However, the pathologic phenotype of these post-traumatic neurodegenerations is largely unknown and there may be pathobiological differences between post-traumatic disease and the corresponding sporadic disorder. By contrast, the pathology of CTE is increasingly well known and is characterized by a distinctive pattern of progressive brain atrophy and accumulation of hyperphosphorylated tau neurofibrillary and glial tangles, dystrophic neurites, 43 kDa TAR DNA-binding protein (TDP-43) neuronal and glial aggregates, microvasculopathy, myelinated axonopathy, neuroinflammation, and white matter degeneration. Clinically, CTE is associated with behavioral changes, executive dysfunction, memory deficits, and cognitive impairments that begin insidiously and most often progress slowly over decades. Although research on the long-term effects of TBI is advancing quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. Critical knowledge gaps include elucidation of pathogenic mechanisms, identification of genetic risk factors, and clarification of relevant variables—including age at exposure to trauma, history of prior and subsequent head trauma, substance use, gender, stress, and comorbidities—all of which may contribute to risk profiles and the development of post-traumatic neurodegeneration and CTE. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

Introduction

Concussive and subconcussive injuries are thought to be produced by rapid acceleration and deceleration of the head (Meaney et al., 1995). Rapid linear or angular acceleration, deceleration or rotational forces cause the brain to deform, stretching individual neurons, glial cells and blood vessels and altering membrane permeability. Although all cell compartments are affected by the injury, blood vessels and axons are especially vulnerable as they often extend long distances within the nervous system. In addition to structural deformation, traumatic acceleration–deceleration forces produce a rapid influx of calcium, efflux of potassium, release of neurotransmitters, and alterations in the function of cellular sodium–potassium (Na +–K +) pumps. These trauma-induced alterations in neuronal homeostasis result in large increases in glucose metabolism and are collectively referred to as the “neurometabolic cascade of concussion” (Giza and Hovda, 2001, Giza and Hovda, 2014). Post-concussive hypermetabolism in the setting of decreased cerebral blood flow produces a disparity between glucose supply and demand or a cellular energy crisis (Giza and Hovda, 2001). Pathological studies show that multifocal axonal injury, microhemorrhage, loss of microvascular integrity, and neuroinflammation occur after concussion (Blumbergs et al., 1994, McKee et al., 2014, Oppenheimer, 1968). The astrocytosis is most severe in the cerebral white matter and brainstem white matter tracts and clusters of activated microglia are most prominent in the white matter around small vessels. Perivascular hemosiderin, hematoidin-laden macrophages and vascular inflammation may also be present after concussion, indicating microvascular damage and breach of the blood–brain barrier. In addition, focal perivascular accumulations of hyperphosphorylated tau (p-tau) and hyperphosphorylated TDP-43 (p-TDP43) occasionally occur after concussive injury (McKee et al., 2013, McKee et al., 2014).

The severity of the axonal injury and microvasculopathy generally parallel the severity of the TBI, with mild injury producing only microscopic axonal damage and rare microhemorrhages, and moderate to severe TBI producing more severe axonal injury with grossly visible petechial hemorrhages. The degree of axonal injury after traumatic impact may also vary with the direction of the head impact rotation, as experimental studies in gyrencephalic piglets demonstrate greater behavioral abnormalities and more persistent axonal injury in piglets exposed to sagittal versus axial rotational injury (Sullivan et al., 2013). The axonal injury produced by mild TBI (mTBI) is multifocal, with a tendency to be most severe in the corpus callosum, fornix, parasagittal white matter and cerebellum, and within these areas, more pronounced around small blood vessels (McKee et al., 2014).

These axonal changes likely contribute to the severity of symptoms after mTBI and are major contributors to the development of post-concussion syndrome (PCS). Acceleration–deceleration injury also causes tau protein, normally associated with microtubules in axons, to become abnormally phosphorylated, misfolded, aggregated and cleaved, all of which generate neurotoxic tau peptide fragments (Amadoro et al., 2006, Chen et al., 2010, Kanaan et al., 2011, Khlistunova et al., 2006, McKee et al., 2013, Zilka et al., 2006). It is not clear how these acute alterations develop into a progressive neurodegeneration after repeated injury in some individuals, however traumatically-induced microvasculopathy with breach of the blood brain barrier and release of normally excluded systemic proteins, such as proinflammatory cytokines or other factors may play a critical role. In addition, recent evidence indicates that a brain-wide network of paravascular channels, the “glymphatic” pathway, facilitates the clearance of interstitial solutes, including tau and beta amyloid (Aβ), from the brain. Experimentally in mice after acute TBI, the glymphatic pathway is functionally impaired, an impairment that persists for one month post injury and enhances the development of neurofibrillary pathology and neurodegeneration in post-traumatic rodent brain. Chronic impairment of glymphatic pathway function after repetitive TBI may be a key factor promoting tau aggregation and the onset of neurodegeneration (Iliff et al., 2014).

Blast injuries resulting from improvised explosive devices have become an increasingly important form of TBI in civilian and military populations. Recent estimates indicate that 10–20% of the 2.5 million U.S. military service members deployed to Iraq and Afghanistan are affected by TBI and the majority of these injuries are associated with blast exposure (The CDC et al., 2013). Individuals exposed to blast are susceptible to neurological injury with acute and long-term neuropsychiatric and cognitive consequences. Military personnel exposed to repetitive mTBI from explosive blast (Goldstein et al., 2012, McKee and Robinson, 2014, Omalu et al., 2011) show neuropathological changes of early stage CTE, axonopathy, microvascular damage, astrocytosis and activated microgliosis at autopsy (Goldstein et al., 2012). Clinical symptoms experienced after blast neurotrauma include progressive affective lability, irritability, distractibility, executive dysfunction, memory disturbances, and cognitive deficits. Four of the five veterans exposed to blast who showed changes of early stage CTE at autopsy were also diagnosed with posttraumatic stress disorder (PTSD) during life suggesting that PTSD and CTE might be biologically and pathologically interconnected (McKee and Robinson, 2014). The focal p-tau changes associated with blast neurotrauma share features of early CTE reported in young American football and soccer players, boxers, head-bangers and others (Geddes et al., 1999, Goldstein et al., 2012, McKee et al., 2013, McKee et al., 2014). However, pathologies associated with blast exposure other than tau accumulation, including axonal injury and microvascular damage, most likely are important contributors to the clinical and behavioral abnormalities observed after blast injury. It is worth noting that laboratory mice exposed to a single experimental blast also demonstrate brain pathology, physiologic and functional changes very similar to those found after human blast injury—including myelinated axonopathy, focal microvasculopathy, neuroinflammation, neuronal loss, phosphorylated tau proteinopathy, electrophysiological abnormalities, behavioral impairments, and cognitive deficits (Goldstein et al., 2012). An independent replication study reported brain tau proteinopathy that persisted for at least one month after exposing mice to a single blast (Huber et al., 2013).

Blast injuries represent a wide range of heterogeneous injuries and are often complicated by other types of TBI, including closed-head impact injury (Nakagawa et al., 2011). The occurrence of microscopic neuropathology related to military blast exposure was first reported in deceased World War I infantry soldiers by Sir Frederick Mott (Mott, 1916, Mott, 1919). While blast-induced brain pathology has been repeatedly reported in humans and experimental animals, the origins of these injuries are only recently beginning to be understood (Goldstein et al., 2014). Kinematic analysis of high-speed videographic records obtained in a military-relevant blast neurotrauma mouse model has shown that blast winds with velocities of more than 330 miles/h—greater than the most intense wind gust ever recorded on earth—produce rapidly oscillating inertial forces on the head that induce injurious shearing forces in the brain (Goldstein et al., 2012). An important point is that blast winds, not blast waves, are responsible for the resulting cerebral injury, whereas the acoustic blast wave produces little deformation of brain tissue as a consequence of rapid shockwave pressure equilibration (Goldstein et al., 2012). Blast injuries may also produce diffuse or focal hemorrhage and edema as blood vessels and brain tissue rapidly contract and expand several times within the fraction of a second following transit of the blast shock wave. Some of the traumatic effects of blast exposure can be mitigated by immobilizing the head during blast exposure.

In children and young adults, minor brain trauma can occasionally produce catastrophic, often fatal, cerebral edema and coma. If the neurological deterioration occurs after a single TBI, it is referred to as juvenile head trauma syndrome (McQuillen et al., 1988). The neurological collapse may be immediate or delayed, occurring after a “lucid interval”. Juvenile head trauma syndrome is thought to represent rapid vasodilation and redistribution of blood into the brain parenchyma after impact injury, a process that may involve a functional age-related channelopathy. Some individuals with juvenile head trauma syndrome have a mutation in the calcium channel subunit gene (CACNA1A) associated with familial hemiplegic migraine (Kors et al., 2001). Occasionally, juvenile head trauma syndrome develops in a young athlete who experiences two head injuries, with the second injury occurring before complete recovery from the first impact, similar to second impact syndrome (SIS) (McQuillen et al., 1988).

SIS occurs when an individual sustains an initial mild head injury or concussion, then suffers a second head injury before the symptoms associated with the first injury have cleared, the condition is associated with rapid diffuse cerebral swelling and neurological deterioration (Cantu, 1998, Cantu and Gean, 2010, Logan et al., 2001, Miele et al., 2004, Mori et al., 2006, Saunders and Harbaugh, 1984). Typically, the second injury is only a minor blow to the head, and there is no immediate loss of consciousness. However, within minutes of the injury, severe cerebrovascular engorgement, cerebral edema and brain herniation develop, associated with precipitous collapse. All reported cases of SIS have involved young athletes, predominantly males (90%) ranging in age from 10–24 years, mean age 17.9 years (Mori et al., 2006). Most affected athletes were American football players, usually at the high school level, but younger players and collegiate athletes have also been reported. SIS has also occurred in association with boxing, karate, skiing and ice hockey. It is thought to result from an abrupt posttraumatic loss of cerebral blood flow autoregulation and catecholamine release that produce a rapid increase in intracranial blood volume and catastrophic cerebral edema (Clifton et al., 1981, Lam et al., 1997). The relationship of SIS to juvenile head trauma syndrome is uncertain, and both may be manifestations of the same underlying pathophysiology.

A single moderate to severe TBI with loss of consciousness (LOC) is associated with a 2–4 fold increased risk of dementia in later life (Institute of Medicine Committee on Gulf War and Health: Brain Injury in, V. a. L.-T. H., Outcomes, 2008, Shively et al., 2012). The dementia is most often categorized as probable or possible Alzheimer's disease (AD) using validated clinical criteria, but few studies included neuropathological verification, and clinical overlaps between AD, CTE and other post-traumatic neurodegenerations are known to occur (Stern et al., 2013). Studies also support a link between a remote single TBI and Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), although the pathological features of traumatically induced PD and ALS may differ considerably from the sporadic versions of these neurodegenerations (Daneshvar et al., 2013, Kenney et al., 2014).

Retired professional football players who sustained 3 or more concussions were found to report more cognitive symptoms including a threefold increase in significant memory impairment, and a fivefold increase in diagnosed mild cognitive impairment compared to retired players without a history of concussion (Guskiewicz et al., 2005). Other studies found cognitive deficits on neurological and neuropsychological examination in retired NFL athletes (Ford et al., 2013, Hart et al., 2013, Randolph et al., 2013), that were associated with white matter pathology on DTI and FLAIR imaging and alterations in regional cerebral blood flow (Hampshire et al., 2013, Hart et al., 2013). A study of fifteen retired professional football players with a history of concussions and free of co-morbid conditions showed that there were decreases in fractional anisotropy and increases in mean and radial diffusivity in the frontal–parietal tracts and corpus callosum on DTI compared to an age and education matched control group (Tremblay et al., 2014). Furthermore, these changes significantly correlated with a decline in episodic memory decline. Retired NFL players with only mild deficits in executive functioning showed hyperactivation and hypoconnectivity of the dorsolateral frontal and frontopolar cortices on fMRI (Hampshire et al., 2013). Clinical and functional impairments in cognition have also been correlated with the frequency of head impacts in high school and collegiate football players wearing helmet-mounted accelerometers (Breedlove et al., 2012, McAllister et al., 2012, Talavage et al., 2014), although not all helmet sensor studies have supported this relationship (Broglio et al., 2011, Gysland et al., 2012).

Brain trauma experienced in sport has also been linked to disturbances in mood. Retired professional football players who experienced three or more concussions reported a threefold increase in diagnosed depression (Guskiewicz et al., 2007). A follow up survey administered nine years later provided further evidence for a dose–response relationship between self reported concussions and depressive symptoms later in life (Kerr et al., 2012). Neuropsychological assessment in former professional football players has confirmed the relationship between increased self reported concussions and depression (Didehbani et al., 2013). Depression in these athletes is also associated with increased fractional anisotropy on DTI, as well as white matter abnormalities on structural imaging (Hart et al., 2013, Strain et al., 2013).

In a meta-analysis of 15 case–control studies, males who had a single head injury associated with loss of consciousness (LOC) had a 50% increased risk of AD dementia (Fleminger et al., 2003). In a recent study of older veterans, a history of TBI was associated with a 60% increase in the risk of developing dementia and an accelerated age of onset by 2 years (Barnes et al., 2014). In the MIRAGE study, head injury increased the risk of AD and the magnitude of the risk was proportional to the severity of the head trauma and heightened among first-degree relatives of AD patients (Guo et al., 2000). A longitudinal study involving World War II Navy veterans also demonstrated increased risk for AD in late life with increasing TBI severity (Plassman et al., 2000). Veterans with severe TBI with loss of consciousness (LOC) or prolonged post-traumatic amnesia (PTA) were 4 times more likely to have AD, whereas veterans with moderate TBI were twice as likely to have AD in late-life compared to controls (Plassman et al., 2000). No increased risk was found for veterans who had a mTBI (LOC or PTA less than 30 min). Other studies indicate that while moderate–severe TBI increases the risk for dementia age groups older than 55 years, mTBI increases the risk of dementia only among individuals older than 65 years (Gardner et al., 2014).

Other studies have also suggested that TBI precipitates an earlier onset of AD. In the Northern Manhattan study, a history of head injury with LOC was associated with earlier onset of AD dementia, whereas mTBI was not significantly associated with earlier onset of AD dementia, and those with severe TBI were at significantly increased risk for AD (Schofield et al., 1997). Reanalysis of the Rochester Epidemiology Project data also indicated that the age of onset of AD among AD patients with head injury was 8 years earlier than the expected time of onset predicted by a life-time method based on 689 AD patents without head injury in the same cohort (Guo et al., 2000). Nordstrom et al. evaluated the risk of young onset of dementia (dementia before the age of 65 years) after TBI in a cohort of more than 800,000 young men followed for over 3 decades. They found a strong dose–response association between TBI and young onset dementia, with more severe or more frequent TBI associated with increasing risk (Nordström et al., 2014).

Most case control and longitudinal epidemiologic studies of dementia after TBI use only clinical criteria to diagnose AD. Recent clinical studies show that CTE and other post-traumatic, neuropathologically verified degenerations share considerable clinical features with AD and may be incorrectly diagnosed as probable AD. There have been only a few reports of head injury that used neuropathological confirmation of the AD diagnosis. Jelling and colleagues examined the incidence of AD pathology in 55 consecutive autopsy cases with a history of single TBI. They found definite or probable AD in 21.8% that was significantly higher than the 14% expected in an age-matched general population (Jellinger et al., 2001).

The pathological link between Alzheimer's neurodegeneration and TBI may be related to the accumulation of Aβ and tau proteins after trauma. Aβ plaques and intra-axonal Aβ deposits have been found in approximately one third of TBI subjects dying shortly after injury (DeKosky et al., 2007, Gentleman et al., 1997, Ikonomovic et al., 2004), even in young subjects (Horsburgh et al., 2000), and may continue to accumulate chronically (Johnson et al., 2010). Murine models also show transient elevation of amyloid precursor protein (APP), and intra-axonal Aβ deposits after acute TBI (Chen et al., 2004). Neuropathological analysis of 18 cases of fatal TBI showed widespread axonal injury, accumulation of neurofilament protein, amyloid APP, Aβ and alpha-synuclein in axonal bulbs and varicosities (Uryu et al., 2007). p-Tau protein was also found to accumulate in both axons and neuronal cell bodies (Uryu et al., 2007). p-Tau immunoreactive neurofibrillary tangles (NFTs) have been observed in young individuals dying weeks to months after their last concussion (McKee et al., 2014). An autopsy study of 32 long-term single TBI survivors (age range: 19–60 years, mean 48 years, 93% male, survival 1–47 years, mean 8.4 years after TBI) found widespread Aβ plaques and p-tau NFTs in one third of subjects. NFTs were particularly increased in subjects under the age of 39 years compared to age-matched controls. The NFTs were described as superficial and slightly clustered at sulcal depths suggesting that a single, moderate to severe traumatic injury may promote the development of an atypical AD-like neurodegeneration (Johnson et al., 2010). In an individual case report, a 62 year old woman developed progressive dementia and parkinsonism 11 years after a severe motor vehicle accident; at autopsy, her brain showed multiple neurodegenerative processes including atypical AD, Lewy body disease, axonopathy and TDP-43 proteinopathy (Fig. 1). A strikingly similar case was reported by Kenney and colleagues (Kenney et al., 2014). The subject was a 75-year-old man who developed a rapidly progressive dementia 12 years before death and 25 years after a moderate to severe TBI. Neuropathological examination revealed atypical AD with hippocampal sparing and severe white matter degeneration. These reports suggest that moderate–severe TBI may generate unique neurodegenerative processes with clinicopathological phenotypes unlike sporadic disease (Kenney et al., 2014). It is also worth noting that many individuals who suffer TBI do not develop dementia, as suggested by Gardner and Yaffe “post-TBI neurodegeneration is a multifactorial process that is likely dependent upon number, mechanics, and timing of TBIs, individual genetics, and many other health-related, lifestyle, and environmental risk and protective factors” (Gardner and Yaffe, 2014).

At autopsy, her brain showed multiple neurodegenerative processes including widespread diffuse plaques in the neocortex (A, B (Aβ immunostaining), C (Bielschowsky silver method)), Lewy body disease with abnormally large Lewy bodies in the thalamus and mammillary bodies (D, E, F (alpha-synuclein immunostaining)), axonopathy with extremely large axonal spheroids in the thalamus (G (SMI-34 immunostain), H (AT8 immunostaining)), and an atypical distribution of p-tau NFTS and dystrophic neurites (AT8 immunostaining) (I, locus coeruleus, J, K, temporal cortex, L, median raphe), all calibration bars = 100 μm.

Several investigators have studied the relationship between inheritance of an apolipoprotein ε4 (APOE ε4) allele and dementia after TBI. In the Northern Manhattan population study, a history of TBI and inheritance of an APOE ε4 allele were associated with a 10-fold increased risk of AD, while APOE ε4 in the absence of TBI resulted in only a 2-fold increased risk (Mayeux et al., 1995). These results are in contrast to findings in the MIRAGE study in which head injury increased the odds of AD to a greater extent among those lacking the APOE ε4 allele compared to those having one or two ε4 alleles (Guo et al., 2000).

There is also evidence that APOE ε4 is associated with deposition of Aβ protein after head injury (Hartman et al., 2002). APOE ε4 has been associated with increased severity of chronic neurologic deficits in boxers with high exposure to repetitive trauma compared to those without an APOE ε4 allele (Jordan et al., 1997). In addition, inheritance of an APOE ε4 allele is associated with longer periods of unconsciousness following severe blunt traumatic injury as well as poorer functional outcome (Friedman et al., 1999). Furthermore, Aβ deposition in CTE is associated with the APOE ε4 allele and significantly increased in CTE compared to a normal aging population (Thor Stein, personal communication).

In addition to AD, a link has been suggested between TBI and PD. In a case–control study, data from the Rochester Epidemiology Project was used to identify 196 subjects who developed PD and compared to controls matched for age and gender. The frequency of head trauma was significantly higher in PD cases compared to controls (OR 4.3). The OR for PD was substantially increased (11.0) in subjects who experienced mTBI with LOC or more severe TBI (Bower et al., 2003). Animal studies have shown that the brains of aged TBI-injured mice develop a transient increase in alpha-synuclein that is not found in sham-injured aged animals or TBI-injured young mice (Uryu et al., 2006). As parkinsonian symptoms may result from neuronal loss in the substantia nigra associated with either accumulation of alpha-synuclein in Lewy bodies, as occurs in PD, or p-tau inclusions in the form of NFTs, as occurs in CTE, AD and many other tauopathies, it is likely that non-alpha synuclein pathologies contribute to the increased frequency of Parkinsonism following TBI (Uryu et al., 2003).

ALS is a fatal progressive degeneration of motor neurons in the brain and spinal cord. Ninety to 95% of ALS cases are sporadic; gene mutations in copper/zinc superoxide dismutase 1, senataxin, dynactin, angiogenic, and TAR-DBP (the gene for TDP-43 on chromosome 1) account for some familial forms of the disease (Bruijn et al., 2004). ALS is pathologically characterized by motor neuron loss and corticospinal tract degeneration. Remaining motor neurons in sporadic ALS often have ubiquitin- and TDP-43 immunoreactive inclusion bodies that appear either as rounded or skein-like inclusions.

Although the etiology of sporadic ALS is unknown, it may involve interaction between genetic and environmental risk factors. Many environmental risk factors have been considered as possible triggers of ALS neurodegeneration, including a history of trauma to the brain and spinal cord (Chen et al., 2007, Schmidt et al., 2010, Strickland et al., 1996). Recent literature points toward a trend not only between CNS trauma and the development of ALS but also between a smaller number of years between the last injury and ALS diagnosis, and older age at the last injury and the development of ALS (Schmidt et al., 2010). In a case control study of 109 cases of ALS and 255 controls, Chen et al. (2007) found that having experienced repeated head injuries or having been injured within the 10 years before diagnosis was associated with a more than 3-fold higher risk of ALS, with a slightly elevated risk for the interval 11 to 30 years. The authors also further performed a meta-analysis of 8 previous ALS studies and estimated a pooled OR of 1.7 (95% CI, 1.3–2.2) for at least one previous head injury. Another case–control study, which was not included in the meta-analysis, reported an increased risk of ALS when the last head injury occurred at an older age and closer to the time of diagnosis (Binazzi et al., 2009).

ALS incidence and mortality are also reported to be unusually high among professional soccer players in Italy (Chio et al., 2005). ALS mortality for Italian professional soccer players was increased 12-fold, whereas mortality from other causes was generally lower or comparable to that of the general population (Belli and Vanacore, 2005). Furthermore, an incidence study involving 7325 Italian professional soccer players showed that the incidence of ALS was 6.5 times higher than expected (Chio et al., 2005). A study looking at cause of death in retired NFL players who played for 5 years or more were found have a 4.31 higher risk of developing ALS and a 3.86 higher risk of developing dementia compared to age and gender matched controls. Although the death certificates indicated dementia and ALS, there was no neuropathological verification of the neurodegenerative processes, and the actual underlying diagnoses might well have included CTE and CTE with motor neuron disease (CTE-MND) (Lehman et al., 2012).

Section snippets

Clinical symptoms of CTE

The symptoms of CTE are insidious, often first manifested as disturbances in attention or concentration or depression that are occasionally associated with headaches. Short-term memory difficulties, aggressive tendencies, executive dysfunction and explosivity are also frequent symptoms. Characteristically the first symptoms usually appear around ages 35–45 years, although the range is broad, from 24 years to 65 years (McKee et al., 2013). There is characteristically a long latent period (mean 8 

Future areas for research

Other than trauma, the risk factors for CTE remain unknown, but are likely multifactorial. Genotypic, diagnostic, and prognostic markers are urgently needed to assess CTE risk, resilience, and responsivity to treatment in individuals at risk for the disease. Other factors such as gender, age at first exposure, number, timing and severity of head injuries, cognitive reserve and flexibility, substance use and neuropsychiatric comorbidities are likely modulators of CTE diathesis and disease

Conclusions

TBI, particularly mTBI, has been largely overlooked as a major health concern until very recently. It is increasingly clear that TBI is a process and not a static injury, and that prolonged symptoms in TBI survivors represent functional and structural damage. Moderate-to-severe TBI may be associated with accelerated neurodegeneration and increased risk of Alzheimer's disease, Parkinson's disease, and motor neuron disease, although it is if the pathologic phenotype of these post-traumatic

Acknowledgments

We gratefully acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA). We also gratefully acknowledge the help of all members of the Boston University and the Boston VA, and the individuals and families whose participation and contributions made this work possible. This work was supported by the Department of Veterans Affairs; Veterans Affairs Biorepository (CSP 501); Translational Research Center for Traumatic Brain Injury and Stress

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