Handbook of Clinical Neurology, Vol. 128 (3rd series) Traumatic Brain Injury, Part II J. Grafman and A.M. Salazar, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 45

Genetic factors in traumatic brain injury THOMAS W. MCALLISTER* Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

INTRODUCTION Outcome after a traumatic brain injury (TBI) can be quite variable and unpredictable. For example, in clinical practice one can see very different cognitive and functional outcomes in individuals with similar preinjury intellectual and educational backgrounds, and seemingly similar degrees of injury. This suggests factors other than injury severity play important roles in outcome. Host genotype might be one such factor. This chapter reviews key concepts important to understanding genetic influences on the response to and recovery from TBI. This is a rapidly changing field and rather than providing an exhaustive list of potential candidate genes and alleles (for reviews see Jordan, 2007; McAllister 2010, 2011; Conley and Alexander, 2011), the intent is to illustrate the different ways that genetic differences influence response to trauma, and to provide representative examples of illustrative mechanisms that may inform treatment in the future.

GENETIC RESPONSE TO NEUROTRAUMA An array of genetic responses is triggered by neurotrauma both acutely and over time (DeKosky et al., 1998; McIntosh et al., 1998; Dutcher and Michael, 2001; Michael et al., 2005). Initial responses include activation of genes involved in expression of stress proteins (e.g., heat shock proteins, ubiquitin), nerve growth factors (BDNF, GDNF, IGF), and immediate early genes (thought to play a role in promoting transcription of other genes that in turn facilitate initiation of excitotoxic cascades) (Dutcher and Michael, 2001; Michael et al., 2005). This makes the task of sorting out genetic contributions to this process complex. As a starting point it is useful to consider four broad contexts in which individual differences in genotype could play an important role

in outcome after trauma. First, individual differences in modulation of injury extent could serve to augment or dampen the impact of a given “dose” of neurotrauma. Second, individual differences in processes governing repair and recovery from injury could impact the trajectory of recovery and ultimate functional outcome. Third, individual differences modulating preinjury traits (e.g., resilience) or cognition might play a role. Individuals with robust cognitive reserve might better absorb a trauma-induced “hit” to cognitive capacity than those with marginal cognitive capacities. Fourth, interactions between genetic vulnerabilities to neurobehavioral disorders and neurotrauma must be considered. For example, some work suggests that a history of brain injury is a predictor of those who develop major psychiatric disorders amongst family pedigrees at risk for major psychiatric disorders (Malaspina et al., 2001) (Fig. 45.1). Although useful as general descriptors, it is important to note that each of these four broad categories involve multiple components and thus are under complex polygenic control. For example, hundreds of genes have been identified as candidates for affecting human cognition (Morley and Montgomery, 2001). This suggests that “good” cognitive or functional outcome following TBI is best viewed as a complex polygenic phenotype. Thus the effects of single polymorphisms, even those with known functional effects, may be difficult to detect. However although the individual contribution of a given allele might be small, the effects of multiple alleles could be quite significant.

GENETIC INFLUENCE ON EXTENT OF INJURY A full discussion of the neuropathology of TBI is beyond the scope of this chapter (see Raghupathi, 2004, Farkas

*Correspondence to: Thomas W. McAllister, M.D., Albert Eugene Sterne Professor and Chair, Department of Psychiatry, Indiana University School of Medicine, 355 W. 16th Street, Suite 4800, Indianapolis, IN 46202, USA. Tel: +1-317–963-7288, E-mail: [email protected]

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T.W. MCALLISTER Representative genes

Point of interaction

Catecholaminergic system genes - Dopaminergic genes • Risk taking behavior • COMT, DAT Cholinergic system genes - Memory and attention Psychopathology risk genes - Serotonin transporter gene

Preinjury function -Personality -Sensorimotor function -Cognition -Risk of injury

Modulation of Ca++ influx into cell - CACNA1A - Immediate early genes - Vascular response to trauma (ACE) - Inflammatory response (IL-1,IL-6) - Initiation of apoptosis (TP53)

Injury event

Extent of injury

Neurotrophins -BDNF Apolipoprotein E -APOE E4 -APOE promoter SNPs

Repair and plasticity

Functional outcome - Cognition - Sensorimotor function - Neurobehavioral status - Risk of future injury - Dementia?

Fig. 45.1. Scheme of potential mechanisms for genetic modulation of outcome after traumatic brain injury. (Adapted from McAllister, 2011, p. 38.) Reproduced with permission from the Textbook of Traumatic Brain Injury, (Copyright ©2011). American Psychiatric Association. All Rights Reserved.

and Povlishock, 2007, and Chs 4, 5, 8). However, processes that amplify or dampen the complex cascade of cellular responses to trauma are under genetic control, thus functional polymorphic alleles in genes that play key roles in the cellular response to trauma could account for some of the variance in injury burden. For example, TBI is accompanied by a dramatic and rapid release of the excitatory amino acids glutamine and aspartate. Excessive release of these compounds has been associated with neuronal death (DeKosky et al., 1998; Laurer and McIntosh, 2001; Gennarelli and Graham, 2005; Smith, 2011). The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system and altered glutamate receptor kinetics associated with functional polymorphisms in the genes coding for glutamate receptors could impact associated injury cascades. Several such polymorphisms have been shown to modulate cognition, epilepsy, hypoxic injury, and neurodegenerative disorders (Lipsky and Goldman, 2003), but to date there is no literature on these polymorphisms in TBI. Another likely set of

candidate genes are those coding for the caspases and calpains, two families of cysteine-dependent proteases that mediate excitotoxic and inflammatory cell damage (Friedlander, 2003). Somewhat surprisingly, there is relatively little known about functional polymorphisms in these genes. Thus, although caspase- and calpain-related genes may well be targets in the future, there are no known likely candidates at this time. There are, however, several reports of genes that that code for proteins felt to play a role in injury response. TP53 Originally identified as a tumor suppressor protein, the p53 protein is also felt to play a facilitating role in orchestrating both cell growth arrest and the onset of apoptosis (Fisher, 2001). A functional nonsynonomous coding polymorphism occurs at codon 72 of TP53 where a change from guanine to cytosine results in a substitution of proline to arginine (Ara et al., 1990). The arginine protein is significantly more effective at initiating apoptosis

GENETIC FACTORS IN TRAUMATIC BRAIN INJURY 725 (Dumont et al., 2003). Martinez-Lucas et al. (2005) come at the cost of cellular energy depletion or failure assessed 90 patients with severe TBI with Glasgow Out(Halmosi et al., 2001). Preclinical studies suggest a role come Scale (GOS) (Wilson et al., 1998) at discharge from for PARP-1 in modulating damage after TBI perhaps the intensive care unit and 6 months after injury. Poor through both energy depletion and subsequent modulaoutcome in this sample was associated with a higher rate tion of apoptosis. Furthermore, genetic deletion of of individuals homozygous for the arginine allele. PARP-1 or inhibition of PARP-1 activity has reduced TBI sequelae in animal models of TBI (Clark et al., 2007). Based on these observations, Sarnaik et al. B-cell lymphoma 2 (BCL-2) (2010) used a tag SNP approach to study the effect of Bcl-2 is one of a family of oncoproteins originally polymorphisms in the PARP-1 gene on 6 month GOS described and named due to its association with certain score in 191 individuals with severe TBI. The AA genotypes of B-cell lymphomas. It is has subsequently been type of a tag SNP for a haploblock encompassing the shown to play a role in the regulation of apoptosis, automodification and catalytic domains of the gene and thus polymorphisms in the BCL-2 gene might be (rs3219119) was associated with favorable outcome, of interest in the modulation of the apoptotic pathway and genotype at the tag SNP for a haploblock spanning triggered by neurotrauma. Bcl-2 has been found to be the PARP-1 promoter region (rs2271347) was associated elevated in pericontusional samples from individuals with PAR-modified cerebrospinal protein levels. with TBI (Minambres et al., 2008), and Bcl-2 concentrations have been linked to mortality rates and outcomes Angiotensin-converting enzyme (ACE) after TBI (Clark et al., 1999). Hoh et al. (2010) studied 205 participants with severe TBI. A tag single nuclear ACE plays a central role in the regulation of blood polymorphism (SNP) approach suggested four polymorpressure through the conversion of angiotensin I to phisms of interest that were associated with outcome angiotensin II. The ACE gene is located on chromosome measures including the Glasgow Outcome Scale, mortal17 and has a common insertion/deletion mutation in ity, the Disability Rating Scale, and the Neurobehavioral intron 16 that may be associated with higher levels of Rating Scale. After multiple comparison correction, the circulating ACE (Tiret et al., 1992). Some reports correlation of the variant allele at rs17759659 with poor have linked one of the alleles (I) with increased risk of GOS remained significant. Alzheimer’s disease, whereas others have reported an Nitric oxide synthase (NOS3) Uncoupling of the physiologic equilibrium between cerebral metabolic demand and blood flow is a frequent occurrence accompanying neurotrauma, particularly more severe injuries. Nitric oxide, produced by endothelial nitric oxide synthase, appears to play a role in basal autoregulation of cerebral perfusion (Robertson et al., 2011). The concentration of nitric oxide is reduced after injury in a variety of animal models of TBI (Robertson et al., 2011). Robertson et al. (2011) found that measures of cerebral hemodynamics were associated with allele status at -786 T > C, a polymorphic site in the 50 -flanking region in 51 patients with severe TBI.

association between the deletion (D) allele and cognitive impairment (Amouyel et al., 1996; Richard et al., 2001). Ariza et al. (2006) found that the D allele was associated with poorer cognitive performance in a cohort of 73 patients with moderate and severe TBI studied shortly after resolution of post-traumatic amnesia (Ariza et al., 2006). The mechanisms underlying this effect were unknown, although the authors speculated that the increased ACE activity associated with the D allele might result in vasospasm and cerebral compromise, thus adding to TBI-related injury, and others have reported that ACE may interact with amyloid b aggregation (Hu et al., 2001). Calcium channel subunit gene (CACNA1A)

Poly(ADP-ribose) polymerase-1 (PARP-1) Poly(ADP-ribose) polymerase-1 is one of a family of proteins that play a role in response to cell stress and neurotrauma. Specifically these enzymes catalyze the addition of ADP-ribose chains to a variety of proteins including DNA repair proteins and transcriptions factors (Virag and Szabo, 2002; Sarnaik et al., 2010). The PARP family of enzymes generally use NAD + for these actions and up to 200 molecules of NAD + may be required for the ADP-ribosylation of a given protein (Sarnaik et al., 2010), thus overactivation of these proteins can

The CACNA1A gene codes for the a-1 subunit (pore forming component) of the neuronal calcium channel. Thus functional polymorphisms in this gene might alter the downstream effects of the influx of calcium into the neuron that is triggered at the time of injury. Kors et al. (2001) published a small case series (n ¼ 3) on the association between delayed cerebral edema after mild brain injury and a novel C/T substitution resulting in a switch from serine (hydrophilic) to leucine (hydrophobic) at codon 218 (Kors et al., 2001). This group recently reported an additional two patients with this same

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mutation (leucine allele) who had early seizures after very mild TBI (Stam et al., 2009). Neuroglobin gene (NGB) One of the factors that can augment injury burden from initial or primary trauma is the development of ischemia or hypoxia. Thus factors that influence response to oxygen deprivation might play a role in overall injury burden. Neuroglobin is a protein found in neurons of both the peripheral and central nervous system that appears to convey some resilience to hypoxic/ischemic insult, perhaps by facilitating oxygen transport across the blood–brain barrier or enhancing availability of oxygen to mitochondria (Chuang et al., 2010). Using a tag SNP approach, Chuang et al. (2010) found a relationship between tag SNP rs3783988 and both the Disability Rating Scale and the Glasgow Outcome Scale in a sample of 196 individuals with severe TBI. Individuals homozygous for the wild-type allele (TT) were significantly more likely to have a better outcome than those with one or more variant alleles. Inflammation Inflammation plays a key role in the injury cascades that occur in TBI (Johnson et al., 2013a, b). A diverse group of soluble proteins and peptides, the cytokines, modulate the inflammatory response (Ibelgaufts, 2013). Cytokines may be proinflammatory or anti-inflammatory and play a role in normal function and pathology in the central nervous system (CNS) (Quan and Herkenham, 2002). They are activated through interaction with the caspases and related proteases, thus it is important to consider the interaction of these two systems in considering response to trauma. Animal models and some human data (Holmin et al., 1998) suggest that TBI is associated with disruption of the blood–brain barrier and access of proinflammatory cells to brain parenchyma (Ray et al., 2002; Johnson et al., 2003). In animal models, TBI is associated with upregulation of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor a (TNF-a) (Ray et al., 2002). Preliminary data suggest that polymorphisms in several cytokines including IL-1 and IL-6 may play roles in human TBI outcome. IL-1 family. The IL-1 family consist of two proinflammatory interleukins (a and b) and an interleukin receptor antagonist (IL-1RA). Functional polymorphisms exist within this family. Uzan et al. (2005) found higher rates of IL-1B + 3953 allele 2 and the IL-1B-511 2 allele in poor outcome (measured by GOS) compared to the good outcome group 6 months after injury (Uzan et al., 2005). The sample consisted primarily of patients with moderate and severe TBI. Hadjigerogiou et al. (2005) reported that

those with the IL-1RN*2 allele had more hemorrhagic events after TBI (Hadjigeorgiou et al., 2005). Tanriverdi et al. (2006) failed to find an association between a polymorphism in the 50 regulatory region of the IL-1A gene and outcome measured by the GOS 6 months after injury in a sample of 71 TBI patients of mixed severity (primarily moderate and severe), although there was a trend for those with the IL1A*2 allele to have a poorer outcome (Tanriverdi et al., 2006). IL-6. IL-6 is a proinflammatory cytokine that has been associated with reduced hippocampal neurogenesis. There is a G/C SNP in the -174 promoter region of the gene that appears to be functional, with the G allele associated with increased production of IL-6. The G allele has been associated with Alzheimer’s disease in some (e.g., Pola et al., 2002) but not all studies (Capurso et al., 2004). Our group found an association between the presence of the G allele and reduced temporal lobe gray matter in elderly individuals with memory problems (Saykin et al., 2005). Interestingly, Winter et al. (2004) have reported that elevated levels of IL-6 are associated with improved outcome 6 months after TBI (Winter et al., 2004), and Dalla Libera et al. (2011) found the G allele over-represented in 77 individuals with severe TBI admitted to an intensive care unit (Dalla Libera et al., 2011). However, Minambres et al. (2003) failed to find an allele effect on TBI outcome for a polymorphism at position -174 of the promoter region (Minambres et al., 2003).

ALLELES IMPACTING ON REPAIR AND RECOVERY Given equivalent amounts of injury, individuals with greater capacity for repair, regeneration, and plasticity may have better functional and cognitive outcomes. The component processes in repair and recovery include neurogenesis, adaptive synaptic organization, and longterm potentiation. Polymorphisms in genes coding for critical proteins points in these processes could account for some of the observed differences in outcome, and may provide therapeutic targets of opportunity in the future. Neurogenesis It is now generally accepted that neurogenesis occurs in the adult human brain (Kempermann, 2002; Schaffer and Gage, 2004; Kaneko and Sawamoto, 2009). Although it may occur in other sites, the hippocampus, particularly the dentate gyrus, is the primary site of neurogenesis. Furthermore a variety of mediators of this process have been identified (for reviews see Kempermann, 2002; Kaneko and Sawamoto, 2009).

GENETIC FACTORS IN TRAUMATIC BRAIN INJURY 727 Fibroblast growth factor-2 (FGF-2), epidermal growth albeit limited evidence suggests roles for several of the factor (EGF), sonic hedgehog (Shh), and central serotonerve growth factor family and the glial-derived factor nergic tone play key roles in facilitating neurogenesis family in the response to neurotrauma (Hicks et al., (Schaffer and Gage, 2004; Kaneko and Sawamoto, 1997; Oyesiku et al., 1999; Ray et al., 2002; Kulbatski 2009). There are few reports of common functional et al., 2005). polymorphic alleles identified in the genes coding for the component processes of neurogenesis, although this Brain-derived neurotrophic factor (BDNF). is likely to change in the future. There is an allele of interBDNF is initially manufactured as a precursor protein est, however, in the serotonin transporter that may (pro-BDNF) and then cleaved to BDNF and stored in impact on central serotonergic tone and thus indirectly and released from secretory vesicles in response to neuon neurogenesis. ral activity. BDNF facilitates both early and late longterm potentiation, a process critical to the formation Serotonin transporter and maintenance of episodic and working memory (Lu and Gottschalk, 2000; Poo, 2001; Egan et al., 2003). Serotonin transmission is terminated by sodium- and BDNF mRNA is elevated in hippocampus within chloride-dependent transporter molecules that move 1 hour of trauma and remains elevated for several days serotonin from the synapse back into the presynaptic (Hicks et al., 1997, 1998). There are a variety of polymorneuron. There is a polymorphic allele located in the prophisms in BDNF, but a nonsynonymous SNP involving a moter region (a 44-bp insertion (the long allele, l) or delechange from G to A in the 50 promoter region in the protion (the short allele, s)) which is of interest. The short BDNF sequence (codon 66, nucleotide 196; rs6265) variant of the 5-HTT-linked polymorphic region results in a change in amino acid from valine to methio(5-HTTLPR) has been shown to result in reduced trannine (Egan et al., 2003) and has garnered the most attenscriptional efficiency (Blum et al., 1997), and has been tion from investigators. Egan et al. (2003) found a associated with major depression (Mann et al., 2000), significant main effect of genotype on Wechsler Memfamily history of depression (Joiner et al., 2003), violent ory Scale-R scores, in a sample of 136 healthy controls, suicide attempts (Bellivier et al., 2000), and the develop106 individuals with schizophrenia spectrum disorders, ment of depression, depressive symptoms, and suicidaland 138 unaffected siblings, with the Met/Met group ity in response to stressful life events, development of scoring lower than the Val/Met or Val/Val groups. The depression after stroke (Ramasubbu et al., 2000), and Met allele was also associated with abnormal storage development of post-traumatic stress disorder (PTSD) and secretion of BDNF in an in vivo cell culture assay. when exposed to trauma (Xie et al., 2009). Studies testThe role of Val 66 Met polymorphism in response and ing the association of this polymorphism with depression recovery of human TBI has not been well characterized. after TBI are underway. Lanctot et al. (2010) studied a Krueger et al. (2011) and Rostami et al. (2011) studied the variety of polymorphisms with links to serotonergic relationship of a measure of general intelligence and function including the 5-HTTLPR in 90 individuals with frontal executive function to seven BDNF polymorpost-TBI depression who were being treated with the phisms, including rs6265, in a cohort of 109 Vietnam selective serotonin reuptake inhibitor citalopram combat veterans with focal penetrating TBI. Two SNPs (Lanctot et al., 2010). Although 5-HTTLPR did not pre(rs712442 and rs1519480), as well as a haploblock containdict response to citalopram, it was associated with meding those two SNPs and rs6265, were associated with ication side-effects. recovery of general intelligence when assessed 10–15 years after injury. Interestingly the Met allele of Synaptic organization and adaptation rs6265 was associated with better performance on the (neurotrophins) frontal executive tasks (Krueger et al., 2011; Rostami et al., 2011). Our group studied 38 healthy subjects Neurotrophins are a second major component in repair and 75 patients with mild TBI approximately 1 month and plasticity (Mufson et al., 1999). A full discussion after injury (McAllister et al., 2012). Participants were of these critical factors is beyond the scope of this chapgiven the Wide-Range Achievement Test, 3rd edition, ter (for reviews see Chao, 2003; Lim et al., 2003; Lang Reading subtest, the WAIS-III Block Design subtest, et al., 2004; Skaper, 2008). In brief there are four broad the California Verbal Learning Test (CVLT), and the categories of neurotrophins: (1) the nerve growth factor Gordon Continuous Performance Test (CPT). There family, (2) the glial derived factor family, (3) the neurowas a significant main effect of three of nine SNPs in kine family, and (4) the non-neuronal growth factor famthe BDNF gene (including val/met SNP rs6265) on meaily (Lang et al., 2004). Each of the neurotrophin families sures of processing speed (CPT; p < 0.005) and two of include factors which in theory could be relevant to the the SNPs on a measure of episodic memory (CVLT; mitigation of and recovery from neurotrauma. The best,

728 T.W. MCALLISTER p < 0.05). Bagnato et al. (2012), however, failed to find a functional outcome rating), in 27 individuals with TBI relationship between rs6265 and emergence from a vegand the e4 allele compared to 42 individuals with TBI etative state in 53 patients with more severe TBI but without an e4 allele. Liberman et al. (2002) found (Bagnato et al., 2012). Taken together these results suglower cognitive performance on several cognitive meagest that polymorphisms in BDNF are associated with sures at 3 weeks but not 6 weeks after injury in the e4 TBI outcome, but the relationship is complex and may (+) patients (Liberman et al., 2002). Of note is that not depend on the type and severity of injury, as well as all studies have found an association between the e4 the injury to assessment interval. allele and poor outcome. Willemse-van Son et al. (2008) found better outcomes on the GOS was associated with the e4 allele in their cohort of 79 individuals Repair with moderate-severe TBI followed up to 3 years after injury (Willemse-van Son et al., 2008). However, Apolipoprotein E (ApoE). Another candidate gene Ponsford et al. (2011) recently found an association of interest in response and repair processes following between presence of the e4 allele and poorer outcome TBI is apolipoprotein E. ApoE is a complex glycolipoassessed by the Extended Glasgow Outcome Scale in protein that facilitates the uptake, transport, and distri648 TBI survivors referred for rehabilitation (Ponsford bution of lipids. A four exon gene codes for ApoE on et al., 2011). chromosome 19 in humans. There are three major alleles: The mechanism by which the e4 allele exerts an effect e2, e3, and e4. These alleles differ in amino acids at posiis unclear. ApoE e4 shows an increased affinity for b tions 112 and 158: e2 (cysteine/cysteine), e3 (cysteine/ amyloid and thus an increased propensity to promote arginine), and e4 (arginine/arginine). ApoE appears to aggregation of b amyloid (Friedman et al., 1999). Howplay an important role in neuronal repair and plasticity ever, rather than an active detrimental effect, it may be after neurotrauma (Chen et al., 1997; Sivanandam and that the ApoE e4 is less effective than ApoE e3 in Thakur, 2012). Animal models suggest a link between promoting neuronal repair, and neuritic growth and the e4 allele and increased mortality, extent of damage, branching. There may be a cholinergic link between and poor repair following trauma (Chen et al., 1997; the ApoE and cognitive impairment (Parasuraman and Hartman et al., 2002). The human e4 allele has been assoGreenwood, 2002). In AD, the degree of reduction of ciated with a variety of disorders with prominent cognicholine acetyl transferase, one of the markers for the tive dysfunction including normals with memory disease, is correlated with the “dose” of e4 (Chen complaints (Laws et al., 2002), Alzheimer’s disease et al., 1997). Parasuraman and Greenwood (2002) have (AD), and poor outcomes in stroke and TBI (Chen argued based on accumulated neuropsychological, elecet al., 1997; Nathoo et al., 2003). trophysiologic, and neuroimaging evidence that the cogSeveral studies have reported that the e4 allele is nitive effects of the e4 allele are mediated through associated with poor outcomes following TBI, using a reduced cholinergic input to posterior parietal systems variety of measures (Chiang et al., 2003; Nathoo et al., regulating selective attention. Alternatively, ApoE may 2003). Teasdale and Engberg (1997) prospectively studplay a role in modulating the neuroinflammatory ied individuals with TBI and found that persons with the response to trauma (and other degenerative disorders) APOE e4 allele had a significantly worse outcome through isoform-specific interaction with glial activation 6 months after brain injury when compared with individ(Laskowitz et al., 2010). For example, Laskowitz et al. uals with similar demographic and brain injury variables, (2010) have shown in a mouse model of TBI that APOE but without the APOE e4 allele (Teasdale and Engberg, polymorphisms impact glial activation, that the ApoE e4 1997). In this study, worse outcome meant being in a vegallele was associated with increased microgliosis and Ab etative state, being severely disabled based on GOS, or deposition, and that an ApoE-mimetic peptide reduced death. Crawford et al. (2002) found poorer memory persome indicators of TBI injury. formance in their sample of 30 individuals with TBI with In addition to the effects of APOE genotype on at least one e4 allele compared to 80 TBI patients without outcome after TBI, there is a concern that APOE genoan e4 allele (Crawford et al., 2002). Lichtman et al. type may interact with TBI to increase risk of developing (2000) found lower total functional independence meaneurodegenerative disorders such as AD later in life sure scores in seven e4(+) patients with TBI compared to (e.g., Van Den Heuvel et al., 2007). After initial observathe 24 individuals with TBI but without an e4 allele tions of progressive dementia in boxers with repetitive (Lichtman et al., 2000). Friedman et al. (1999) found a brain injury (Martland, 1928), neuropathologic studies significantly higher percentage of poor outcome indicashowed predominant neurofibrillary tangles and then tors both acutely (prolonged loss of consciousness) and subsequently amyloid plaques similar to those found at 6–8 months after injury (significant dysarthria, global

GENETIC FACTORS IN TRAUMATIC BRAIN INJURY 729 in AD and other neurodegenerative disorders (Roberts NEUROBEHAVIORAL FUNCTION and Bruton, 1990). Furthermore TBI-associated disrupAND COGNITIVE CAPACITY/RESERVE tion of axonal transport results in the rapid accumulation As noted earlier, genes that effect cognitive capacity and of amyloid precursor protein (APP) in both animals (Van reserve play a role in cognitive outcome after TBI. Den Heuvel et al., 1999, 2007) and humans (Blumbergs A large number of factors determine cognitive peret al., 1995; Graham et al., 1995). formance including genetic factors (Morley and Current evidence suggests that APP, Ab, as well as Montgomery, 2001; Savitz et al., 2006; Deary et al., other proteins associated with Alzheimer’s and other 2009). Because the effect of a single allele on cognitive neurodegenerative disorders accumulate quite rapidly performance may be small, it may be overwhelmed by after a TBI (Uryu et al., 2004, 2007; Chen et al., other factors such as educational opportunity, parental 2009), and that in some but not all individuals, these education and expectations, nutrition, other health facabnormal deposits can be chronic. Johnson et al. have tors, etc. However, it may be the case that the effects reported that up to 30% of individuals with a single of different “cognitive alleles” are additive and that in TBI have increased density of neurofibrillary tangles sum they might have measurable effects on outcome. and Ab plaques (Johnson et al., 2012, 2013b). Such difIn addition, such “adverse alleles” might not be noticeferences have led investigators to question whether able until an individual’s cognitive reserve is depleted genetic factors play a role. For example, Mayeux et al. by an injury. Much of the work to date focuses on genes (1995) retrospectively studied 113 older adults with that play a role in catecholaminergic and cholinergic AD, comparing them with a control group of 123 healthy function because of the central role that these neuroolder individuals (Mayeux et al., 1995). They found that a transmitters play in cognition. Several representative history of TBI alone did not increase the risk of AD, but examples are presented. that the presence of the APOE e4 allele alone increased the risk twofold. Most importantly, a combination of Dopamine (DA) receptor gene polymorphisms APOE e4 and history of TBI increased the risk of AD by a factor of 10. Not all studies agree that TBI increases DA plays an important role in the regulation and moduthe risk of developing AD in people with APOE e4. lation of mood, cognition (particularly memory, attenA large prospective population-based study of 6645 indition, and executive functions), reward functions, viduals, who were aged 55 and older and free of demenendocrine systems, and motor function. Thus dopamitia at baseline, found that mild brain trauma was not a nergic system genes are ideal candidates to probe for major risk factor for the development of AD. Moreover, roles in neuropsychiatric disorders. To date most of brain trauma did not appear to increase the risk of develthe attention has focused on polymorphisms in genes oping AD in people carrying the APOE e4 allele (Mehta coding for DA receptor subtypes, DA reuptake (the et al., 1999). Raymont et al. (2008) failed to find an assodopamine transporter or DAT), and DA metabolism ciation between APOE e4 allele and cognitive decline in a (catechol-O-methyltransferase or COMT). carefully characterized cohort of military personnel with penetrating head injury, after accounting for preinjury Dopamine D2Receptor (DRD2) measures of general intelligence. Thus the relationship between TBI and dementia needs further study. The gene for the DRD2 is located on chromosome 11. There are a dozen or more polymorphisms described for this gene, three that result in amino acid substitutions APOE promotor polymorphisms. There are also and two that reduce the expression of DRD2 receptors. several polymorphisms in the promoter region of the Most work has focused on the three restriction fragment APOE gene (Artiga et al., 1998). Two common SNPs length polymorphisms known as TaqI A, B, and C. in the promoter region, one at site 219 the other at 491, A large body of work suggests that a TaqI A polymorappear to influence promoter activity and thus presumphism plays a role in modulation of the reward system, ably APOE expression (Artiga et al., 1998). Lendon et al. and to lesser extent movement disorders and psychosis. (2003) studied the effects of genotype at both SNPs on Originally thought to be in the DRD2 gene, the TAQ1A 6 month outcome in 92 individuals hospitalized at a allele (rs1800497) is actually in an adjacent gene – trauma center with TBI. In this sample, being homozyANKK1. Autopsy studies have found reduced DRD2 gous for the T allele at site G-219 T (associated with binding in the striatum of individuals with the A1 allele decreased promoter activity) was associated with poorer (Noble et al., 1991; Thompson et al., 1997). This appears outcome as measured by GOS. No allele effect on outto be a reduction in the number of DRD2 receptors rather come was found for the A-491 T polymorphism than a change in receptor affinity. Polymorphisms in this (Lendon et al., 2003).

730 T.W. MCALLISTER region appear to play a role in cognitive outcome after among others. In the untranslated 30 region, this gene conmild TBI. Our group reported an association between tains a region with a 40 base-pair variable number of tanthe TAQ1A allele and response latency after mild TBI dem repeats (VNTR). There are at least 10 different (McAllister et al., 2005). We studied a second cohort alleles known, corresponding to a range of 3 to 13 repeat of 54 patients with TBI and 21 comparison subjects gensequences. Furthermore, these variations in the number otyped for rs1800497 (McAllister et al., 2008). Ninetyof tandem repeats appear to have an effect on the expresthree patients with TBI and 48 comparison subjects were sion of DAT (Miller and Madras, 2002). The 10 repeat genotyped for 31 additional neighboring polymorphisms allele has received the most attention and several studies in NCAM, ANKK1, and DRD2. Once again the T allele have linked this allele to attention deficit hyperactivity (rs1800497) was associated with poorer performance disorder (ADHD). Cook et al. (1995) showed an associaon the CVLT and there was a significant diagnosis-bytion between ADD and the 10/10 homozygous genotype. allele interaction on the CPT largely driven by slower perThis was confirmed by Waldman et al. ( 1998) and Daly formance in the TBI participants with the T allele. et al. (1999). A haploblock of three SNPs in ANKK1 showed the greatest association with cognitive outcome measures. Serotonin (5-hydroxytryptamine) transporter DRD2 receptor alleles may also be associated with (5-HTT). The gene for the 5-HTT is located on the long certain personality styles or traits (for review see arm of chromosome 17 and was mentioned earlier with Ebstein et al., 2000), and thus potentially with risk for respect to potential effects on neurogenesis as well as sustaining a TBI. Most of these studies use self-report links to gene/environment interactions and risk for questionnaires or personality inventories to classify perdepression and PTSD. sonality styles or traits along a limited number of domains such as “novelty seeking,” “harm avoidance,” Norepinephrine transporter gene (NET). Similar and “reward dependence.” These dimensions are generto the other monoamine transporters, NET plays a crually considered to be constructs representing exploratory cial role in the modulation of brain noradrenergic tone. behavior, inhibition of approach behaviors, and attachA variety of polymorphisms in various regions of the ment or persistence of intermittently re-enforced behavgene have been described, though there is little informaiors respectively (Ebstein et al., 2000). Associations have tion on the functional significance of these alleles and no been reported between the TaqI A1 allele and schizoid/ data to date in TBI. avoidant behavior (Blum et al., 1997) and impulsive/ addictive behavior such as pathological gambling Polymorphisms of enzymes involved (Comings et al., 1996). Several reports have linked the in catecholamine synthesis and metabolism D4.7 allele (part of the D2 family) to increased novelty Dopamine b-hydroxylase (DBH). The gene for seeking (Ebstein et al., 1998; Wong et al., 2000) in adults, neonates (Ebstein et al., 1998), and D4 receptor knockDBH is located on the long arm of chromosome 9. out mice (Dulawa et al., 1999). DBH catalyzes the conversion of dopamine to norepinephrine (NE) and plays an important role in the moduPolymorphisms of monoamine transporters lation of dopaminergic and noradrenergic tone. Inhibition of DBH results in a reduction of NE. Under After their release into the synapse, dopamine, serotoordinary circumstances NE exerts an inhibitory effect nin, and norepinephrine bind to presynaptic membrane on tyrosine hydroxylase and thus the conversion of tyroproteins known as transporters, and are taken back into sine to dopamine and subsequently norepinephrine. the presynaptic neuron. The activity of these transDBH inhibition and the subsequent reduction in NE porters plays a major role in the regulation of neurocan therefore result in an increase of DA (Comings transmitter tone. Thus polymorphisms in the genes et al., 1996). Changes in DBH activity have been linked coding for these transporters could play important roles to conduct disorder and a variety of personality traits in the etiology of neuropsychiatric disorders, and mediin several studies (Comings et al., 1996). There is a funccations modulating the activity of these transporters tional polymorphism of the DBH gene (TaqB), occurring could, and in fact already do, play important therapeutic in 50% of non-Hispanic Caucasians, that does appear roles (i.e., serotonin reuptake inhibitors). to effect transcription of the gene product. Our group reported preliminary findings suggesting that DBH Dopamine transporter (DAT). The gene for the allele status was related to several measures of cognitive DAT is located on the short arm of chromosome 5. Blockfunction in a cohort of 100 individuals with mildade of DAT is thought to be the mechanism of action for a moderate TBI studied approximately 1 month after variety of different drugs including cocaine, amphetinjury (McAllister et al., 2009). amine, phencyclidine, methylphenidate, and bupropion,

GENETIC FACTORS IN TRAUMATIC BRAIN INJURY Catechol-O-methyltransferase (COMT). COMT catalyzes the metabolic breakdown of catecholamines through the methylation of dopamine and norepinephrine. The gene for COMT is located on the long arm of chromosome 22. There is a common functional polymorphism of this gene characterized by a single nucleotide change from G to A at position 472. This switch results in a code change to methionine instead of valine. The effect of this amino acid substitution is a significant change in the efficiency of the enzymatic activity at normal body temperatures (Weinberger et al., 2001). The valine version (val allele) is almost four times as active as the methionine version of the gene (met allele). Thus individuals homozygous for the val allele presumably metabolize DA much more rapidly than those with the met allele. This is of particular importance in the frontal cortex, where DAT shows relatively less expression compared to striatal regions. In frontal cortex COMT becomes a major modulator of dopaminergic tone, accounting for 60% of the metabolic degradation of DA (Malhotra et al., 2002). Although COMT also catalyzes the methylation of NE, the regional brain differences in transporter density/expression are not found with NET, thus the val/met polymorphism appears to have a relatively specific effect on frontal dopaminergic tone (Weinberger et al., 2001). Changes in COMT activity alter frontal dopaminergic activity and cognitive capacity in both animals and humans. COMT knockout mice show reduced frontal but not striatal DA relative to wild-type mice (Gogos et al., 1998). COMT inhibitors given to rats (Liljequist et al., 1997) and humans have been shown to improve memory. Egan et al. (2001) found that the Val allele was associated with poorer performance (more perseverative errors) and that there was an allelic load effect (i.e., val/val homozygotes did worse than val/met heterozygotes) in healthy controls and individuals with schizophrenia and their siblings (Egan et al., 2001). Lipsky et al. (2003) studied 113 individuals with traumatic brain injury (TBI) with a battery of frontal-executive tests. Analysis of variance showed significant between group differences with the val/val group making the most perseverative errors on the WCST, the met/met group making the least number of errors, and the val/met group making an intermediate number of errors (Lipsky et al., 2003). Thus the weight of evidence suggests that the val158met polymorphism impacts on frontal dopaminergic tone, and that this change in tone is reflected in altered performance of some measures of frontal-executive cognitive function. Monoamine oxidase-A (MAO-A). Monoamine oxidases are enzymes that catalyze the metabolism of monamines including norepinephrine, dopamine, and

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serotonin among others. Although they metabolize more than catecholamines, they are included in this section. There are two families, MAO-A and MAO-B, that differ in their affinity for various monoamine substrates. The MAO-A gene contains a variable number tandem repeat (VNTR) functional polymorphic site. The 3.5 and 4 repeat variants are associated with high MAO activity, whereas the 2, 3, and 5 repeats have relatively lower transcriptional activity. Pardini et al. (2011) studied the interaction of prefrontal lesion location and MAO-A genotype at the VNTR site in a cohort of 155 Vietnam veterans with penetrating brain injuries (Pardini et al., 2011). Prefrontal lesion location was the best predictor of aggression; however, MAO-A genotype was associated with levels of aggression in the noninjured group and the group with nonprefrontal brain injuries.

Polymorphisms relevant to the cholinergic system There are several genetic variations that impact on CNS cholinergic function and play a role in certain neuropsychiatric conditions. Surprisingly very little work has been done on these alleles in TBI. Cholinergic receptors There are two broad categories of cholinergic receptors, muscarinic and nicotinic, based on receptor responses to muscarine or nicotine. We will focus on the nicotinic receptor system. Nicotinic receptors (nAChR) are part of the superfamily of ligand-gated ion channels. Binding of an agonist to the receptor results in a conformational change, allowing cations to flow across the membrane. Nicotinic receptors are made up of different combinations of five subunits (designated a and b). Each subunit has four transmembrane components and the N-terminal region that is located extracellularly (Mihailescu and Drucker-Colin, 2000; Weiland et al., 2000). There are eight different a subunits (a2–a9) and three b subunits (b2–b4), all coded for by different genes, many of which have potentially significant polymorphisms. Thus there are a large number of neuronal nAChRs, characterized by the different arrays of subunits that comprise the specific receptor. The most common neuronal nAChR comprises the a4b2 subunits, accounting for almost 90% of brain nicotinic receptors (Mihailescu and Drucker-Colin, 2000; Weiland et al., 2000). Attempts have been made to link some of the subunit polymorphisms to a variety of neuropsychiatric disorders. For example, deficits in sensory gating as manifested by abnormalities in the P50 auditory evoked response are very common in individuals with schizophrenia, as well as individuals with TBI and persistent postconcussive complaints (Arciniegas et al., 2000),

732 T.W. MCALLISTER and have been linked to a dinucleotide repeat polyto genes and functional polymorphisms that impact on moprhism in the gene coding for the a7 subunit on the response to injury and repair from injury, the story is long arm of chromosome 15 (Weiland et al., 2000). Of likely to be more complicated. For example, the neuropainterest is that the P50 deficit can be attenuated with thology of primary blast injury is still being elucidated. the use of nicotine (Adler et al., 1992, 1993, 1998; In so far as the excitotoxic cascades and subsequent Weiland et al., 2000). repair mechanisms overlap with those known to be important in closed head injury, the same genes/alleles associated with better outcome in closed head TBI are IMPLICATIONS FOR TREATMENT likely also to be associated with better outcome in blast TBI – especially since pure blast injury is relatively The study of the role of genetic factors on outcome uncommon and is most often a combination of blast following TBI is still in its early stages. To date, most and conventional biomechanical forces and related prostudies have used a candidate gene approach and there cesses. As more is learned about the neuropathology of are no published genome-wide association studies in blast injury, it may well be that additional pathways and human TBI. Although the candidate gene approach the genes/alleles associated with these pathways will has been useful in demonstrating that genetic differbe identified that can be exploited in minimizing the ences do in fact play a role in accounting for some of response to injury or maximizing the repair following the clinically observed outcome variance after TBI, the the injury. Genetic factors that confer vulnerability to effect sizes are typically quite small, and replication comorbid psychiatric conditions are likely to show a simstudies are few and far between (Conley and ilarly complex interaction with injury type. It is assumed Alexander, 2011). Furthermore, genetic and genomic (but not yet demonstrated) that the observed increase approaches can account for only part of the story. in relative risk for psychiatric disorders following Although genotype is important, it is also helpful to brain injury can be largely understood in terms of know whether a particular gene is active and the gene a gene–environment interaction. In this case the product is being expressed, particularly where it is plau“environment” is the brain injury in general, particularly sible to expect a biological effect. Furthermore the the fact that brain regions typically injured in closed head timing of the expression of the gene product is important injury overlap significantly with regions known to medias interventions based on such knowledge is likely to be ate regulation of mood, stress response, impulse control/ time-sensitive. judgment, and anxiety. This is likely to also be the case in It is worth considering whether the impact of the blast and blast-plus injuries, as well as penetrating injugenetic factors outlined above might vary in terms of ries to these same regions. Cohorts of individuals with effects on outcome as a function of injury type (closed penetrating injuries that do not involve these brain versus penetrating, versus blast TBI). These questions regions might not show these same genetic associations. have yet to be addressed empirically but some general This is, however, a testable hypothesis and is a strong comments seem possible. For example, with respect to argument for study designs that carefully characterize genetic modulators of cognitive reserve, such factors clusters of injury profiles. might be expected to play a role regardless of type of Epigenetic factors that alter the expression of gene injury, the general principle at work being that for any products through methylation of chromatin or acetyladecrement in function, if one starts from a higher basetion of histones are also critical to consider. Work in aniline (more cognitive reserve, for example), one will end mals suggests that such epigenetic factors play an up at a higher end point than someone starting at a lower important role in the response to neurotrauma (for dispoint. Thus alleles associated with better baseline funccussion see Conley and Alexander, 2011). Efforts to tion will probably confer an advantage on outcome address these issues are very limited in the human literregardless of the general category of injury. Complicatature and are only just emerging in the animal literature ing this simplistic view, however, is that functional (Conley and Alexander, 2011). Thus although the role of deficits associated with penetrating injuries are more APOE allele status in outcome is the most replicated likely to be strongly associated with which brain finding to date, the implications for treatment are region(s) sustained the bulk of the injury. Thus for indilagging. The work of Laskowitz et al. (2010) is thus parviduals with penetrating injury to occipital (primary ticularly noteworthy as it suggests an avenue and a ratiovisual) cortex, the impact of COMT allele status on nale for developing ApoE mimetic agents that might working memory function may not be as evident as it have therapeutic utility (Laskowitz et al., 2010). Furthermight be with someone whose penetrating injury was more, a study of combination of histone deacetylation predominatly in dorsolateral prefrontal cortical areas inhibitors and behavioral therapy to improve learning associated with working memory circuitry. With respect

Table 45.1 Polymorphisms affecting outcome after traumatic brain injury Domain Affected

Gene

Polymorphism

Functional mechanism

Comments

G/C (arg to pro) at codon 72 rs17759659

Arg allele more efficient initiator of apoptosis

Arg homozygosity assoc. with lower GOS in one study (Martinez-Lucas et al., 2005) Variant allele associated with poor outcome following severe TBI in 205 patients. (Hoh et al., 2010) Rs3219119 AA associated with favorable 6 mos outcome Rs2771347 genotype assoc with PAR-modified protein levels in CSF D allele assoc. with poorer cognitive performance in moderate/severe TBI (Ariza et al., 2006)

Response to neurotrauma Initiation of apoptosis Modulation of apoptosis

TP53 BCL-2

Unknown

Modulation of apoptosis

PARP-1

rs3219119 rs2771347

Rs3219119 is tag SNP spanning catalytic domain; rs2771347 associated with activity and is tag SNP spanning promotor region

? Effect on vascular response to trauma Vascular response to trauma Calcium influx into cell

Angiotensinconverting enzyme gene

Insertion/deletion in intron 16

Alters circulating levels of ACE (higher in D/D)

Nitric oxide synthase (NOS3)

-786C variant

Unknown

Calcium channel subunit gene (CACNA1A) NGB

C/T substitution at codon 218 (serine to leucine switch) Tag SNP rs3783988

Alters configuration of Ca++ pore forming component

Interleukin-1 b (proinflammatory cytokine) Interleukin-6 (proinflammatory cytokine)

Restriction site at position +3953 exon 5

Not known – presumed effect on degree of inflammatory response

G/C SNP in promoter region (position -174)

G allele associated with increased production of IL-6

Resilience to hypoxia/ ischemia Inflammatory response Inflammatory response

Unknown. Ngb may facilitate oxygen transfer across BBB

Altered cerebral hemodynamics following severe TBI in 51 patients (Robertson et al., 2011) Small case series associated L allele with cerebral edema and seizures after mild TBI (Kors et al., 2001; Stam et al., 2009) Wild-type homozygotes (TT) significantly more likely to have good outcome after severe TBI (Chuang et al., 2010) Poor 6 month outcome associated with allele*2 after moderate/severe TBI (Uzan et al., 2005) Conflicting results on association of G allele with TBI outcome (Minambres et al., 2003; Winter et al., 2004) Continued

Table 45.1—Continued Domain Affected

Gene

Polymorphism

Functional mechanism

Comments

G/A SNP in promoter region (codon 66). Results in val to met switch

Met allele assoc with abn storage and secretion of BDNF Mechanism of allele effect for this gene is not known

Preliminary study shows association with Met allele and lower memory and attention scores 1 month after mild TBI (McAllister et al., 2008) e4 allele associated with poor outcome in several studies of TBI (e.g., see Alexander et al., 2007) T allele at the G-219 T site in promoter region associated with poor outcome (Lendon et al., 2003)

Repair and plasticity Repair and plasticity Repair

Brain-derived neurotrophic factor (BDNF) Apolipoprotein E

Three major alleles: e2, e3, e4 differ in amino acids at positions 112 and 158. Also several polymorphsisms in the promoter region

Pre- and postinjury cognitive capacity and reserve Catecholamine receptors

Catecholamine transporters Catecholamine metabolism Catecholamine synthesis Monoamine oxidase

Dopamine D2 receptor region DRD2 and ANKK1 Dopamine transporter (DAT) Catechol-O-methyl transferase (COMT) Dopamine b-hydroxylase (DBH) Monoamine oxidaseA (MAO-A)

Numerous polymorphisms in this region. Unclear how many are functional

Rs1800497 associated with reduced expression of D2 receptors in striatum

rs 1800497 associated with measures of memory and attention one month after mild TBI (McAllister et al., 2005; 2008)

40 base pair variable number tandem repeat (VNTR)

Different alleles impact on expression of DAT

G/A SNP (val158met) resulting in Met/Val switch at position 472 Functional polymorphism affects gene transcription

Met allele less efficient in metabolizing DA

Preliminary data suggest association of 10 allele with measures of memory and attention 1 month after mild TBI (McAllister et al., 2009) Met allele associated with reduced performance on some frontal-executive tasks after TBI (Lipsky et al., 200XXX; McAllister et al., 20XXX) 5 SNPs in DBH gene associated with memory and attention measures 1 month after mild TBI (McAllister et al., 2009)

VNTR

2, 3, and 5 repeats associated with lower transcriptional activity

Not known

BBB, blood–brain barrier; GOS, Glasgow Outcome Scale; TBI, traumatic brain injury; CSF, cerebrospinal fluid.

Genotype associated with levels of aggression in controls and cohort with penetrating brain injury (Pardini et al., 2011)

GENETIC FACTORS IN TRAUMATIC BRAIN INJURY and memory in a rodent TBI model suggests another novel therapeutic approach (Dash et al., 2009). Whether genotype can be used to predict response to other types of rehabilitation efforts and treatment, rather than simply predicting injury outcome is not yet known.

CONCLUSIONS The study of genetic determinants of outcome after TBI is at a very early stage. The complex series of events set in motion by a TBI suggests that functional polymorphisms in genes that regulate the brain’s response to neurotrauma, repair processes after injury, and neural plasticity play a role in determining outcome (Table 45.1). Currently there is reasonable evidence that APOE allele type affects outcome although the mechanism is not clear. It also appears that polymorphisms in nerve growth factors and the inflammatory cascades, particularly in genes for interleukin 1 and interleukin 6, are promising candidates. To date these preliminary studies confirm the “proof of concept.” What is less clear is how the different “adverse” alleles interact with each other. Largely unexplored are the questions of genetic contributors to the increased burden of psychiatric disorders associated with TBI, and whether there are certain candidate genes/alleles that put an individual at increased risk of sustaining a TBI. Such questions will have to be addressed by careful, large multicenter studies since minor allele frequencies are often in the range of 10–20%, thus limiting cohort sizes.

ACKNOWLEDGMENTS Supported in part by grants: NICHD R01 HD048176, 1R01HD047242,and1R01HD48638;NINDS1RO1NS055020; CDC R01/CE001254.

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Genetic factors in traumatic brain injury.

Outcome after a traumatic brain injury (TBI) can be quite variable and unpredictable. This suggests factors other than injury severity play important ...
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