Neurometabolic Aspects of Sports-Related Concussion 1
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Delfina C. Dom|¤ nguez, C.L.S. (ASCP), Ph.D. and Mrudula Raparla, M.S.2
ABSTRACT
Concussion is a transitory brain injury resulting from a blow to the head. Concussion is considered a mild traumatic brain injury (mTBI), which is self-limited. Repetitive mTBI has been associated with chronic, progressive neurologic damage. Extreme biochemical changes occur in neuron cells as a result of mTBI. These metabolic disturbances may reflect the symptoms observed in patients who had concussions. However, it has been difficult to match clinical signs and symptoms. Currently, there is no test to diagnose concussion. Further studies are needed to elucidate the biochemical details of the metabolic cascade and the associated time frame, which will help determine when an athlete can safely return to the game. KEYWORDS: Mild traumatic brain injury, concussion, chronic traumatic encephalopathy, second impact syndrome
Learning Outcomes: As a result of this activity, the reader will be able to (1) define concussion; (2) differentiate between concussion and mild traumatic brain injury; (3) describe four neurometabolic abnormalities that occur immediately after a concussion; (4) explain how multiple concussions can lead to severe brain damage; and (5) indicate how and when chronic traumatic encephalopathy is diagnosed.
Concussion is defined as a transitory brain injury resulting from a blow, bump, or jolt to the head.1–3 Concussion is considered a subset of mild traumatic brain injury (mTBI), which is self-limited and less severe than other brain injuries.3 The terms mild traumatic brain injury and concussion have been used interchangeably.4
However, although all concussions are mTBI, not all mTBIs are concussions. mTBI may induce swelling and stretching of white matter axons leading to disconnection, also called diffuse axonal injury.5–7 Moreover, repetitive mTBI has been associated with chronic, progressive neurologic damage.8
1
Concussion 101 for SLPs; Guest Editor, Anthony P. Salvatore, Ph.D., CCC-SLP Semin Speech Lang 2014;35:159–165. Copyright # 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 5844662. DOI: http://dx.doi.org/10.1055/s-0034-1384677. ISSN 0734-0478.
Clinical Laboratory Sciences; 2Interdisciplinary Health Sciences, The University of Texas at El Paso, El Paso, Texas. Address for correspondence: Delfina C. Domı´nguez, C.L.S. (ASCP), Ph.D., Clinical Laboratory Sciences, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902 (e-mail: [email protected]).
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During the past few years, there has been an increased interest in concussion diagnosis and management. Public awareness about the consequences of repeated concussion/mTBI has risen considerably, and research investigating the biomechanics and biophysics of mTBI has exploded.9 At present, there is no standardized, accurate test to diagnose concussion.10,11 This article will review the metabolic and cellular pathophysiology as a consequence of concussion. Also, the implications of repetitive mTBI in the development of chronic traumatic encephalopathy (CTE) are reviewed.
PATHOPHYSIOLOGY OF CONCUSSION At present, the pathophysiology of concussion is not completely understood. This is due to the inability to study its neurometabolic events in humans.1,12 Most of the experimental data have been derived from animal models. mTBI is believed to be the result of two phases: the first phase is the initial impact caused by linear and rotational biomechanical forces, followed by the secondary injury, which involves multiple neuropathologic processes evolving over minutes to days.9,13 Immediately after impact, a complex cascade of neurochemical events develops. Some changes that have been consistently observed in various studies include: (1) altered membrane conductivity, (2) altered glucose metabolism, (3) altered protein and axonal function, and (4) alterations in cerebral blood flow (CBF). The rapid stretching of axons causes transient neuronal membrane damage resulting in an uncontrolled flux of ions. The neuron undergoes an abrupt change in metabolic reactions affecting glucose metabolism and oxygen levels. A brief description of what happens at the molecular level follows. As soon as a concussion occurs, nerve cells undergo abrupt changes in membrane electrical charges. There is efflux of potassium ions into the extracellular fluid and influx of sodium ions to the interior of the cell, leading to a phenomenon called cellular depolarization. Cellular depolarization activates a series of intracellular processes leading to disruption of cell homeostasis. Several membrane-bound transporters resembling ion channels become very active,
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further destabilizing the intracellular environment and increasing intracellular calcium (Ca2þ) levels.1,4 The Ca2þ ion is, perhaps, the most important intracellular messenger playing a pivotal role in regulating many cellular events. Cells respond to different stimuli by transient changes in Ca2þ concentration; however, prolonged high intracellular Ca2þ may be toxic and/or cause cell death.14,15 High intracellular Ca2þ levels lead to Ca2þ accumulation in mitochondria, to impaired oxidative metabolism, and to energy failure.1,2,9 For the cell to restore homeostasis, adenosine triphosphate–dependent pumps located on the cell membrane are activated to stabilize the ion concentrations within the cell. The functioning of these pumps demands high energy obtained from glucose metabolism. However, due to excess demand, the cell eventually depletes its glucose stores. The increase in glycolysis initiates lactic acid production, increased acidity, and accumulation of fluids leading to swelling of tissue. As a result of these events, there is impaired neuronal transport, neurofilament damage, and axon swelling, which eventually may lead to brain cell death.1,2,16 Fig. 1 illustrates the metabolic events that occur following a traumatic injury. Investigations, in humans, show a similar decrease in glucose metabolism occurs that lasts 2 to 4 weeks after mTBI.1 Interestingly, this global cerebral hypoglycemic state does not correlate with the level of consciousness in patients, as measured by Glasgow Coma Score. Low glucose levels have been seen in comatose as well as noncomatose (walking and talking) patients.1 These observations raise several questions: (1) Is this low glucose metabolism responsible for neurocognitive deficits? (2)Is there a time frame when the brain is protected from secondary injury? (3) Is the brain more susceptible because of its inability to respond to further energy demands?1 Electron microscopy studies show that microtubules in axons break and collapse at the time of injury. Damage of microtubules results from an accumulation of protein in the nerve cell affecting transport within the cell. Neurofilament compaction has been observed from 5 minutes after injury and lasting up to approximately 6 hours.17 Microtubule
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Figure 1 Metabolic cascade in nerve cells following traumatic injury. (1) Changes in ion fluxes. (2) Release of glutamate. (3) Considerable efflux of potassium. (4) Increase activity of membrane pumps to restore homeostasis of ions. (5) Increase in glycolysis to generate energy in the form of ATP. (6) Lactate accumulation as a result of glycolysis. (7) Increased Ca2þ in mitochondria leading to impaired oxidative metabolism. (8) Decreased energy (ATP). (9) Activation of the enzyme calpain and initiation of programmed cell death. (A) Damage of neuron cell. (B) Neurofilament damage. (C) Impaired neuronal transport. (D) Axon swelling. Abbreviations: AMPA, a-Amino-3-hydroxy-5-methyl-4-isoxazolepropinoic acid; ATP, adenosine triphosphate; Ca2þ, calcium; Kþ, potassium; Mg2þ, magnesium; Naþ, sodium, NMDA, N-methyl-D-aspartate. Illustration from Giza and Hovda, J Athletic Training 2001. Used with permission from Giza CC, Hovda DA. J Athl Train 2001;36(3):228–235.1
disassembly results in axonal transport disruption and protein accumulation. Increased axonal Ca2þ levels promote protein phosphorylation, which affects neurofilament stability and activates the Ca2þ-binding protein calpain, which mediates a proteolysis of cytoskeletal proteins. All these series of events leads to neurofilament collapse.1,4,18,19 Eventually, axonal disconnection occurs, which in humans, may persist for days to weeks.5 The overall evidence from several studies indicates that the traumatic insult is responsible for many of the extreme biochemical changes that occur immediately after the injury and eventually lead to subsequent cognitive deficiency.2
CEREBRAL BLOOD FLOW CBF is remarkably constant due to the contribution of large arteries and the ability to regulate constant blood flow despite changes in perfusion pressure.20 After mTBI or concussion, blood flow and oxygen levels in the brain have been shown to decrease quickly.21 Studies conducted in concussed athletes found that blood flow is reduced under the stress of exercise for 3 to 7 days after concussion when compared with concussion-free athletes.22 Another study found that alterations in CBF were documented in children and adolescents and persisted for 14 to 30 days after injury in 27% of the participants.23 Giza and Hovda argue that even though blood flow does not approach 85% seen in ischemia, in
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a time frame in which glucose is depleted and there is a metabolic crisis, alterations in blood flow may have serious consequences.1
IMMUNOTOXICITY: NEURON DAMAGE AS A RESULT OF IMMUNE OVERREACTIVITY Microglia are resident macrophages (professional phagocytes) of the brain and spinal cord that play an active role in immune defense mechanisms in the central nervous system. These cells form 12% of the brain cells.24 After disturbances in brain homeostasis such as in mTBI, these macrophages became activated rapidly to function in neuron survival. Besides having a beneficial effect, activated microglia can be detrimental to neural functioning. Activated microglia produce several toxic factors with neurotoxic effects such as a large number of chemokines, cytokines, nitric oxide, tumor necrosis factor, and reactive oxygen species.24 These neurotoxins are released to the extracellular space, which may attract peripheral macrophages, and differentiate into microglia, participating in further cytokine release.24,25 Repeated trauma may lead to increased activity of microglia or create a permanent activation state, which may cause neuron destruction and eventually a progressive neurodegenerative disease. Some investigators believe that this increased immune activity could play a role in the development of CTE.25 Figure 2 illustrates neuron damage due to immunotoxicity.
MULTIPLE CONCUSSIONS One of the most important issues in sport medicine is how soon an athlete can return to play after a head injury. Studies indicate that the injured brain cells are capable of recovering after an insult, but the time frame of brain susceptibility to a second injury and its consequences are unknown.1,2 As noted previously, after an mTBI, a cascade of metabolic reactions occurs that may last from minutes to weeks after the insult. Giza and Hovda proposed that there are specific time frames when brain cells could be highly susceptible to cell death if a second injury occurs.1 Several cases have been published in
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which athletes, still symptomatic (headache, dizziness), have undergone a second injury resulting in a catastrophic outcome.26,27 This entity, which is rare, is called second impact syndrome (SIS). According to Giza and Hovda, these time frames could be at the hyperglycolitic period, during Ca2þ overload, or perhaps at a time of neurotransmitter impairment.1 If there is an additional energy demand, due to a second injury, the cell will not be able to obtain the energy and eventually will die. A second concussion during high Ca2þ accumulation may cause programmed cell death due to uncontrolled massive depolarization and Ca2þ-dependent protease activation. However, every head injury is different, making very difficult to predict the true duration of vulnerability.1 The pathophysiology of SIS is controversial, but it is believed to occur as a result of loss of cerebrovascular autoregulation, leading to cerebral edema, increased intracranial pressure, and brain stem compression.27 Repeated trauma in animals is associated with attention deficit, learning, and cognitive disabilities.1,9,28 Other studies have demonstrated that repeated mild brain injury may induce accumulation of cytoskeletal proteins and amyeloid deposits like those seen in Alzheimer disease pathology.29–31 Study conducted in brain cell cultures demonstrated that repeated mild injury caused cumulative damage to hippocampal cells.30 Due to the increase in public awareness and the large number of mTBI occurring each year worldwide, there is an increased concern that the recurrent concussion may contribute to various neurologic disorders such as posttraumatic stress disorder, neurocognitive impairment, and CTE.3,9
CHRONIC TRAUMATIC ENCEPHALOPATHY CTE is a progressive, degenerative disease that occurs as the result of repetitive brain injury.32 This condition was first reported by Martland in 1928.33 Martland described the clinical neuropathology in boxers after repeated trauma.33 The pathology hallmark of CTE is the accumulation of hyperphosphorylated tau protein in
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Figure 2 Microglia (specialized white cells) can become overactivated and cause neuron damage through immunotoxicity. One mechanism that these specialized white cells can start neuron damage is by recognizing proinflammatory stimuli, becoming activated, and producing neurotoxic factors. A second mechanism is by activating microglia in response to neuron damage, which is toxic to neighboring neurons, resulting in a continuous cycle leading to neuronal death. Abbreviations: IL-1b, interleukin 1b; LPS, lipopolysaccharide; MMP3, matrix metalloproteinase 3; MPP þ, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; NO, nitric oxide; NOO, peroxonitrite; O2, superoxide; PGE2, prostaglandin E2; TNFa, tumor necrosis factor-a.
the brain.32–34 According to McKee (2013), neurologic changes are distinctive of CTE and are easily differentiated from other neurodegenerative disorders such as Alzheimer disease, which also shows tau protein deposition.25,35 The diagnosis of CTE is done only after autopsy results confirming the histopathology. Symptoms associated with CTE include irritability, depression, short-term memory, and aggression and occur 8 to 10 years after repeated mTBI.3,36 Symptoms suggest a link between neurobehavioral patterns and neuroanatomical areas of the brain that have been affected. It is interesting to note that not all athletes diagnosed with CTE postmortem reported a history of concussions. These findings raise the question if subconcussion injuries and other factors such as genetic predisposition contribute to the development of CTE.3 The pathological mechanism concerning how the development of CTE occurs has not
been elucidated. However, investigators have suggested that immunotoxicity may explain the neurodegenerative processes of CTE. The term chronic traumatic encephalopathy was coined by Blaylock and Maroon to explain the pathological events in autism and the Gulf War syndrome.25 As mentioned earlier, after traumatic brain injury, the interaction and activation of the immune components in the central nervous system, such as microglia and other factors, lead to immunotoxicity. After repeated insult, this immunotoxicity causes neuronal damage and subsequent neurodegeneration. In the case of nonpathological conditions, microglia is nondestructive and may remain so, which may explain why only those receiving repeated head injury are affected.24,25 The prevalence of CTE remains unknown.3 More epidemiological studies are required to understand the causes of CTE and its prevention.
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CONCLUSIONS Extreme biochemical changes occur in neuron cells as a result of mTBI or concussion. These metabolic disturbances in cells sometimes may reflect the symptoms seen in patients who had suffered concussions, which include headache, dizziness, blurred vision, disturbances in memory and cognition, emotional control, and others. However, it has been difficult to match clinical signs and symptoms. A major concern is that if the brain is in a state of high vulnerability, a second injury may lead to severe brain trauma and may be fatal. Currently, it is not possible to predict when the brain cells are highly vulnerable. Further studies are needed to elucidate the biochemical details of the metabolic cascade and their time frame, which will determine when an athlete can safely return to the game. Although mild head injury has been known to be a serious risk since the 16th century, there have been few advances in the neuropathologic, functional, and metabolic details associated with mTBI.
REFERENCES 1. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train 2001;36(3):228–235 2. Signoretti S, Lazzarino G, Tavazzi B, Vagnozzi R. The pathophysiology of concussion. PM R 2011; 3(10, Suppl 2):S359–S368 3. Harmon KG, Drezner JA, Gammons M, et al. American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med 2013;47(1):15–26 4. Zetterberg H, Smith DH, Blennow K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol 2013;9(4): 201–210 5. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ. Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 1994;344(8929): 1055–1056 6. Browne KD, Chen XH, Meaney DF, Smith DH. Mild traumatic brain injury and diffuse axonal injury in swine. J Neurotrauma 2011;28(9): 1747–1755 7. Smith DH, Nonaka M, Miller R, et al. Immediate coma following inertial brain injury dependent on axonal damage in the brainstem. J Neurosurg 2000; 93(2):315–322
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8. Baugh CM, Stamm JM, Riley DO, et al. Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain Imaging Behav 2012;6(2):244–254 9. Dashnaw ML, Petraglia AL, Bailes JE. An overview of the basic science of concussion and subconcussion: where we are and where we are going. Neurosurg Focus 2012;33(6, Suppl 5):E5, 1–9 10. McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport, Zurich, November 2012. J Athl Train 2013; 48(4):554–575 11. Di Battista AP, Rhind SG, Baker AJ. Application of blood-based biomarkers in human mild traumatic brain injury. Front Neurol 2013;4:44 12. Ommaya AK. Head injury mechanisms and the concept of preventive management: a review and critical synthesis. J Neurotrauma 1995;12(4):527–546 13. Frattalone AR, Ling GS. Moderate and severe traumatic brain injury: pathophysiology and management. Neurosurg Clin N Am 2013;24(3): 309–319 14. Dominguez DC. Calcium signalling in bacteria. Mol Microbiol 2004;54(2):291–297 15. Domiguez D, Lopes R, Holland B, Campbell A. Proteome analysis of B. subtilis in response to calcium. J Anal Bioanal Tech 2011;S6:001 16. Vagnozzi R, Signoretti S, Cristofori L, et al. Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients. Brain 2010;133(11):3232–3242 17. Maxwell WL, Graham DI. Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers. J Neurotrauma 1997; 14(9):603–614 18. Sternberger LA, Sternberger NH. Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci U S A 1983;80(19):6126–6130 19. Nakamura Y, Takeda M, Angelides KJ, Tanaka T, Tada K, Nishimura T. Effect of phosphorylation on 68 KDa neurofilament subunit protein assembly by the cyclic AMP dependent protein kinase in vitro. Biochem Biophys Res Commun 1990; 169(2):744–750 20. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990;2(2):161–192 21. Muir JK, Boerschel M, Ellis EF. Continuous monitoring of posttraumatic cerebral blood flow using laser-Doppler flowmetry. J Neurotrauma 1992;9(4):355–362 22. Len TK, Neary JP, Asmundson GJ, Goodman DG, Bjornson B, Bhambhani YN. Cerebrovascular reactivity impairment after sport-induced concussion. Med Sci Sports Exerc 2011;43(12):2241–2248
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23. Maugans TA, Farley C, Altaye M, Leach J, Cecil KM. Pediatric sports-related concussion produces cerebral blood flow alterations. Pediatrics 2012; 129(1):28–37 24. Block ML, Hong JS. Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 2007;35(Pt 5):1127–1132 25. Blaylock RL, Maroon J. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—a unifying hypothesis. Surg Neurol Int 2011;2:107 26. Saunders RL, Harbaugh RE. The second impact in catastrophic contact-sports head trauma. JAMA 1984;252(4):538–539 27. Cantu RC, Gean AD. Second-impact syndrome and a small subdural hematoma: an uncommon catastrophic result of repetitive head injury with a characteristic imaging appearance. J Neurotrauma 2010;27(9):1557–1564 28. Hovda DA. Effect of hyperglycemia after cortical injury. Crit Care Med 1997;25(8):1267– 1268 29. Kanayama G, Takeda M, Niigawa H, et al. The effects of repetitive mild brain injury on cytoskeletal protein and behavior. Methods Find Exp Clin Pharmacol 1996;18(2):105–115
30. Conte V, Uryu K, Fujimoto S, et al. Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. J Neurochem 2004;90(3):758–764 31. Uryu K, Laurer H, McIntosh T, et al. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 2002;22(2):446–454 32. McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 2009;68(7):709–735 33. Martland HS. Punch drunk. Journal of the American Medical Association 1928;91(15):1103–1107 34. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 2005;57(1):128–134, discussion 128–134 35. McKee AC, Stein TD, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 2013;136(1):43–64 36. McKee AC, Daneshvar DH, Alvarez VE, Stein TD. The neuropathology of sport. Acta Neuropathol 2014;127(1):29–51
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This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Delfina C. Dom|¤ nguez, C.L.S. (ASCP), Ph.D. and Mrudula Raparla, M.S.2
ABSTRACT
Concussion is a transitory brain injury resulting from a blow to the head. Concussion is considered a mild traumatic brain injury (mTBI), which is self-limited. Repetitive mTBI has been associated with chronic, progressive neurologic damage. Extreme biochemical changes occur in neuron cells as a result of mTBI. These metabolic disturbances may reflect the symptoms observed in patients who had concussions. However, it has been difficult to match clinical signs and symptoms. Currently, there is no test to diagnose concussion. Further studies are needed to elucidate the biochemical details of the metabolic cascade and the associated time frame, which will help determine when an athlete can safely return to the game. KEYWORDS: Mild traumatic brain injury, concussion, chronic traumatic encephalopathy, second impact syndrome
Learning Outcomes: As a result of this activity, the reader will be able to (1) define concussion; (2) differentiate between concussion and mild traumatic brain injury; (3) describe four neurometabolic abnormalities that occur immediately after a concussion; (4) explain how multiple concussions can lead to severe brain damage; and (5) indicate how and when chronic traumatic encephalopathy is diagnosed.
Concussion is defined as a transitory brain injury resulting from a blow, bump, or jolt to the head.1–3 Concussion is considered a subset of mild traumatic brain injury (mTBI), which is self-limited and less severe than other brain injuries.3 The terms mild traumatic brain injury and concussion have been used interchangeably.4
However, although all concussions are mTBI, not all mTBIs are concussions. mTBI may induce swelling and stretching of white matter axons leading to disconnection, also called diffuse axonal injury.5–7 Moreover, repetitive mTBI has been associated with chronic, progressive neurologic damage.8
1
Concussion 101 for SLPs; Guest Editor, Anthony P. Salvatore, Ph.D., CCC-SLP Semin Speech Lang 2014;35:159–165. Copyright # 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 5844662. DOI: http://dx.doi.org/10.1055/s-0034-1384677. ISSN 0734-0478.
Clinical Laboratory Sciences; 2Interdisciplinary Health Sciences, The University of Texas at El Paso, El Paso, Texas. Address for correspondence: Delfina C. Domı´nguez, C.L.S. (ASCP), Ph.D., Clinical Laboratory Sciences, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902 (e-mail: [email protected]).
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During the past few years, there has been an increased interest in concussion diagnosis and management. Public awareness about the consequences of repeated concussion/mTBI has risen considerably, and research investigating the biomechanics and biophysics of mTBI has exploded.9 At present, there is no standardized, accurate test to diagnose concussion.10,11 This article will review the metabolic and cellular pathophysiology as a consequence of concussion. Also, the implications of repetitive mTBI in the development of chronic traumatic encephalopathy (CTE) are reviewed.
PATHOPHYSIOLOGY OF CONCUSSION At present, the pathophysiology of concussion is not completely understood. This is due to the inability to study its neurometabolic events in humans.1,12 Most of the experimental data have been derived from animal models. mTBI is believed to be the result of two phases: the first phase is the initial impact caused by linear and rotational biomechanical forces, followed by the secondary injury, which involves multiple neuropathologic processes evolving over minutes to days.9,13 Immediately after impact, a complex cascade of neurochemical events develops. Some changes that have been consistently observed in various studies include: (1) altered membrane conductivity, (2) altered glucose metabolism, (3) altered protein and axonal function, and (4) alterations in cerebral blood flow (CBF). The rapid stretching of axons causes transient neuronal membrane damage resulting in an uncontrolled flux of ions. The neuron undergoes an abrupt change in metabolic reactions affecting glucose metabolism and oxygen levels. A brief description of what happens at the molecular level follows. As soon as a concussion occurs, nerve cells undergo abrupt changes in membrane electrical charges. There is efflux of potassium ions into the extracellular fluid and influx of sodium ions to the interior of the cell, leading to a phenomenon called cellular depolarization. Cellular depolarization activates a series of intracellular processes leading to disruption of cell homeostasis. Several membrane-bound transporters resembling ion channels become very active,
2014
further destabilizing the intracellular environment and increasing intracellular calcium (Ca2þ) levels.1,4 The Ca2þ ion is, perhaps, the most important intracellular messenger playing a pivotal role in regulating many cellular events. Cells respond to different stimuli by transient changes in Ca2þ concentration; however, prolonged high intracellular Ca2þ may be toxic and/or cause cell death.14,15 High intracellular Ca2þ levels lead to Ca2þ accumulation in mitochondria, to impaired oxidative metabolism, and to energy failure.1,2,9 For the cell to restore homeostasis, adenosine triphosphate–dependent pumps located on the cell membrane are activated to stabilize the ion concentrations within the cell. The functioning of these pumps demands high energy obtained from glucose metabolism. However, due to excess demand, the cell eventually depletes its glucose stores. The increase in glycolysis initiates lactic acid production, increased acidity, and accumulation of fluids leading to swelling of tissue. As a result of these events, there is impaired neuronal transport, neurofilament damage, and axon swelling, which eventually may lead to brain cell death.1,2,16 Fig. 1 illustrates the metabolic events that occur following a traumatic injury. Investigations, in humans, show a similar decrease in glucose metabolism occurs that lasts 2 to 4 weeks after mTBI.1 Interestingly, this global cerebral hypoglycemic state does not correlate with the level of consciousness in patients, as measured by Glasgow Coma Score. Low glucose levels have been seen in comatose as well as noncomatose (walking and talking) patients.1 These observations raise several questions: (1) Is this low glucose metabolism responsible for neurocognitive deficits? (2)Is there a time frame when the brain is protected from secondary injury? (3) Is the brain more susceptible because of its inability to respond to further energy demands?1 Electron microscopy studies show that microtubules in axons break and collapse at the time of injury. Damage of microtubules results from an accumulation of protein in the nerve cell affecting transport within the cell. Neurofilament compaction has been observed from 5 minutes after injury and lasting up to approximately 6 hours.17 Microtubule
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Figure 1 Metabolic cascade in nerve cells following traumatic injury. (1) Changes in ion fluxes. (2) Release of glutamate. (3) Considerable efflux of potassium. (4) Increase activity of membrane pumps to restore homeostasis of ions. (5) Increase in glycolysis to generate energy in the form of ATP. (6) Lactate accumulation as a result of glycolysis. (7) Increased Ca2þ in mitochondria leading to impaired oxidative metabolism. (8) Decreased energy (ATP). (9) Activation of the enzyme calpain and initiation of programmed cell death. (A) Damage of neuron cell. (B) Neurofilament damage. (C) Impaired neuronal transport. (D) Axon swelling. Abbreviations: AMPA, a-Amino-3-hydroxy-5-methyl-4-isoxazolepropinoic acid; ATP, adenosine triphosphate; Ca2þ, calcium; Kþ, potassium; Mg2þ, magnesium; Naþ, sodium, NMDA, N-methyl-D-aspartate. Illustration from Giza and Hovda, J Athletic Training 2001. Used with permission from Giza CC, Hovda DA. J Athl Train 2001;36(3):228–235.1
disassembly results in axonal transport disruption and protein accumulation. Increased axonal Ca2þ levels promote protein phosphorylation, which affects neurofilament stability and activates the Ca2þ-binding protein calpain, which mediates a proteolysis of cytoskeletal proteins. All these series of events leads to neurofilament collapse.1,4,18,19 Eventually, axonal disconnection occurs, which in humans, may persist for days to weeks.5 The overall evidence from several studies indicates that the traumatic insult is responsible for many of the extreme biochemical changes that occur immediately after the injury and eventually lead to subsequent cognitive deficiency.2
CEREBRAL BLOOD FLOW CBF is remarkably constant due to the contribution of large arteries and the ability to regulate constant blood flow despite changes in perfusion pressure.20 After mTBI or concussion, blood flow and oxygen levels in the brain have been shown to decrease quickly.21 Studies conducted in concussed athletes found that blood flow is reduced under the stress of exercise for 3 to 7 days after concussion when compared with concussion-free athletes.22 Another study found that alterations in CBF were documented in children and adolescents and persisted for 14 to 30 days after injury in 27% of the participants.23 Giza and Hovda argue that even though blood flow does not approach 85% seen in ischemia, in
161
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NEUROMETABOLIC ASPECTS OF SPORTS-RELATED CONCUSSION/DOMI´NGUEZ, RAPARLA
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a time frame in which glucose is depleted and there is a metabolic crisis, alterations in blood flow may have serious consequences.1
IMMUNOTOXICITY: NEURON DAMAGE AS A RESULT OF IMMUNE OVERREACTIVITY Microglia are resident macrophages (professional phagocytes) of the brain and spinal cord that play an active role in immune defense mechanisms in the central nervous system. These cells form 12% of the brain cells.24 After disturbances in brain homeostasis such as in mTBI, these macrophages became activated rapidly to function in neuron survival. Besides having a beneficial effect, activated microglia can be detrimental to neural functioning. Activated microglia produce several toxic factors with neurotoxic effects such as a large number of chemokines, cytokines, nitric oxide, tumor necrosis factor, and reactive oxygen species.24 These neurotoxins are released to the extracellular space, which may attract peripheral macrophages, and differentiate into microglia, participating in further cytokine release.24,25 Repeated trauma may lead to increased activity of microglia or create a permanent activation state, which may cause neuron destruction and eventually a progressive neurodegenerative disease. Some investigators believe that this increased immune activity could play a role in the development of CTE.25 Figure 2 illustrates neuron damage due to immunotoxicity.
MULTIPLE CONCUSSIONS One of the most important issues in sport medicine is how soon an athlete can return to play after a head injury. Studies indicate that the injured brain cells are capable of recovering after an insult, but the time frame of brain susceptibility to a second injury and its consequences are unknown.1,2 As noted previously, after an mTBI, a cascade of metabolic reactions occurs that may last from minutes to weeks after the insult. Giza and Hovda proposed that there are specific time frames when brain cells could be highly susceptible to cell death if a second injury occurs.1 Several cases have been published in
2014
which athletes, still symptomatic (headache, dizziness), have undergone a second injury resulting in a catastrophic outcome.26,27 This entity, which is rare, is called second impact syndrome (SIS). According to Giza and Hovda, these time frames could be at the hyperglycolitic period, during Ca2þ overload, or perhaps at a time of neurotransmitter impairment.1 If there is an additional energy demand, due to a second injury, the cell will not be able to obtain the energy and eventually will die. A second concussion during high Ca2þ accumulation may cause programmed cell death due to uncontrolled massive depolarization and Ca2þ-dependent protease activation. However, every head injury is different, making very difficult to predict the true duration of vulnerability.1 The pathophysiology of SIS is controversial, but it is believed to occur as a result of loss of cerebrovascular autoregulation, leading to cerebral edema, increased intracranial pressure, and brain stem compression.27 Repeated trauma in animals is associated with attention deficit, learning, and cognitive disabilities.1,9,28 Other studies have demonstrated that repeated mild brain injury may induce accumulation of cytoskeletal proteins and amyeloid deposits like those seen in Alzheimer disease pathology.29–31 Study conducted in brain cell cultures demonstrated that repeated mild injury caused cumulative damage to hippocampal cells.30 Due to the increase in public awareness and the large number of mTBI occurring each year worldwide, there is an increased concern that the recurrent concussion may contribute to various neurologic disorders such as posttraumatic stress disorder, neurocognitive impairment, and CTE.3,9
CHRONIC TRAUMATIC ENCEPHALOPATHY CTE is a progressive, degenerative disease that occurs as the result of repetitive brain injury.32 This condition was first reported by Martland in 1928.33 Martland described the clinical neuropathology in boxers after repeated trauma.33 The pathology hallmark of CTE is the accumulation of hyperphosphorylated tau protein in
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Figure 2 Microglia (specialized white cells) can become overactivated and cause neuron damage through immunotoxicity. One mechanism that these specialized white cells can start neuron damage is by recognizing proinflammatory stimuli, becoming activated, and producing neurotoxic factors. A second mechanism is by activating microglia in response to neuron damage, which is toxic to neighboring neurons, resulting in a continuous cycle leading to neuronal death. Abbreviations: IL-1b, interleukin 1b; LPS, lipopolysaccharide; MMP3, matrix metalloproteinase 3; MPP þ, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; NO, nitric oxide; NOO, peroxonitrite; O2, superoxide; PGE2, prostaglandin E2; TNFa, tumor necrosis factor-a.
the brain.32–34 According to McKee (2013), neurologic changes are distinctive of CTE and are easily differentiated from other neurodegenerative disorders such as Alzheimer disease, which also shows tau protein deposition.25,35 The diagnosis of CTE is done only after autopsy results confirming the histopathology. Symptoms associated with CTE include irritability, depression, short-term memory, and aggression and occur 8 to 10 years after repeated mTBI.3,36 Symptoms suggest a link between neurobehavioral patterns and neuroanatomical areas of the brain that have been affected. It is interesting to note that not all athletes diagnosed with CTE postmortem reported a history of concussions. These findings raise the question if subconcussion injuries and other factors such as genetic predisposition contribute to the development of CTE.3 The pathological mechanism concerning how the development of CTE occurs has not
been elucidated. However, investigators have suggested that immunotoxicity may explain the neurodegenerative processes of CTE. The term chronic traumatic encephalopathy was coined by Blaylock and Maroon to explain the pathological events in autism and the Gulf War syndrome.25 As mentioned earlier, after traumatic brain injury, the interaction and activation of the immune components in the central nervous system, such as microglia and other factors, lead to immunotoxicity. After repeated insult, this immunotoxicity causes neuronal damage and subsequent neurodegeneration. In the case of nonpathological conditions, microglia is nondestructive and may remain so, which may explain why only those receiving repeated head injury are affected.24,25 The prevalence of CTE remains unknown.3 More epidemiological studies are required to understand the causes of CTE and its prevention.
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CONCLUSIONS Extreme biochemical changes occur in neuron cells as a result of mTBI or concussion. These metabolic disturbances in cells sometimes may reflect the symptoms seen in patients who had suffered concussions, which include headache, dizziness, blurred vision, disturbances in memory and cognition, emotional control, and others. However, it has been difficult to match clinical signs and symptoms. A major concern is that if the brain is in a state of high vulnerability, a second injury may lead to severe brain trauma and may be fatal. Currently, it is not possible to predict when the brain cells are highly vulnerable. Further studies are needed to elucidate the biochemical details of the metabolic cascade and their time frame, which will determine when an athlete can safely return to the game. Although mild head injury has been known to be a serious risk since the 16th century, there have been few advances in the neuropathologic, functional, and metabolic details associated with mTBI.
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