The Science

PREVALENCE & SOCIOECONOMIC BURDEN OF CONCUSSION

Traumatic brain injuries (TBI) are a category of trauma-induced damage to central nervous system structures. Concussion exists under the umbrella of TBI as a clinical diagnosis with without a universally accepted set of symptoms required for its identification.

Traumatic brain injury affects an estimated 545 cases per 10,000 people, 88% of which were determined to be concussions.1 Upward of 3.8 million of these TBIs are sports and recreation-related and it has been suggested that latent undiagnosed concussion-related symptoms impose a 1-2 billion dollar burden on the U.S. annually.

A wide-range of telltale symptoms including headache, nausea, vomiting, dizziness, fatigue, and altered sleeping patterns following impact usually precipitate a diagnosis of concussion. Initially a mechanical event, trauma causes nerve axon stretching and swelling leading to a cascade of biochemical events that generate the clinical symptoms of concussion. The pathophysiology of concussion has been well described. An immediate post-traumatic rise in brain excitatory neurotransmitters leads to neuron mitochondrial alterations and astrocyte and microglia activation, causing a rise in oxidative stress and an increase in proinflammatory mediator molecules release. This acute metabolic cascade increases the permeability of the blood-brain barrier allowing for the infiltration of peripheral immune cells to the site of injury generating a proinflammatory milieu and neuroinflammation ensues.

PATHOPHYSIOLOGICAL UNDERSTANDING

The immediate signs and symptoms of concussion are due to an “energy crisis” created from oxidative stress, the anaerobic over-utilization of glucose as an energy substrate, and decreased cerebral blood flow. The latter two processes are generally due to the acute metabolic cascade and subside shortly following injury; oxidative stress has been demonstrated up to 45 days post-injury.33 Neuroinflammation can continue for days-years while microglial activation can be present for up to 17 years after TBI. Both these processes are responsible for the secondary injuries observed in concussion and generate chronic neuroinflammation that is associated with increased nuclear factor kappa-B activity and advanced neurodegeneration.21

Neuronal cell phospholipid membranes are known to concentrate the omega-6 (n6) polyunsaturated fatty acid (PUFA) arachidonic acid (AA) and the omega-3 (n3) PUFA docosahexaenoic acid (DHA). Evidence suggests that activated astrocytes readily release AA in response to proinflammatory stimuli and AA metabolism leads to the generation of proinflammatory eicosanoids.4 Research has implicated prostaglandin E2 (PGE2), an AA-derived eicosanoid, in the learning and memory impairments seen in TBI. It has been postulated that this is due to the genetic suppression of the rise of brain-derived neurotrophic factor (BDNF) normally seen with memory and learning processes.12

Animal models show that low brain DHA content increases sensorimotor deficits and further decreases brain DHA content following experimentally induced TBI. Research has also demonstrated the ability for DHA-rich diets to cause a significant accumulation of DHA in brain tissues and improve the ratio of n6/n3 PUFAs.31 This suggests that the amount of DHA and AA metabolized by astrocytes should theoretically correspond with the amounts of their diet-derived n3 or n6 precursors.

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EVIDENCE FOR DHA SUPPLEMENTATION

The majority of scientific evidence suggests a role for n3 PUFA supplementation in the prevention of cognitive decline and neurodegenerative disease. Low intakes of EPA and DHA are characteristic of the Western diet and its n6/n3 ratio has been estimated as high as 16.7:1.3 A recent review of clinical data suggests an association between a high n6/n3 ratio, cognitive decline, incidence of dementia, and the risk of Alzheimer’s disease1 5. Separately, it has been suggested that low blood DHA is linked with a higher risk for cognitive decline.2 A recent large cohort study (n=1,219) associated higher n3 intake with lower plasma levels of beta-amyloid precursors. In humans, dietary supplementation with ALA does not significantly increase serum EPA or DHA levels whereas dietary DHA supplementation has been shown to significantly increase (from 2-7% ;28 in Bradbury) both serum and neuronal DHA levels.

Omega-3 PUFA supplementation is generally well tolerated with mild gastrointestinal upset most commonly reported.1 There is substantial evidence to suggest that increasing dietary DHA consumption is neuroprotective in TBI. There is also substantial evidence to suggest that DHA supplementation is neuroprotective via increasing neuronal membrane flexibility, decreasing oxidative stress, and ameliorating neuroinflammation. Considering its excellent safety profile, the co-occurrence of low dietary n3 levels in the Western diet, and the high incidence of neurodegenerative diseases in the “Western Lifestyle,” DHA supplementation should be considered as prophylaxis for those at risk for mTBI and concussion.

EVIDENCE FOR ANTIOXIDANT SUPPLEMENTATION

Endogenous oxygen and nitrogen free radical scavengers in addition to lipid radical scavengers exist and include: alpha-tocopheol (vitamin E), vitamin C, glutathione, and lipoic acid. Vitamin E, DHA, curcumin (and various derivative compounds), lipoic acid, and resveratrol are the endogenous antioxidants best characterize as having a potential role in the treatment of oxidative stress in TBI. Combination therapy utilizing both free-radical scavengers, LP scavengers, and LP propagation interrupters has been proposed as the most viable form of antioxidant therapy. In the presence of major oxidative stress, vitamins C and E are rapidly consumed in the minutes to hours following injury. This implied a short therapeutic window for their use in antioxidant therapy and requires other endogenous antioxidants to reduce their oxidized forms. Lipid peroxidation begins immediately following injury in TBI and has been documented up to 3-4 days following trauma.1 This, and evidence from other studies suggests that interrupting the propagation of LP may be the most viable mechanism to mitigate oxidative stress in TBI, in part due to the longer therapeutic window.¹ Pharmacological antioxidants have attempted to ameliorate oxidative damage via inhibition of the COX and 5-LOX enzymes with minimal efficacy.1 In the face of many pharmaceutical antioxidant therapies failing phase II testing for the treatment of TBI, preclinical studies demonstrate that curcumin, resveratrol, and lipoic acid can effectively provide neuroprotection in TBI via LP scavenging.1 Simultaneously, these diet-derived antioxidants have also been shown to modulate oxidative stress via novel mechanisms.

EVIDENCE FOR CURCUMIN SUPPLEMENTATION

Curcumin is derivative of the spice turmeric that displays both anti-inflammatory and antioxidant properties. It is highly lipophilic, crosses the blood-brain barrier with the ability to scavenge lipid radicals and down-regulate inflammation at the nuclear level.1 Pre-traumatic brain injury supplementation with curcumin has been shown to improve post-traumatic deficits and reduce inflammation via IL1-beta and NF-kB dependent mechanisms.2 Pre-clinical data also suggests that post-impact curcumin supplementation can normalize the post-traumatic drop in hippocampal BDNF levels and its downstream markers in plasticity.3 Current evidence suggests that a drop in hippocampal BDNF levels and its effects on plasticity is the best mechanism underlying the learning and memory deficits seen in the days-weeks following mTB.31 Animal models have suggested that curcumin supplementation may benefit neurodegenerative disease such as Alzheimer’s.2

References

  1. Arterburn, L.M., Hall, E.B. & Oken, H. (2006). Distribution, interconversion, and dose response of n-3fatty acids in humans. American Journal of Clinical Nutrition, 83(6), 1467-1476.
  2. Bradbury, J. (2011). Docosahexaenoic acid (DHA): an acient nutrient for the modern human brain. Nutrients, 3, 529-554.
  3. Cunnane, S.C. et al. (2012). Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s Journal of Alzheimer’s Disease, 29(3), 691-697.
  4. Das, M., Mohapatra, S. & Mohapatra, S.S. (2012). New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammation, 9(236),
  5. Engstrom, K., Saldeen, A.S., Yang, B., Mehta, J.L. & Saldeen, T. (2009). Effect of fish oils containing different amounts of EPA, DHA, and antioxidants on plasma and brain fatty acids and brain nitric oxide synthase activity in rats. Upsala Journal of Medicine Sciences, 11(4), 206-213.
  6. Gallagher, C.N. et al. (2009). The human brain utilizes lactate via the tricarboxylic acid cycle: a 13c-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain: A Journal of Neurology, 132(10), 2839-49.
  7. Gu, Y., Schupf, N., Cosentino, S.A., Luchsinger, J.A. &Scarmeas, N. (2012). Nutrient intake and plasma ß-amyloid. Neurology, 78(23), 1832-40.
  8. Hall, E.D., Vaishnav, R.A. & Mustafa, A.G. (2010). Antioxidant therapies for traumatic brain injury. Neurotherapeutics: The journal of the American Society for Experimental Neurotherapeutics, 7(1), 51-61.
  9. Hall, E.D., Vaishnav, R.A., & Mustafa, A.G. (2010). Antioxidant therapies for traumatic brain injury. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 7, 51-61.
  10. Hashimoto, M. & Hossain, S. (2011). Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: beneficial effect of docosahexaenoic acid on cognitive decline in Alzheimer’s disease. Journal of Pharmacological Sciences, 116(2), 150-62.
  11. Hein, A.M. & O’Banion, M.K. (2009). Neuroinflammation and memory: the role of prostaglandins. Molecular Neurobiology, 40(1), 15-32.
  12. Horio, Y., Hayashi, T., Kuno, A. & Kunimoto, R. (2011). Cellular and molecular effects of sirtuins in health and disease. Clinical Science, 121(5), 191-203.
  13. Laird, M.D., Sangeetha, S.R., Swift, A.E.B, Meiler, S.E., Vender, J.R., & Dhandapani, K.M. (2010). Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? Journal of Neurochemistry, 113(3), 637-648.
  14. Loef, M. & Walach, H. (2013). The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. Journal of Nutrition in Gerontology and Geriatrics, 32(1), 1-23.
  15. Meehan, W.P. (2011). Medical therapies for concussion. Clinical Sports Medicine, 30(1),
  16. Mills, J.D., Bailes, J.E., Sedney, C.L., Hutchins, H. & Sears, B. (2011). Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. Journal of Neurosurgery, 114(1), 77-84.
  17. Nilsson, A., Radeborg, K., Salo, I. & Bjork, I. (2012). Effects of supplementation with n-3 polyunsaturated fatty acids on cognitive performance and cardiometabolic risk markers in healthy 51 to 72 years old subjects: a randomized controlled cross-over study. Nutrition Journal, 11,
  18. Patterson, Z. R. & Holahan, M. R. (2012). Understanding the neuroinflammatory response following concussion to develop treatment strategies. Front Cell Neurosci, 6(58),
  19. Petraglia, A.L., Winkler, E.A., & Bailes, J.E. (2011). Stuck at the bench: potential natural neuroprotective compounds for concussion. Surgical Neurology International, 2,
  20. Prokop, S., Miller, K.R. & Heppner, F.L. (2013). Microglia actions in Alzheimer’s disease. Acta Neuropathol, 126(4), 461-77.
  21. Ramlackhansingh, A.F. et al. (2011). Inflammation after trauma: microglial activation and traumatic brain injury. Annals of Neurology, 70(3), 374-83.
  22. Russell, K.L., Berman, N.E. & Levant, B. (2013). Low brain DHA content worsens sensorimotor outcomes after TBI and decreases TBI-induced timp1 expression in juvenile rats. Prostaglandins Leukot Essent Fatty Acids, 89(2-3), 97-105.
  23. Sharma, S., Zhuang, Y., Ying, Z., Wu, A., & Gomez-Pinilla, F. (2009). Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain trauma. Neuroscience, 161(4), 1037-44.
  24. Simopoulos, A.P. (2008). The omega-6/omega-3 fatty acid ratio, genetic variation, and cardiovascular disease. Journal of Clinical Nutrition, 17, 131-134.
  25. Taber, K.H., & Hurley, R.A. (2013). Update on mild traumatic brain injury: neuropathology and structural imaging. Journal of neuropsychiatry and Clinical Neurosciences, 25(1), 1-5.
  26. Toklu, H.Z., Hakan, T., Biber, N., Solakoglu, S., Ogunc, A.V., & Sener, G. (2009). The protective effect of alpha lipoic acid against traumatic brain injury in rats. Free Radical Research, 43(7), 658-67.
  27. Van De Rest, O., Van Hooijdonk, L.W.A., Doets, E., Scheipers, O.J.G., Eilander A. & De Groot, L.C.P.G.M. (2012). B vitamins and n-3 fatty acids for brain development and function: review of human studies. Annals of Nutrition and Metabolism, 60(4), 272-292.
  28. Wu, A., Ying, Z. & Gomez-Pinilla, F. (2010). Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil Neural Repair, 24(3), 290-8.
  29. Wu, A., Ying, Z. & Gomez-Pinilla, F. (2013). Exercise facilitates the action of dietary DHA on functional recovery after brain trauma. Neuroscience, 17(248), 655-63.
  30. Wu, A., Ying, Z., Schubert, D. Gomez-Pinilla, F. (2011). Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair, 25(4), 332-342.
  31. Zetterburg, H., Smith, D.H. & Blennow, K. (2013). Biomakers of mild traumatic brain injury in cerebrospinal fluid and blood. Nature Reviews Neurology, ,. 201-210.
  32. Zhang, F., Wang, S., Gan, L., Vosler, P.S., Gao, Y., & Chen, J. (2011). Protective effects and mechanisms of sirtuins in the nervous system. Prog Neurobiol, 95(3), 373-395.

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