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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel 13 Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) Polyunsaturated fatty acids are classified as n-3 (omega-3) or n-6 (omega-6) depending on whether their first double bond is located on the third or sixth carbon from the terminal methyl group (Jones and Kubow, 2006). More than 80 percent of dietary polyunsaturated fatty acids consumed in the United States consist of the 18-carbon, 2 double bond, n-6 (18:2, n-6) linoleic acid, with an average intake of about 17 g/day (IOM, 2005). The major dietary n-3 fatty acid is alpha-linolenic acid (ALA) (18:3, n-3), which is derived from certain nuts and vegetable oils (Kris-Etherton et al., 2000). Although the long-chain n-3 fatty acids eicosapentaenoic acid (EPA) (20:5, n-3) and docosahexaenoic acid (DHA) (22:6, n-3) can be synthesized from linolenic acid, the efficiency (yield) of the enzymatic reactions involved is rather low (Jones and Kubow, 2006). Epidemiological studies have indicated that Inuit populations in Greenland whose diets contain a high level of fish (and concomitant high levels of EPA and DHA) have low incidences of cardiovascular disease and rheumatoid arthritis, conditions with a significant inflammatory etiology (Dyerberg, 1993). Several mechanisms affected by n-3 fatty acids may account for these findings. Polyunsaturated fatty acids serve as the precursor molecules for eicosanoids. The primary precursor is arachidonic acid (20:4, n-6), which is enzymatically transformed into inflammatory prostaglandins or leukotrienes that contain two and four double bonds, respectively. Prostaglandins and leukotrienes synthesized from n-3 fatty acids contain three and five double bonds, respectively, and are less biologically active (Jones and Kubow, 2006). Dietary fish oil supplementation reduces synthesis of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) (Endres et al., 1989). Supplementation with n-3 fatty acids likewise reduces reactive oxygen species (ROS) production by leukocytes (Massaro et al., 2008). EPA and DHA are also the precursors for resolvins, which bring about a programmed resolution of the inflammatory process (Schwab et al., 2007), and DHA serves as the precursor for synthesis of protectins that have anti-inflammatory and neuroprotective activities (Serhan, 2006).
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel EPA AND DHA AND THE BRAIN Long-chain polyunsaturated fatty acids are important structural components in cell membrane phospholipid bilayers, with EPA and DHA concentrated in synaptic membranes in the brain and in the retina (Dyall and Michael-Titus, 2008). Variations in the ratio of n-3:n-6 composition may affect membrane fluidity, thickness, or other characteristics, as well as influence how proteins embedded in the membrane move and function (Lauritzen et al., 2001). There is evidence that n-3 fatty acids protect normal mitochondrial function and reduce excitotoxicity (reviewed in Dyall and Michael-Titus, 2008). Human studies (years 1990 and later) addressing the influence of EPA/DHA on resilience or treatment of central nervous system (CNS) injuries or disorders, such as stroke, epilepsy, and subarachnoid hemorrhage, are presented in Table 13-1. Likewise, Table 13-1 also lists animal studies on the effects of EPA/DHA on TBI. There are various models that explain the transportation of fatty acids through the blood-brain barrier, most of them involving complexes with albumin and circulating lipoproteins. Other models propose that there are no specific transporters that participate in this process (Hamilton and Brunaldi, 2007). USES AND SAFETY There are insufficient data to correlate reduced concentrations of n-3 fatty acids with functional impairments; therefore, no Estimated Average Requirements (EARs) have been established. An Adequate Intake (AI) for alpha-linolenic acid, based on the average daily intake by apparently healthy people that is therefore assumed to be adequate, has been set at 1.6 g/day for adult men and 1.1 g/day for adult women (IOM, 2005). Any intake of EPA and DHA, which normally accounts for about 10 percent of total n-3 fatty acids in the diet, is considered to contribute to the AI for ALA. The most effective way to increase body stores of EPA and DHA is through increased dietary intake of oil from cold-water fish species and from krill. Intake of up to 1 g/day of n-3 fatty acids from dietary fish intake is generally regarded as having very low risk, but higher intakes can increase the risk of gastrointestinal upset as well as increases in blood glucose and concentrations of low-density lipoprotein (LDL) cholesterol (Kris-Etherton et al., 2002). Increased intake of n-3 fatty acids will decrease the synthesis of the eicosanoid thromboxane A2, which promotes platelet aggregation (Kramer et al., 1996). Excessive intake can therefore increase the risk of bleeding, although this was not generally observed in a number of randomized clinical trials of fish-oil supplementation (Huang et al., 2007; Javierre et al., 2006). Environmental contaminants such as mercury and polychlorinated biphenyls can accumulate in certain species of fish, presenting another potential risk. The risk from mercury toxicity can be diminished, however, by avoiding some fish species (e.g., swordfish, mackerel), and ingestion of other contaminants can be diminished by removing the skin and fat from fish before cooking. Alternatively, purified EPA and DHA can be taken in capsule form. Although increased dietary n-3 fatty acid intake reduces cellular production of ROS, the increased desaturation (double bonds) of these fatty acids increases susceptibility to lipid peroxidation, which may have detrimental effects on specific cellular processes, such as T cell–mediated immune function (Wu and Meydani, 1998). This can be ameliorated, however, by adequate supplementation with the antioxidant vitamin E (Wu and Meydani, 1998).
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel TABLE 13-1 Relevant Data Identified for n-3 Fatty Acids (DHA, EPA, ALA) Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Tier 1: Clinical trials Garbagnati et al., 2009 Ischemic stroke Randomized, double-blind, placebo-controlled trial Postinjury, n-3 polyunsaturated fatty acids (PUFA, 500 mg), antioxidants, PUFA and antioxidants, or placebo for 12 months Neurological and function status was not significantly affected by any supplements. Although PUFA was associated with lower mortality rate, the trend was not statistically significant. na=72 stroke patients No adverse effects were observed. Poppitt et al., 2009 Ischemic stroke Randomized, placebo-controlled trial 3 g/day of fish oil capsules containing approx 1.2 g total n-3 fatty acid (0.7 DHA, 0.3 EPA) or placebo for 12 weeks Fish oil had no effect on triglyceride level, though there was a nonsignificant 7% increase in the fish oil-treated group and a nonsignificant 3% decrease in the placebo group. n=102 stroke patients Fish oil also had no significant effect on total cholesterol level, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), LDL particle size, different sized LDL-C, high sensitivity C-reactive protein, erythrocyte sedimentation, ferritin, or fibrinogen. Analysis of the 28-item General Health Questionnaire showed that fish oil–treated group had a mean 1.41 point decrease in total score (95% CIb: –2.76 to –0.06; p=0.04) and a mean 1.24 point decrease in social dysfunction (95% CI: –2.33 to –0.14; p=0.03). There was no change in scores for somatic symptoms, anxiety and insomnia, or depression. Adverse effects related to treatment were not assessed.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Bromfield et al., 2008 Intractable focal or generalized epilepsy Randomized, double-blind trial for 12 weeks, then open-label for 4 weeks PUFA supplement (EPA + DHA) at 2.2 mg/day in 3:2 ratio or placebo During the double-blind phase, the number of subjects experiencing a > 50% reduction in seizure frequency was not significantly higher than baseline. Median seizure frequency during this study phase also showed no significant difference between the two groups. n=21 PUFA treatment also had no effect on quality of life, as measured by Quality of Life in Epilepsy survey. During the open-label phase, 79% of patients experienced decreased seizure frequency, with 33% of these patients experiencing a > 50% reduction. Analysis of serum drug concentration showed a 16% decrease in lamotrigine levels (p < 0.05); there were no changes in other drugs. Although not significant, nausea and/or diarrhea was reported more frequently in the treatment group (p=0.18). DeGiorgio et al., 2008 Refractory epilepsy Randomized, double-blind, cross-over clinical trial 9,600 mg of fish oil/day (2,800 mg of n-3 fatty acids) or same quantity of placebo An average 11% increase in seizure frequency from baseline was observed in patients taking fish oil, and an average 14% increase was observed in those taking placebo, but these increases were not significant (p=0.051). n=11 There was no significant change of seizure severity from baseline in either group. Fish oil treatment also had no effect on total cholesterol level, LDL level, high-density lipoprotein level, mean arterial pressure, or heart rate variability. However, fish oil treatment was inversely correlated with heart rate variability (SDNNc) in the highest risk patients (rsd=–0.65, p=0.03); there was no correlation between placebo and heart rate variability (SDNN).
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Tanaka et al., 2008 Stroke Prospective, randomized, open-label, blinded endpoint trial EPA (1,800 mg/day) supplementing statin or statin alone for approximately 5 years During the study period, subjects with no history of stroke who were taking EPA had significantly greater reduction in total cholesterol level (17.6% vs. 17.0%; p < 0.0001) and triglyceride level (7.3% vs. 2.6%; p < 0.0001) than subjects in the same subgroup who were not taking EPA. EPA subjects with history of stroke had greater reduction of triglyceride level (p < 0.001) than subjects not taking EPA. n=18,645 EPA supplementation had no significant effect in preventing stroke in subjects without a history of stroke, but it significantly reduced total stroke incident in subjects who had a history of stroke (HRe=0.80, 95% CI: 0.64–0.997; p=0.047). No adverse effects were mentioned. Yoneda et al., 2008 Subarachnoid hemorrhage (SAH) Prospective, non-randomized trial Oral administration of EPA (1,800 mg) daily for 10 days (day 4–14); control group did not receive EPA EPA supplementation significantly reduced the incidence of symptomatic vasospasm in the treatment group compared to the control group (14% vs. 36%, p=0.019). The EPA group also had a lower level of low-density areas attributable to vasospasm than the controls (4% vs. 29%, p=0.001). n=101 SAH patients More patients from the EPA group had a good outcome at 1 month after onset of SAH (85% vs. 64% in control group, p=0.022). The control group had more deaths than the EPA group (11% vs. 0%, p=0.020). No adverse effects were observed. Puri et al., 2007 Chronic refractory epilepsy Pilot, randomized, double-blind, placebo-controlled trial EPA (1 g) + DHA (0.7 g) or placebo daily for 12 weeks Treatment with n-3 fatty acids had no significant effect on the percentage change of phosphodiesters, γ-nucleotide triphosphate, or broadband component. No adverse effects were mentioned. n=7 patients average age: 50.7±13.6 years
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Yuen et al., 2005 Epilepsy Randomized, placebo-controlled, double-blind trial for 12 weeks, followed by open-label trial for another 12 weeks when all patients received PUFA 1 g of EPA + 0.7 g of DHA or matching placebo daily Greater proportion of patients on PUFA than on placebo had a > 50% seizure reduction in the first 6 weeks (17% vs. 0%, 95% CI: 1.5–3.6%; p < 0.05), but there was no difference between weeks 6 and 12. During the open-label period (weeks 13–24), total seizure and complex partial seizure in previously placebo-treated patients was reduced in weeks 13–18 compared to the first 6 weeks of the trial (p=0.051). There was no significant difference in rescue medication doses between the two groups during the blind period. But the PUFA group had greater decrease during weeks 19–24, with 1.2 from previous range of 1.9–2.3. There was no significant difference in serum antiepileptic drug concentration. n=57 Sleepiness, fatigue and breathlessness, diarrhea, recurrence of depression and paranoia, and status epilepticus were reported among only a small number of subjects on supplements (n=5, one subject reporting per adverse effect).
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results GISSI-Prevenzione Investigators, 1999 Myocardial infarction (MI), stroke, and death from cardiovascular causes (primary outcome events) Randomized, placebo-controlled, multi-center, open-label trial (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico) 2×2 factorial design: vitamin E (300 mg synthetic α-tocopherol) or placebo and n-3 PUFA (850–882 mg EPA and DHA as ethyl esters in average ratio of EPA/DHA 1:2) At 6 months, patients taking PUFA had decreased triglyceride concentration compared to controls (p < 0.05). Two-way analysis of PUFA treatment (vs. no PUFA) for the entire study period showed that PUFA-treatment patients were at lower risk for combined endpoints of death, non-fatal MI, and non-fatal stroke (RRf=0.90, 95% CI: 0.82–0.99; p=0.048). Four-way analysis of all four treatment groups confirmed that PUFA group was at lower risk for combined endpoints of death, non-fatal MI, and non-fatal stroke (RR=0.85, 95% CI: 0.74–0.98; p=0.023) and combined endpoints of cardiovascular disease (CVD) death, non-fatal MI, and non-fatal stroke (RR=0.80, 95% CI: 0.68–0.95; p=0.008). n=11,324 patients aged 49–70 years with recent (≤ 3 months) MI PUFA patients also had reduced risk of individual mortality events: CVD death (RR=0.70, 95% CI: 0.56–0.87; p=0.042), coronary death (RR=0.65, 95% CI: 0.51–0.84; p=0.0226), and sudden death (RR=0.55, 95% CI: 0.40–0.76; p=0.01). Analyzing the combined effects of PUFA and vitamin E showed that treatment reduced the risk for combined endpoints of death, non-fatal MI, and non-fatal stroke (RR=0.86, 95% CI: 0.74–0.99) and for CVD death, non-fatal MI, and non-fatal stroke (RR=0.88, 95% CI: 0.75–1.03). Total mortality also was reduced in PUFA + vitamin E group (RR=0.80, 95% CI: 0.67–0.95) compared to controls. The risk of combined death, non-fatal MI, and non-fatal stroke in PUFA + vitamin E patients was similar to patients taking PUFA alone. Gastrointestinal disturbances and nausea were reported as the most frequent side effects among 4.9% and 1.4% of n-3 PUFA recipients, respectively.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Tier 2: Observational studies Mozaffarian et al., 2005 Ischemic stroke Prospective cohort study Fish consumption (tuna, other baked or broiled fish, and fried fish or fish sandwich. Note: intake of tuna and other baked or broiled fish is positively correlated with DHA+EPA levels, but fried fish and fish sandwich are not) Tuna/other baked or broiled fish: compared to subjects with consumption of < 1 time/month, HR (adjusted for CVD risk factors) for those with intake of 1–3 times/month was 0.86 (95% CI: 0.65–1.13), 1–4 times/week was 0.74 (95% CI: 0.57–0.97), and ≥ 5 times/week was 0.72 (95% CI: 0.53–0.98); this trend was significant (p for trend=0.02). n=4,775 > 65 years old, with no history of cerebrovascular disease at baseline Further analysis of the trend showed that the significance existed for period between baseline and 6 years (p=0.03), but not years 6 to 12. follow-up at approximately 12 years Risk of ischemic stroke was reduced in tuna/other fish consumers: HR=0.85 for 1–3 times/month (95% CI: 0.63–1.15), HR=0.72 for 1–4 times/week (95% CI: 0.54–0.96), and HR=0.68 for ≥ 5 times/week (95% CI: 0.48–0.95; p for trend=0.009). Again, the trend was significant from baseline to 6 years (p=0.02), but not from years 6 to 12. Intake frequency had no significant impact on hemorrhagic stroke. Fried fish/fish sandwich: compared to those who ate < 1 time/month, total stroke risk was increased in those who consumed 1–3 times/month (HR=1.15, 95% CI: 0.95–1.39) and ≥ 1 time/week (HR=1.30, 95% CI: 1.04–1.61; p for trend=0.02). Analysis of follow-up period breakdown was not significant. Increased risk of ischemic stroke also was observed in these two groups consuming fried fish/fish sandwiches (1–3 times/month: HR=1.17, 95% CI: 0.96–1.43; ≥ 1 time/week: HR=1.36, 95% CI: 1.08–1.72; p for trend=0.008). This trend was significant during years 6 to 12 (p=0.03). Intake frequency had no significant impact on hemorrhagic stroke. Apart from the increased risk of stroke associated with fried fish/fish sandwich consumption, no other adverse effects were mentioned.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Caicoya, 2002 Stroke Population-based, case-control study Fish consumption Using intake of > 1 g/day as reference, stroke risk in subjects eating 1–22.5 g of fish per day was 70% lower (adjusted ORg=0.30, 95% CI: 0.12–0.78). Adjusted OR was 0.44 in those with intake of 23–45 g/day (95% CI: 0.18–1.41), 0.59 in those with intake of 46–90 g/day (95% CI: 0.24–1.47), and 0.76 in those with intake of 91–250 g/day (95% CI: 0.27–2.1). n=913 Risk of stroke increased with consumption of n-3 fatty acid. Compared to those consuming < 115 mg/day, adjusted OR for 116–319 mg/day was 1.14 (95% CI: 0.60–1.88), for 320–659 mg/day was 1.37 (95% CI: 0.91–2.20), and for > 659 mg/day was 1.76 (95% CI: 0.96–3.26); the trend was significant (χ2 for trend=2.7, p=0.01). Compared to those with fish intake of < 11.2 g/day, adjusted OR for cerebral infarction in those consuming 11.3–28.7 g/day was 1.05 (95% CI: 0.64–1.65), intake of 28.8–46.5g/day had OR=0.90 (95% CI: 0.55–1.48), and intake of > 46.5 g/day had OR=1.98 (95% CI: 1.08–3.45); the trend was not significant. OR of small, deep cerebral infarction in subjects consuming > 46.5 g/day was 3.21 (95% CI: 1.11–9.20); however, OR for superficial cerebral infarction and intraparenchymatous hemorrhage were not significant. Cerebral infarction in those consuming > 659 mg/day of n-3 fatty acid had adjusted OR=1.89 (95% CI: 0.95–3.75). Besides finding that increased fish consumption was associated with increased risk of stroke and cerebral infarction, no other significant adverse effects were mentioned.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results He et al., 2002 Stroke Prospective cohort study (Health Professional Follow-up Study) Fish consumption Men who consumed fish > 1 time/month had significantly lower risk of ischemic stroke than those who consumed fish < 1 time/month (p < 0.05). Specifically, cumulative consumption of 1–3 times/month had a 43% reduction in risk (RR=0.57, 95% CI: 0.35–0.95), once/week had a 44% reduction (RR=0.56, 95% CI: 0.37–0.84), 2–4 times/week had 45% reduction (RR=0.36–0.85), and ≥ 5 times/week had a 46% reduction (RR=0.54, 95% CI: 0.31–0.94); however, test for trend was not significant. n=43,671 men Compared to men whose cumulative intake of n-3 PUFA was < 0.05 g/day, those with higher intake had lower risk of ischemic stroke. Intake of 0.05–0.2 g/day was associated with 44% risk reduction (RR=0.56, 95% CI: 0.35–0.88), 0.2–0.4 g/day was associated with 36% reduction (RR=0.63, 95% CI: 0.40–0.98), and 0.4–0.6 g/day was associated with 46% reduction (RR=0.54, 95% CI: 0.32–0.91). Intake of > 0.06 g/day did not significantly reduce risk of ischemic stroke. And test for trend was also not significant. Fish consumption and n-3 PUFA intake had no effect on hemorrhagic stroke. And effects of fish consumption on ischemic stroke were not modified by use of fish oil, vitamin E, aspirin, or linolenic acid. Schlanger et al., 2002 Epilepsy secondary to other CNS diseases n=5 5 g/day of a spread containing 65% n-3 PUFAs After 6 months, seizures of grand mal stopped completely in 3 patients, reduced to once a month in 1 patient, and reduced to 3 times/week in another patient. 1 patient experienced seizure of petit mal. In this patient, frequency of petit mal was reduced to once/week from 5 times/week. observation period: 6 months None of the patients experienced adverse effects.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Iso et al., 2001 Stroke Prospective cohort study (Nurses Health Study) Fish and seafood consumption Increase of fish intake was inversely associated with risk (adjusted for age and smoking) of total stroke (p for trend=0.005), ischemic stroke (p=0.04), thrombotic infarction (p=0.02), and lacunar infarction (p=0.008). After further adjusting for CVD risk factors, intake of fruits and vegetables, saturated and trans fat, linoleic acid, animal protein, and calcium, inverse association was still significant for thrombotic infarction (p=0.03) and lacunar infarction (p=0.007). n=79,839 women with no history of stroke, cancer, CVD, diabetes, or high cholesterol level For thrombotic infarction, compared to fish intake of < 1 time/month, multivariate RR for intake of 1–3 times/month was 0.77 (95% CI: 0.46–1.30) and for > 2 times/week was 0.52 (95% CI: 0.27–0.99). For lacunar infarction, multivariate RR for fish intake of 1–3 times/month was 0.63 (95% CI: 0.32–1.24) and for > 2 times/week was 0.28 (95% CI: 0.12–0.67). 14-year observation period Increase in PUFA intake was inversely associated with risk of total stroke (p for trend=0.01), lacunar infarction (p=0.01), hemorrhagic stroke (p=0.03), and SAH (p=0.03). After further adjustment for CVD risk factors and dietary pattern, the inverse association remained significant only for lacunar infarction (p=0.004). Compared to PUFA intake in the lowest quintile (median intake of 0.077 g/day), multivariate RR for lacunar infarction was 0.89 (95% CI: 0.55–1.43) in the 2nd quintile and 0.37 (95% CI: 0.19–0.73) in the 5th quintile. When n-3 fatty acid intake exceeded 3 g/day (or, approximately the consumption of fish 3 times or more per day), bleeding time was prolonged.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Tier 3: Animal studies Mills et al., 2010; Bailes and Mills, 2010 Traumatic axonal injury, impact acceleration injury Adult, male Sprague-Dawley rats Postinjury, oral supplementation of n-3 fatty acids (10 or 40 mg/kg/day) or no treatment Immunohistochemical analysis showed that injured rats without n-3 fatty acids supplement had significantly increased amyloid precursor protein-labeled axons than sham-injured rats (p < 0.05) and rats receiving n-3 fatty supplements (p < 0.05); there was no significant difference between supplemented rats and sham-injured rats. Further immunohistochemical analysis showed that sham-injured rats and rats receiving n-3 supplementation had significantly fewer caspase-3 positive axons than injured, unsupplemented rats (p < 0.05). Wu et al., 2007 TBI, mild fluid percussion injury (FPI) Sprague-Dawley rats Preinjury, diet supplemented with n-3 fatty acids (1.4% DHA and 13.5% EPA) or regular diet for 4 weeks Injury significantly reduced Sir2α expression (p < 0.05 vs. sham-injured rats), but n-3 fatty acid supplementation significantly restored it (p < 0.05). Level of oxidized protein was increased after injury (p < 0.01 vs. sham), but was reduced by n-3 fatty acid supplementation (p < 0.01). Sir2α expression was negatively correlated with oxidized protein level (ri=−0.67, p < 0.05). AMPK and p-AMPK levels were significantly reduced by injury (p < 0.05 vs. sham), but were increased to the same level as sham-injured rats by n-3 fatty acid supplementation. In sham-injured and n-3 fatty acid treated rats, Sir2α was correlated with AMPK (r=0.82, p < 0.05) and p-AMPK (r=0.96, p < 0.05). The correlations were not significant in injured rats. Ubiquitous mitochondrial creatine kinase was significantly reduced in injured rats (p < 0.05 vs. sham), but was restored in n-3 fatty acid treated rats.
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel Reference Type of Injury/Insult Type of Study and Subjects Treatment Findings/Results Wu et al., 2004 TBI, mild fluid percussion injury model Male, Sprague-Dawley rats Preinjury, diet supplemented with fish oil (12.4% DHA and 13.5 EPA) or regular diet for 4 weeks before injury and for 1 week after injury Learning ability in rats was assessed with Morris water maze. Rats fed with fish oil supplemented diet performed significantly better than rats fed with regular diet (p < 0.05) and were similar to sham-injured rats. Swimming speed was similar across all groups. Levels of BDNF, CREB, and synapsin I were significantly reduced by injury (p < 0.05 vs. sham), but were restored to normal levels with n-3 fatty acid supplementation. Compared to sham-injured rats, injured rats on regular diet had higher level of oxidized protein (p < 0.01). But injured rats fed with n-3 fatty acid supplemented diet had significantly lower level of oxidized protein compared to injured rats on regular diet and sham-injured rats on both diets (p < 0.01). a n: sample size. b CI: confidence interval. c SDNN: standard deviation of all normal R-R intervals for 1 hour, where R-R is the time between two r-waves on the ECG. d rs: Spearman’s correlation. e HR: hazard ratio. f RR: relative risk. g OR: odds ratio. h χ2: Chi-square. i r: correlation coefficient. EVIDENCE SUGGESTING INCREASED RESILIENCE Human Studies There have been no human studies examining the role of EPA/DHA in providing resilience to traumatic brain injury (TBI). However, several randomized clinical trials have examined the effect of EPA/DHA on other neurological diseases, such as epilepsy and stroke, with mixed results. In a clinical trial including 942 Japanese hypercholesterolemic patients with stroke, use of EPA (1,800 mg/day for approximately five years) led to a significant reduction of stroke recurrence (Tanaka et al., 2008). Use of n-3 fatty acids also was associated with a lower risk of mortality in stroke patients in a small trial (n = 72) (Garbagnati et al., 2009). In another trial including 102 ischemic stroke patients, however, fish oil supplementation (1,200 mg/day) for 12 weeks produced no significant differences from placebo in any lipids, inflammatory, hemostatic, or composite mood parameters (Poppitt et al., 2009). In a small trial including 51 epilepsy patients, seizure frequency was reduced over the first six weeks of supplementation with n-3 fatty acids (1,700 mg/day), but the protective effect was not sustained thereafter (Yeun et al., 2005). Additional studies (from 1990) addressing the influence of EPA/DHA on other CNS injuries or disorders in humans, such as stroke, epi-
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel lepsy, subarachnoid hemorrhage, and Alzheimer’s disease are presented in Table 13-1. The occurrence or absence of adverse effects in humans is included if reported by the authors. Animal Studies A series of animal studies (Wu et al., 2004, 2007) showed that preinjury intake of an n-3 fatty acid–enriched diet (8 percent of total energy) could counteract some of the damaging effects of TBI by, for example, normalizing levels of molecular systems associated with energy homeostasis (e.g., Sir2α), ameliorating protein oxidation, and improving learning ability (Table 13-1). These results suggest potential neuroprotective effects of n-3 fatty acids on TBI. EVIDENCE INDICATING EFFECT ON TREATMENT Human Studies There have been no clinical trials conducted to determine the efficacy of n-3 fatty acid infusion for treatment of TBI. Nevertheless, n-3 fatty acid infusion into healthy human subjects affects several inflammatory pathways in a way that could be beneficial for TBI patients: platelet aggregation and thromboxane B2 synthesis were reduced within 60 minutes of infusion (Elmadfa et al., 1993). In a different study, the ratio of n-3 to n-6 fatty acids in monocyte membranes likewise increased, monocyte synthesis of interleukin-1 and TNF decreased, and monocyte adhesion/transendothelial migration decreased within 48 hours after initiation of infusion (Mayer et al., 2003). Animal Studies In a 2010 study using an impact acceleration head injury model, 40 adult male Sprague-Dawley rats were assigned to four groups (n = 10 per group), of which two groups received dietary supplementation of n-3 fatty acids (EPA:DHA = 2:1) at a dosage of 10 or 40 mg/kg/day, starting on postinjury day one (Mills et al., 2010). The authors found that, compared to injured rats on the control diet, n-3 fatty acids significantly reduced the number of beta-amyloid precursor protein-positive (injured) axons at 30 days postinjury, achieving levels similar to those in uninjured animals. CONCLUSIONS AND RECOMMENDATIONS The n-3 fatty acid status of the active-duty military population is unknown. A survey by Lieberman et al. (2010) sought to determine the current usage of dietary supplements in U.S. Army soldiers on active duty. Fish oil was grouped in an “other” category that included supplements such as melatonin, caffeine, coenzyme Q10, and lycopene. The authors reported that 11 percent of military personnel in combat-arms positions and 23 percent of those in Special Forces were taking “other” supplements. Data on the EPA and DHA concentrations measured in frozen serum (some archived for up to several years) from military personnel suggest that the levels are lower than in the civilian population (Lewis et al., 2011). There were a number of methodological differences, however, in the comparison civilian studies, such as measurement of fresh (not frozen) serum samples, expression of DHA as a percentage of fatty acids in serum phospholipids (rather than total fatty acids), or measurement of DHA levels in red blood cell membranes (rather than serum). Differences in DHA concentra-
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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel tions between military and civilian populations might thus be attributable to methodological issues. In order to definitively determine if such differences exist, it will be necessary to conduct a prospective study in which samples from both populations are collected, stored, processed, and assayed in a uniform manner. By better determining the n-3 fatty acid status of military personnel, these data will also provide a basis for recommending increases in intake of n-3 fatty acid should future research findings indicate a role in resilience to TBI. It is well documented that fish-oil supplementation will decrease inflammation. The influences of n-3 fatty acids on prostaglandin, leukotriene, cytokine, and ROS were described earlier in this chapter, and extensive reviews are available (Calder, 2006; Massaro et al., 2008). When taken orally, the effects of n-3 fatty acids are not evident for days to weeks because of their slow incorporation into cellular membranes. Initiation of oral administration after TBI therefore may not be of immediate benefit (although when evaluated 30 days after injury, the 2010 animal study by Mills and colleagues showed reductions in neuronal toxicity). On the other hand, evidence from human subjects indicates that intravenous administration of n-3 fatty acids can have more immediate effects. This is especially relevant to military operational settings, where the feasibility of a feeding tube or oral administration is greatly reduced immediately following injury. Overall, continuous administration—whether enteral, parenteral, or intravenous—is considered to be most effective in the early phase of severe TBI. RECOMMENDATION 13-1. DoD should conduct animal studies that examine the effectiveness of preinjury and postinjury oral administration of current commercial preparations of purified n-3 fatty acids on TBI outcomes. RECOMMENDATION 13-2. Based on the evidence that fish oil decreases inflammation within hours of continuous administration, human clinical trials that investigate fish oil or purified n-3 fatty acids as a treatment of TBI are recommended. For acute cases of TBI, it should be noted that there are intravenous fish oil formulations available in Europe, but these are not approved by the Food and Drug Administration. Continuous enteral feeding with a feeding formula containing fish oil should provide equivalent effects for this purpose in the early phase of severe TBI when enteral access becomes available. REFERENCES Bailes, J. E., and J. D. Mills. 2010. Docosahexaenoic acid reduces traumatic axonal injury in a rodent head injury model. Journal of Neurotrauma 27(9):1617–1624. Bromfield, E., B. Dworetzky, S. Hurwitz, Z. Eluri, L. Lane, S. Replansky, and D. Mostofsky. 2008. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy and Behavior 12(1):187–190. Caicoya, M. 2002. Fish consumption and stroke: A community case-control study in Asturias, Spain. Neuroepidemiology 21(3):107–114. Calder, P. C. 2006. N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. American Journal of Clinical Nutrition 83(6 Suppl.):1505S–1519S. DeGiorgio, C. M., P. Miller, S. Meymandi, and J. A. Gornbein. 2008. N-3 fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of sudep: Clues from a pilot, double-blind, exploratory study. Epilepsy and Behavior 13(4):681–684. Dyall, S. C., and A. T. Michael-Titus. 2008. Neurological benefits of omega-3 fatty acids. Neuromolecular Medicine 10(4):219–235. Dyerberg, J. 1993. Epidemiology of n-3 fatty acids and disease. In Fatty acids and vascular disease, edited by R. De Caterina, S. Endres, S. D. Kristensen and E. B. Schmidt. London: Springer-Verlag.
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