Skip to main content
Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

A Fat to Forget: Trans Fat Consumption and Memory

Abstract

Purpose

We sought to assess the relation of dietary trans fatty acid (dTFA) consumption to word-memory.

Methods

We analyzed cross-sectional data from the 1999-2005 UCSD Statin Study. Participants were 1018 adult men and non-procreative women age ≥20 without diagnosed diabetes, CVD, or extreme LDL-cholesterol. Primary analyses focused on men, as only men (N = 694) were effectively represented in younger adult ages. “Recurrent words” assessed word memory. dTFA (grams/day) estimates were calculated from the Fred Hutchinson Food Frequency Questionnaire. Regression, stratified at age 45, assessed the relation between memory and dTFA in various adjustment models. Major findings were replicated in the full sample (including women). Potential mediators were examined.

Results

An age-by-dTFA interaction was significant. dTFA adversely predicted memory in younger adults (only), robust to adjustment model. Each gram/day dTFA was associated with an estimated 0.76 fewer words recalled (full model) (SE = 0.27, 95%CI = 0.22,1.3, P = 0.006). Adjustment for systolic blood pressure, waist circumference and BMI (but not lipid or glycemic variables) attenuated the relationship, consistent with mediation by factors involving, relating to, or concurrently influencing, these factors.

Conclusion

Greater dTFA was significantly associated with worse word recall in younger adults. Prooxidant and energetic detriments of dTFA and triangulation with other evidence offer prospects for causality.

Introduction

Dietary trans fatty acids (dTFAs), which are primarily from industrial production[1], have been linked to adverse effects on lipid profiles, metabolic function, insulin resistance, inflammation, and cardiac and general health[217]. Each of these in turn has adverse associations with, and potential for adverse consequences to, cognitive function[1822].

Additionally, long chain omega-3 fatty acids (n3FAs)[2325], which are anti-inflammatory and for which production is inhibited by dTFAs[26, 27], are important to brain health with favorable central nervous system effects reported for behavior[24] and mood[24]. For those outcomes, dTFAs have shown adverse associations[28, 29]. n3FAs have been presumptively linked to favorable cognitive function[30, 31], adding further rationale for assessing for an adverse dTFA relation to memory.

Moreover, dTFAs adversely affect oxidative stress[12, 32], which has adverse consequences to cell energy. Oxidative stress promotes endothelial dysfunction (limiting adequacy of blood flow and hence delivery of energy substrates), as well as mitochondrial dysfunction (reducing production of ATP from energy substrates that are delivered)[33]. Among cognitive functions, memory may be particularly sensitive to cell energy effects. Hippocampal cells (area CA1) are selectively vulnerable to death in settings of impaired energy, such as episodes of hypoxemia, hypoglycemia, or ischemia[3436]. Thus, oxidative-energetic effects may be expected to potentiate the impact of other insults on hippocampal cell viability, and hence memory function.

It was previously shown that more frequent consumption of chocolate—a dietary substance that is rich in antioxidants[37, 38], which enhances cerebral blood flow[39] and improves mitochondrial biogenesis[40]—was linked to better memory performance[41]. This effect was strong among younger adults, but evident only in younger adult ages, particularly age <45[41]. (Children were not assessed.)

Indeed, in the prior chocolate analysis, none of the memory predictors, including chocolate, that were significant in younger age retained significance into older adult age in cross-sectional analysis. This is despite the fact that cocoa flavanols experimentally improve cognition in older age[42]. This is likely because of twin factors that affect detection of cognitive compromise in older age. In older age, any effect of a memory-adverse exposure is superimposed on the effects of other sources of (generally downward) variability that add variance and extend the range downward, and then those whose function is below some threshold disproportionately fail to participate in studies[43]. Together these effects compromise ability to detect the association or effect of an exposure on memory, cross-sectionally, in older age. Indeed, the mean word-recall score in older participants (up to age 85 years) was closely similar to that in younger age[41], rather than markedly worse, and variance—expected to be higher where there are accrued age-related sources of loss—was actually lower.

We capitalized on baseline data from a clinical trial sample with broad participation parameters that included dietary and word memory assessments to test the conjectures that dTFAs, in contradistinction to chocolate, might be associated with worse memory performance, and that an effect, if present, may be selectively evident in younger adult ages.

Methods

Participants were 1,018 adult men and nonprocreative women (surgically or chronologically postmenopausal), who had been screened for participation in the UCSD Statin Study. Participants were relatively broadly sampled including male and female adults age ≥20, with no restriction on ethnicity, education or occupation. However, persons on lipid medications, or with extremes of LDL-cholesterol (<115mg/dL or >190mg/dL), known diabetes, cardiovascular disease, HIV, or cancer were excluded[28][44]. Since participants were screenees for a drug trial[44, 45], women of procreative potential were excluded. For this reason, only males are well-represented in younger adult ages, thus spanning the adult age spectrum. Males are therefore the focus of the primary analysis.

The study protocol was approved by the University of California, San Diego Human Research Protections Program. All participants gave written informed consent.

Dietary Trans Fatty Acid Estimation

645 of 694 men (93%) completed a dietary survey prior to their baseline visit, using a questionnaire developed by the Nutrition Assessment Shared Resource of the Fred Hutchinson Cancer Research Center[46]. Consumption frequency and portion size were queried for a series of food categories, each in turn defined by a series of foods or beverages. Additional questions relating to food preparation and purchasing further refine nutrient calculations (http://www.fhcrc.org/science/shared_resources/nutrition/ffq/)[28].

Calculations for trans fats and other nutrients “were performed using the Nutrient Data System for Research software version 4.03, developed by the Nutrition Coordinating Center, University of Minnesota Food and Nutrient Database (version 31, released November 2000), which added trans fatty acid values in 1998”[28]. Values for trans fats “were determined for all foods in the database (0% missing) and include individual contributions of 16:1 trans (trans-hexadecenoic acid); 18:1 trans (trans-octadecenoic acid); and 18:2 trans (trans-octadecadienoic acid), which encompasses cis-trans, trans-cis, and trans-trans forms; as well as total trans-fatty acids. The USDA table ‘Fat and Fatty Acid Content of Selected Foods Containing Trans-Fatty Acids’…was the primary source of trans-fatty acid information for assignment of values to foods in the database. Additional data sources included other nutrient databases and articles in the scientific literature containing trans-fatty acid values for US foods, using appropriate methodologies”[47]. dTFA is given in grams/day.

Word memory assessment

In a “recurrent words” task[41, 48, 49], participants were sequentially presented a set of 104 cards each bearing a word. 82 of the cards displayed words shown for the first time in the set, while 22 cards displayed words that had been presented previously. Participants state whether each word was new (presented for the first time) or recurrent (presented previously). The score was the summed “hits” (correct responses, whether for a new or recurrent word), conforming to reported use of this test elsewhere[41, 48, 49].

Covariates

Assessed covariates that could serve as confounders included age, exercise (times/week vigorous exercise for more than 20 minutes), education (scored 1–9), ethnicity (Caucasian vs. other), chocolate consumption (time/week, previously shown to relate to this memory measure[50]), and mood (Center for Epidemiological Studies Depression Scale—CES-D). Mood was significantly adversely linked to dTFAs in this sample (though the published results relatively emphasized the correlated but stronger aggression relationship)[28], and in the literature[29].

Analyses

Descriptive statistics characterized the primary outcome, primary predictors, covariates, and assessed mediator variables, in all men and stratified at age 45 (with 164 men age <45, and 530 men age ≥45). Linear regression analyses stratified at age 45 was performed for men, the group in whom younger age was represented, with word memory as the outcome variable and dTFA as the primary predictor. Models assessed the dTFA relationship adjusted for age, then added sequentially exercise; ethnicity and education which were interrelated variables; and chocolate frequency and depression—also interrelated[51]. The full-adjustment models were run with addition of women from the sample (though fewer than 10 were under age 45 years) for qualitative similarity.

To affirm an age-interaction of relevance to the 45-year stratification in men, the fully adjusted model was repeated with addition of an age-by-dTFA interaction term, with equal years represented on each side of 45 (20–44, 45–69). (Both components of the interaction term were included in the regression.)

Analyses designed to assess potential mediators added adjustment for metabolic markers individually and in combination: HDL (mg/dL), triglycerides (mg/dL), LDL (mg/dL), glucose (mg/dL), insulin (mU/mL), waist circumference (cm), BMI (kg/m2), and systolic blood pressure (SBP) (mmHg). dTFAs have elsewhere related to these variables, and in this sample significantly predicted waist circumference and BMI[52], as well as SBP.

Analyses used Stata 8.0 and 11.0, College Station, TX. A 2-sided P-value <0.05 defined statistical significance.

Results

Table 1 shows participant characteristics for men, the focus of the main analysis. (Age range for men and for all participants was 20–85 years.) The average word memory score (out of a possible 104) was 85 words correctly identified as new or recurrent. The mean scores were 86 for those age <45; and 85 for those age ≥45. dTFA was higher in young men than in the remainder of the sample (mostly older, as there were few young women), P = 0.001. Mean dTFA was 3.8 grams/day overall; 4.1 in age <45, and 3.7 in age ≥45. The maximum estimated dTFA was 15.5 grams/day in men under age 45, and 27.7 for the overall sample.

Table 2 shows the relationship between dTFAs and memory performance in men age <45 years, in a range of models adjusting for potential confounders—adjusted for age only, then successively adding exercise, ethnicity and education (related to one another including in this sample), and chocolate frequency and mood (also related in this sample[51]). Trans fat consumption adversely predicted word-recall performance in younger adults age across the adjustment models.

thumbnail
Table 2. Dietary Trans Fat Relation to Memory, Stratified by Age: Men Age <45.

https://doi.org/10.1371/journal.pone.0128129.t002

In contrast, there was no relation of dTFAs to word memory in those over age 45 (Table 3). Other predictors (chocolate, mood, ethnicity) also lost significance in older age.

thumbnail
Table 3. Dietary Trans Fat Relation to Memory, Stratified by Age: Men Age ≥45.

https://doi.org/10.1371/journal.pone.0128129.t003

The primary analysis focused on men, since women under age 45 were few and were surgically or chronologically postmenopausal, and thus not reflective of their age group. Of note, however, findings did not differ materially with inclusion of women under age 45, and retained the same significance value of P<0.006 in the fully-adjusted model.

Assessing the age-interaction using the fully adjusted model affirmed a strong age-by-dTFA interaction term: per year of age and gram/day of dTFAs, interaction β = 0.028 (SE = 0.013, 95%CI = 0.004, 0.053), P = 0.025. The dTFA term was separately significant β = -1.52 (SE = 0.64; 95%CI = -2.79, -0.26), P = 0.018. This supports the age-stratified analysis.

Table 4 shows the effect of adjusting for potential mediating variables, variables that dTFAs have been reported to influence, that might serve in the causal pathway to adverse memory (or alternatively, that factors in the causal pathway might concurrently influence). Addition of variables in the causal pathway (or concurrently affected by mechanisms in the causal pathway) is expected to attenuate or obviate the association. Adjustment for HDL, triglycerides, LDL, glucose and insulin, separately or together, did not materially attenuate the relationship of dTFAs to memory. However, adjustment for SBP, waist circumference and BMI did substantially attenuate significance of the dTFA prediction. Of relevance, SBP, waist circumference and BMI did not themselves significantly predict memory performance, suggesting that mechanisms by which dTFAs affect BMI (rather than BMI itself) may also affect memory impairment, further supporting use of these terms as (proxies for) mediators, rather than as confounders. The relationship remained (just) significant with adjustment for these three predictors separately and together. Adjustment for all metabolic variables together did abrogate significance, but in a model that is “overadjusted” (violating the heuristic of 10 participants per predictor, with 15 predictor variables).

thumbnail
Table 4. Dietary Trans Fat Relation to Memory: Effect of Adding Potential Metabolic Mediators to Full Model (Men Age <45)*.

https://doi.org/10.1371/journal.pone.0128129.t004

Discussion

Greater dTFA consumption showed an adverse relation to word recall performance in adults age <45 years, working years in which much productive and creative work is undertaken. To our knowledge, an adverse relationship of dTFAs to memory or cognition in younger adulthood has not been previously shown. The relevance of the effect, an estimated 0.76 fewer words recalled per gram/day dTFA should be viewed in the context that participant dTFAs at the time of the study ranged up to 28 grams/day—which in a man age <45 would yield an estimated 21 fewer correct word-recall responses, in the setting of an average score of 86. (In the smaller sample of men age <45, the maximum reported consumption of 15.7 grams/day would yield an estimated 11–12 fewer correct responses. Since younger men on average had higher dTFA than others, P = 0.001, and higher variance, it might be expected that a higher maximum dTFA would be observed had a larger sample of young men been available.) The relationship was robust within the younger adult group to adjustment for potential confounders such as age, exercise, education, ethnicity, and mood. Younger adults were predominantly men, and the analysis focused on that group; however, including the small number of women under 45 did not modify the strong significance of the adverse dTFA relationship to word memory.

An association of dTFAs to word memory was not observed in older adults (age ≥45), consistent with expectation from findings with other predictors, and consistent with nonparticipation of more impaired participants, increasingly removing a relevant part of the distribution with increasing age[43]. (Greater variance in word memory introduced by accrued cognitive losses with age, leading the range to be extended downward into cognitive territory that may contribute to nonparticipation in studies[41], could mean the restricted visible portion of the distribution no longer retains comparable power to detect associations.) This limits implications of the study in the older age group, but does not diminish authority of observed associations in younger age.

In those age <45, in whom dTFAs adversely predicted word memory: only SBP, waist circumference, and BMI (which relates to dTFAs in humans[52] and animals[53]), among assessed potential mediators, materially attenuated significance of the relationship. Despite reducing significance of the dTFA association to memory, none independently predicted memory performance. This suggests that dTFA-related mechanisms influenced these metabolic parameters in parallel with cognition, rather than these metabolic variables themselves bearing a mediating role. dTFA consequences to oxidative stress and cell energy are leading candidates for this effect: triangulating evidence links oxidative stress and adverse cell energy deleteriously to BMI, SBP and other metabolic syndrome variables[33]. Oxidative stress is tied to cognitive decline observationally in humans[54, 55] and experimentally in animals[56]. Adverse energy is expected to affect brain function particularly: the brain is highly energy demanding, representing ~2–4% of body weight but consuming ~20% of the oxygen[57] and ~50% of the glucose[58]; and hippocampal vulnerability to energy depletion may make memory particularly vulnerable[3436].

These findings expand adverse associations of dTFAs to health generally, and to central nervous system function in particular. Previously, dTFAs were adversely linked to behavior[28], and to mood[29]. The findings presented here add evidence for adverse associations to a third key prong of brain function—cognition. Findings cohere with previous findings linking food products that have favorable effects on oxidative stress, cell energy, and blood flow to favorable memory performance also confined to younger adult age[41].

This study has limitations. Data are cross-sectional, and unaccounted sources of bias and confounding cannot be excluded. However, documented adverse effects of dTFAs to mechanisms with documented relevance to brain function, including effects on essential fatty acids, oxidative stress, and cell energetics, offer material prospects for causality. This study used dietary report rather than objective markers of trans fatty acids such as red blood cell membrane trans fats[59], or plasma phospholipid trans fats[60]. This can be viewed as a strength or a limitation: while nutrient markers have the advantage of being objective, they have the considerable disadvantage that associations of nutrient levels to outcomes need not reflect any effect of either nutrient intake or nutrient levels per se, but may rather reflect effects of factors that modify the relation of nutrient intake to blood level[28]. For example, folate levels are influenced by genetic variants of methylenetetrahydrofolate reductase (MTHFR)—independent of intake[61]; and variants of MTHFR relate to numerous health conditions, in part through effects of MTHFR on DNA synthesis and DNA methylation[62]. Analogous processes could be in play for trans fat marker levels. Nonetheless, if further human studies of dTFAs were conducted, reassessment of the association using such measures would provide relevant triangulating information. dTFA was estimated from dietary recall. Not all foods that go by the same label have the same trans fat content. However, provided the misclassification is non-differential, this might be expected to produce bias toward the null (suggesting these findings may understate the true association). Although analyses that included the available women did not differ in findings, women were too few in number to draw separate conclusions. However, men represent half of the population, and a finding in this group is of independent importance. The study also did not include children, precluding conclusions about the dTFA-memory association in that group. Notably, though, the finding was stronger in younger individuals within the age group available for assessment.

This study also has material strengths. A randomized trial of dTFAs is unlikely to occur for ethical reasons (except perhaps of short duration), even if (or where) trans fats remain in the food chain. The window of opportunity for even observational assessment in humans may be closing, given the recent move of the USA Food and Drug Administration (FDA) to declare that trans fats are no longer “generally recognized as safe”[63]. This study occurred in a privileged window, after dTFA assessments had been added to the dietary assessment instrument, but before legislated trans fat labeling or restrictions were in place[64]—providing unusually favorable timing for examination of dTFA associations. Assessment of potentially important covariates, extending to exercise, mood and chocolate consumption, as well as evaluation of the full spectrum of metabolic markers, represents a key strength. The premise (and results) rest on a biological foundation. Factors including the relative strength of association, consistency of the main finding across a range of models bearing potential confounders, biological gradient (“dose response”), biological plausibility, and coherence with other literature were evident in our findings, and add weight to the possibility that the association we identify could have a causal basis.

Implications

These findings, in which greater dTFA consumption is linked to worse word memory in adults during years of high productivity, adults age <45, add to evidence for unfavorable health correlates of trans fat consumption. They extend findings to a third pillar of central nervous system function, cognition—complementing evidence for adverse dTFA relations to behavior (aggression/irritability)[28] and mood[29]. Findings comport with recent FDA moves to rescind the designation as “generally recognized as safe” for dTFAs[65]; and add support to similar efforts in other nations.

Acknowledgments

Findings were presented at the AHA Scientific Sessions 2014 in Chicago, IL on Nov 18, 2014.

Author Contributions

Conceived and designed the experiments: BAG. Performed the experiments: BAG. Analyzed the data: BAG AKB. Wrote the paper: BAG AKB.

References

  1. 1. Stender S, Astrup A, Dyerberg J. Ruminant and industrially produced trans fatty acids: health aspects. Food Nutr Res. 2008;52. pmid:19109659. Epub 2008/12/26. eng.
  2. 2. Mensink RP, Katan MB. Effect of a diet enriched with monounsaturated or polyunsaturated fatty acids on levels of low-density and high-density lipoprotein cholesterol levels in healthy women and men. N Engl J Med. 1989;321:436–41. pmid:2761578
  3. 3. Mensink RP, Katan MB. Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects [see comments]. N Engl J Med. 1990;323(7):439–45. pmid:2374566
  4. 4. Mensink RP, Katan MB. Trans monounsaturated fatty acids in nutrition and their impact on serum lipoprotein levels in man. Prog Lipid Res. 1993;32(1):111–22. pmid:8415796
  5. 5. Mensink RP, Temme EH, Hornstra G. Dietary saturated and trans fatty acids and lipoprotein metabolism. Ann Med. 1994;26(6):461–4. pmid:7695873
  6. 6. Hill EG, Johnson SB, Holman RT. Intensification of essential fatty acid deficiency in the rat by dietary trans fatty acids. J Nutr. 1979 Oct;109(10):1759–65. pmid:573784.
  7. 7. Mozaffarian D, Pischon T, Hankinson SE, Rifai N, Joshipura K, Willett WC, et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004 Apr;79(4):606–12. pmid:15051604.
  8. 8. Mozaffarian D, Rimm EB, King IB, Lawler RL, McDonald GB, Levy WC. Trans fatty acids and systemic inflammation in heart failure. Am J Clin Nutr. 2004 Dec;80(6):1521–5. pmid:15585763.
  9. 9. Sundram K, Ismail A, Hayes KC, Jeyamalar R, Pathmanathan R. Trans (elaidic) fatty acids adversely affect the lipoprotein profile relative to specific saturated fatty acids in humans. J Nutr. 1997;127(3):514S–20S. pmid:9082038
  10. 10. Sundram K, Karupaiah T, Hayes K. Stearic acid-rich interesterified fat and trans-rich fat raise the LDL/HDL ratio and plasma glucose relative to palm olein in humans. Nutr Metab (Lond). 2007;4:3. pmid:17224066.
  11. 11. Dyerberg J, Christensen JH, Eskesen D, Astrup A, Stender S. Trans, and n-3 polyunsaturated fatty acids and vascular function-a yin yang situation? Atheroscler Suppl. 2006 May;7(2):33–5. pmid:16713391.
  12. 12. Cassagno N, Palos-Pinto A, Costet P, Breilh D, Darmon M, Berard AM. Low amounts of trans 18:1 fatty acids elevate plasma triacylglycerols but not cholesterol and alter the cellular defence to oxidative stress in mice. Br J Nutr. 2005 Sep;94(3):346–52. pmid:16176604.
  13. 13. Mensink RP. Metabolic and health effects of isomeric fatty acids. Curr Opin Lipidol. 2005 Feb;16(1):27–30. pmid:15650560.
  14. 14. Ibrahim A, Natrajan S, Ghafoorunissa R. Dietary trans-fatty acids alter adipocyte plasma membrane fatty acid composition and insulin sensitivity in rats. Metabolism. 2005 Feb;54(2):240–6. pmid:15789505.
  15. 15. Natarajan S, Ibrahim A. Dietary trans fatty acids alter diaphragm phospholipid fatty acid composition, triacylglycerol content and glucose transport in rats. Br J Nutr. 2005 Jun;93(6):829–33. pmid:16079026.
  16. 16. Corcoran MP, Lamon-Fava S, Fielding RA. Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. Am J Clin Nutr. 2007 Mar;85(3):662–77. pmid:17344486.
  17. 17. Albuquerque KT, Sardinha FL, Telles MM, Watanabe RL, Nascimento CM, Tavares do Carmo MG, et al. Intake of trans fatty acid-rich hydrogenated fat during pregnancy and lactation inhibits the hypophagic effect of central insulin in the adult offspring. Nutrition. 2006 Jul-Aug;22(7–8):820–9. pmid:16815496.
  18. 18. van Exel E, de Craen AJ, Remarque EJ, Gussekloo J, Houx P, Bootsma-van der Wiel A, et al. Interaction of atherosclerosis and inflammation in elderly subjects with poor cognitive function. Neurology. 2003 Dec 23;61(12):1695–701. pmid:14694032.
  19. 19. Geroldi C, Frisoni GB, Paolisso G, Bandinelli S, Lamponi M, Abbatecola AM, et al. Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol. 2005 Jul;62(7):1067–72. pmid:16009759. Epub 2005/07/13. eng.
  20. 20. Messerotti Benvenuti S, Zanatta P, Valfre C, Polesel E, Palomba D. Preliminary evidence for reduced preoperative cerebral blood flow velocity as a risk factor for cognitive decline three months after cardiac surgery: an extension study. Perfusion. 2012 Jul 13. pmid:22798170. Epub 2012/07/17. Eng.
  21. 21. Eggermont LH, de Boer K, Muller M, Jaschke AC, Kamp O, Scherder EJ. Cardiac disease and cognitive impairment: a systematic review. Heart. 2012 Sep;98(18):1334–40. pmid:22689718. Epub 2012/06/13. eng.
  22. 22. Atzmon G, Gabriely I, Greiner W, Davidson D, Schechter C, Barzilai N. Plasma HDL levels highly correlate with cognitive function in exceptional longevity. J Gerontol A Biol Sci Med Sci. 2002 Nov;57(11):M712–5. pmid:12403798.
  23. 23. Iribarren C, Markovitz JH, Jacobs DR Jr., Schreiner PJ, Daviglus M, Hibbeln JR. Dietary intake of n-3, n-6 fatty acids and fish: relationship with hostility in young adults—the CARDIA study. Eur J Clin Nutr. 2004 Jan;58(1):24–31. pmid:14679363.
  24. 24. Conklin SM, Harris JI, Manuck SB, Yao JK, Hibbeln JR, Muldoon MF. Serum omega-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers. Psychiatry Res. 2007 Jul 30;152(1):1–10. pmid:17383013.
  25. 25. Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, Lodi L. Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. Eur J Clin Invest. 2005 Nov;35(11):691–9. pmid:16269019.
  26. 26. De Schrijver R, Privett OS. Interrelationship between dietary trans Fatty acids and the 6- and 9-desaturases in the rat. Lipids. 1982 Jan;17(1):27–34. pmid:7087680.
  27. 27. Kurata N, Privett OS. Effects of dietary trans acids on the biosynthesis of arachidonic acid in rat liver microsomes. Lipids. 1980 Dec;15(12):1029–36. pmid:7219072.
  28. 28. Golomb BA, Evans MA, White HL, Dimsdale JE. Trans fat consumption and aggression. PLOS One. 2012;7(3):e32175. pmid:22403632. Epub 2012/03/10. eng.
  29. 29. Sanchez-Villegas A, Verberne L, De Irala J, Ruiz-Canela M, Toledo E, Serra-Majem L, et al. Dietary fat intake and the risk of depression: the SUN Project. PLOS One. 2011;6(1):e16268. pmid:21298116. Epub 2011/02/08. eng.
  30. 30. Lim WS, Gammack JK, Van Niekerk J, Dangour AD. Omega 3 fatty acid for the prevention of dementia. Cochrane Database Syst Rev. 2006 (1):CD005379. pmid:16437528.
  31. 31. Robinson JG, Ijioma N, Harris W. Omega-3 fatty acids and cognitive function in women. Womens Health (Lond Engl). 2010 Jan;6(1):119–34. pmid:20088735. Epub 2010/01/22. eng.
  32. 32. Tomey KM, Sowers MR, Li X, McConnell DS, Crawford S, Gold EB, et al. Dietary fat subgroups, zinc, and vegetable components are related to urine F2a-isoprostane concentration, a measure of oxidative stress, in midlife women. J Nutr. 2007 Nov;137(11):2412–9. pmid:17951478. Epub 2007/10/24. eng.
  33. 33. Golomb BA. The starving cell: Metabolic syndrome as an adaptive process. Nature Precedings. 2011; Available: http://precedings.nature.com/documents/6535/version/1.
  34. 34. Lavenex P, Sugden SG, Davis RR, Gregg JP, Lavenex PB. Developmental regulation of gene expression and astrocytic processes may explain selective hippocampal vulnerability. Hippocampus. 2011 Feb;21(2):142–9. pmid:20014383. Epub 2009/12/17. eng.
  35. 35. Hong YM, Jo DG, Lee JY, Chang JW, Nam JH, Noh JY, et al. Down-regulation of ARC contributes to vulnerability of hippocampal neurons to ischemia/hypoxia. FEBS Lett. 2003 May 22;543(1–3):170–3. pmid:12753927. Epub 2003/05/20. eng.
  36. 36. Tanaka Y, Takata T, Satomi T, Sakurai T, Yokono K. The double-edged effect of insulin on the neuronal cell death associated with hypoglycemia on the hippocampal slice culture. Kobe J Med Sci. 2008;54(2):E97–107. pmid:18772618. Epub 2008/09/06. eng.
  37. 37. Spadafranca A, Martinez Conesa C, Sirini S, Testolin G. Effect of dark chocolate on plasma epicatechin levels, DNA resistance to oxidative stress and total antioxidant activity in healthy subjects. Br J Nutr. 2010 Apr;103(7):1008–14. pmid:19889244. Epub 2009/11/06. eng.
  38. 38. Vinson JA, Proch J, Bose P, Muchler S, Taffera P, Shuta D, et al. Chocolate is a powerful ex vivo and in vivo antioxidant, an antiatherosclerotic agent in an animal model, and a significant contributor to antioxidants in the European and American Diets. J Agric Food Chem. 2006 Oct 18;54(21):8071–6. pmid:17032011. Epub 2006/10/13. eng.
  39. 39. Sorond FA, Lipsitz LA, Hollenberg NK, Fisher ND. Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat. 2008 Apr;4(2):433–40. pmid:18728792. Epub 2008/08/30. eng.
  40. 40. Nogueira L, Ramirez-Sanchez I, Perkins GA, Murphy A, Taub PR, Ceballos G, et al. (-)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. The Journal of Physiology. 2011 September 15, 2011;589(18):4615–31. pmid:21788351
  41. 41. Golomb BA, Huynh K, Vomberg Z, Hathaway Meskimen A. More Frequent Chocolate Consumption is Linked to Better Word Memory Circulation. 2012;126:A16156.
  42. 42. Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, et al. Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment: The Cocoa, Cognition, and Aging (CoCoA) Study. Hypertension. 2012 Sep;60(3):794–801. pmid:22892813. Epub 2012/08/16. eng.
  43. 43. Golomb BA, Chan VT, Evans MA, Koperski S, White HL, Criqui MH. The older the better: are elderly study participants more non-representative? A cross-sectional analysis of clinical trial and observational study samples. BMJ Open. 2012;2(6). pmid:23242479. Epub 2012/12/18. eng.
  44. 44. Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH. Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial. Arch Intern Med. 2008 Apr 14;168(7):721–7. pmid:18413554. Epub 2008/04/17. eng.
  45. 45. Golomb BA, Criqui MH, White HL, Dimsdale JE. The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes. Control Clin Trials. 2004 Apr;25(2):178–202. pmid:15020036.
  46. 46. Schakel SF. Procedures for estimating nutrient values for food composition databases. J Food Comp and Anal. 1997;10:102–14.
  47. 47. Harnack L, Lee S, Schakel SF, Duval S, Luepker RV, Arnett DK. Trends in the trans-fatty acid composition of the diet in a metropolitan area: the Minnesota Heart Survey. J Am Diet Assoc. 2003 Sep;103(9):1160–6. pmid:12963944.
  48. 48. Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000 May;108(7):538–46. pmid:10806282. Epub 2000/05/12. eng.
  49. 49. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004 Dec 1;117(11):823–9. pmid:15589485.
  50. 50. Golomb BA, Koperski S, White HL. Association between more frequent chocolate consumption and lower body mass index. Arch Intern Med. 2012 Mar 26;172(6):519–21. pmid:22450943. Epub 2012/03/28. eng.
  51. 51. Rose N, Koperski S, Golomb BA. Mood food: chocolate and depressive symptoms in a cross-sectional analysis. Arch Intern Med. 2010 Apr 26;170(8):699–703. pmid:20421555. Epub 2010/04/28. eng.
  52. 52. Golomb BA, Koslik HJ. Trans Fats Consumption Linked to Higher BMI. Circulation. 2014;pending.
  53. 53. Kavanagh K, Jones KL, Sawyer J, Kelley K, Carr JJ, Wagner JD, et al. Trans fat diet induces abdominal obesity and changes in insulin sensitivity in monkeys. Obesity (Silver Spring). 2007 Jul;15(7):1675–84. pmid:17636085. Epub 2007/07/20. eng.
  54. 54. Berr C. Cognitive impairment and oxidative stress in the elderly: results of epidemiological studies. Biofactors. 2000;13(1–4):205–9. pmid:11237183. Epub 2001/03/10. eng.
  55. 55. Berr C, Balansard B, Arnaud J, Roussel AM, Alperovitch A. Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel. J Am Geriatr Soc. 2000 Oct;48(10):1285–91. pmid:11037017. Epub 2000/10/19. eng.
  56. 56. Fukui K, Omoi NO, Hayasaka T, Shinnkai T, Suzuki S, Abe K, et al. Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Ann N Y Acad Sci. 2002 Apr;959:275–84. pmid:11976202. Epub 2002/04/27. eng.
  57. 57. Erecinska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol. 2001 Nov 15;128(3):263–76. pmid:11718758.
  58. 58. Fehm HL, Kern W, Peters A. The selfish brain: competition for energy resources. Prog Brain Res. 2006;153:129–40. pmid:16876572.
  59. 59. Lemaitre RN, King IB, Raghunathan TE, Pearce RM, Weinmann S, Knopp RH, et al. Cell membrane trans-fatty acids and the risk of primary cardiac arrest. Circulation. 2002 Feb 12;105(6):697–701. pmid:11839624.
  60. 60. Lemaitre RN, King IB, Mozaffarian D, Sotoodehnia N, Rea TD, Kuller LH, et al. Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study. Circulation. 2006 Jul 18;114(3):209–15. pmid:16818809.
  61. 61. Vohnout B, Arnout J, Krogh V, Donati MB, de Gaetano G, Iacoviello L. Association between MTHFR C677T genotype and circulating folate levels irrespective of folate intake: data from the IMMIDIET Project. Nutrition. 2011 Nov-Dec;27(11–12):1209–10. pmid:21967996. Epub 2011/10/05. eng.
  62. 62. Pu D, Shen Y, Wu J. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res. 2013 Oct;6(5):384–92. pmid:23653228. Epub 2013/05/09. eng.
  63. 63. Administration UFaD. FDA takes step to further reduce trans fats in processed foods [Press release]. Available: http://wwwfdagov/newsevents/newsroom/pressannouncements/ucm373939htm. 2013.
  64. 64. US Food and Drug Administration. Guidance for Industry: Trans Fatty Acids in Nutrition Labeling, Nutrient Content Claims, Health Claims; Small Entity Compliance Guide. Available: http://wwwfdagov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm053479htm. 2003.
  65. 65. Food and Drug Administration. FDA targets trans fats in processed foods. Available: http://wwwfdagov/forconsumers/consumerupdates/ucm372915htm. Accessed 07 November 2013.