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The effects of omega-3 fatty acids on neuropsychological functioning and brain morphology in mid-life adults: a randomized clinical trial

Published online by Cambridge University Press:  04 October 2019

Regina L. Leckie ,
David E. Lehman ,
Peter J. Gianaros ,
Kirk I. Erickson ,
Susan M. Sereika ,
Dora C. H. Kuan Open the ORCID record for Dora C. H. Kuan [Opens in a new window] ,
Stephen B. Manuck ,
Christopher M. Ryan ,
Jeffrey K. Yao  and
Matthew F. Muldoon Open the ORCID record for Matthew F. Muldoon [Opens in a new window]
Regina L. Leckie
Affiliation:
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
David E. Lehman
Affiliation:
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Peter J. Gianaros
Affiliation:
Psychology Department, University of Pittsburgh, Pittsburgh, PA, USA
Kirk I. Erickson
Affiliation:
Psychology Department, University of Pittsburgh, Pittsburgh, PA, USA
Susan M. Sereika
Affiliation:
University of Pittsburgh School of Nursing, Pittsburgh, PA, USA
Dora C. H. Kuan
Affiliation:
Psychology Department, University of Pittsburgh, Pittsburgh, PA, USA
Stephen B. Manuck
Affiliation:
Psychology Department, University of Pittsburgh, Pittsburgh, PA, USA
Christopher M. Ryan
Affiliation:
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Jeffrey K. Yao
Affiliation:
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Matthew F. Muldoon*
Affiliation:
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
*
Author for correspondence: Matthew F. Muldoon, E-mail: mfm10@pitt.edu
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Abstract

Background

The diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation.

Methods

In a randomized, controlled trial, 271 mid-life adults (30–54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes.

Results

Capsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology.

Conclusions

In healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.

Keywords

Cognitive functioningmagnetic resonance imagingneuropsychological performanceomega-3 fatty acidsrandomized clinical trial

Information

Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 14 , October 2020 , pp. 2425 - 2434
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Copyright
Copyright © Cambridge University Press 2019

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Footnotes

*

Drs Leckie and Lehman contributed equally to this manuscript.

References

Ahmad, A, Moriguchi, T and Salem, N (2002) Decrease in neuron size in docosahexaenoic acid-deficient brain. Pediatric Neurology 26, 210–218.CrossRefGoogle ScholarPubMed
Andrieu, S, Guyonnet, S, Coley, N, Canete, C, Bonnefoy, M, Bordes, S, Bories, L, Cufi, MN, Dantoine, T, Dartigues, JF, Desclaux, F, Gabelle, A, Gasnier, Y, Pesce, A, Sudres, K, Touchon, J, Robert, P, Rouaud, O, Legard, P, Payoux, P, Caubere, JP, Weiner, M, Carrie, I, Ousset, PJ, Vellas, B and Group, MS (2017) Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurolology 16, 377–389.CrossRefGoogle ScholarPubMed
Antypa, N, Van Der Does, AJ, Smelt, AH and Rogers, RD (2009) Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers. Journal of Psychopharmacology 23, 831–840.CrossRefGoogle ScholarPubMed
Arterburn, LM, Hall, EB and Oken, H (2006) Distribution, interconversion, and dose response of n-3 fatty acids in humans. American Journal of Clinical Nutrition 83, 1467S–1476S.CrossRefGoogle ScholarPubMed
Bauer, I, Hughes, M, Rowsell, R, Cockerell, R, Pipingas, A, Crewther, S and Crewther, D (2014) Omega-3 supplementation improves cognition and modifies brain activation in young adults. Human Psychopharmacology 29, 133–144.CrossRefGoogle ScholarPubMed
Berger, A, Mutch, DM, German, JB and Roberts, MA (2002) Unraveling lipid metabolism with microarrays: effects of arachidonate and docosahexaenoate acid on murine hepatic and hippocampal gene expression. Genome Biology 3, REPRINT0004.CrossRefGoogle ScholarPubMed
Boespflug, EL, McNamara, RK, Eliassen, JC, Schidler, MD and Krikorian, R (2016) Fish oil supplementation increases event-related posterior cingulate activation in older adults with subjective memory impairment. J Nutr Health Aging, 20, 161–169.CrossRefGoogle ScholarPubMed
Bos, DJ, Van Montfort, SJ, Oranje, B, Durston, S and Smeets, PA (2016) Effects of omega-3 polyunsaturated fatty acids on human brain morphology and function: what is the evidence? European Neuropsychopharmacology 26, 546–561.CrossRefGoogle ScholarPubMed
Brenna, JT (2011) Animal studies of the functional consequences of suboptimal polyunsaturated fatty acid status during pregnancy, lactation and early post-natal life. Maternal & Child Nutrition 7(suppl. 2), 59–79.CrossRefGoogle ScholarPubMed
Brenna, JT and Carlson, SE (2014) Docosahexaenoic acid and human brain development: evidence that a dietary supply is needed for optimal development. Journal of Human Evolution 77, 99–106.CrossRefGoogle ScholarPubMed
Chew, EY, Clemons, TE, Agron, E, Launer, LJ, Grodstein, R, Bernstein, PS and Age-related Eye Disease Study 2 Research Group (2015) Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial. Journal of the American Medical Associaton 314, 791–801.CrossRefGoogle ScholarPubMed
Cohen, PA (2016) The supplement paradox: negligible benefits, robust consumption. Journal of the American Medical Associaton 316, 1453–1454.CrossRefGoogle ScholarPubMed
Conklin, SM, Gianaros, PJ, Brown, SM, Yao, JK, Hariri, AR, Manuck, SB and Muldoon, MF (2007) Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults. Neuroscience Letters 421, 209–212.CrossRefGoogle ScholarPubMed
Conway, V, Allard, MJ, Minihane, AM, Jackson, KG, Lovegrove, JA and Plourde, M (2014) Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype? Lipids in Health Disease 13, 148.CrossRefGoogle ScholarPubMed
Cukierman-Yaffe, T, Bosch, J, Diaz, R, Dyal, L, Hancu, N, Hildebrandt, P, Lanas, F, Lewis, BS, Marre, M, Yale, JF, Yusuf, S, Gerstein, HC and ORIGIN Investigators (2014) Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes & Endocrinology 2, 562–572.CrossRefGoogle ScholarPubMed
Danthiir, V, Hosking, DE, Nettelbeck, T, Vincent, AD, Wilson, C, O'Callaghan, N, Calvarsei, E, Clifton, P and Wittert, GA (2018) An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults. American Journal of Clinical Nutrition 107, 754–762.CrossRefGoogle ScholarPubMed
De Groot, RH, Hornstra, G and Jolles, J (2007) Exploratory study into the relation between plasma phospholipid fatty acid status and cognitive performance. Prostaglandins Leukotrienes & Essential Fatty Acids 76, 165–172.CrossRefGoogle ScholarPubMed
Del Gobbo, LC, Imamura, F, Aslibekyan, S, Marklund, M, Virtanen, JK, Wennberg, M, Yakoob, MY, Chiuve, SE, Dela Cruz, L, Frazier-Wood, AC, Fretts, AM, Guallar, E, Matsumoto, C, Prem, K, Tanaka, T, Wu, JH, Zhou, X, Helmer, C, Ingelsson, E, Yuan, JM, Barberger-Gateua, P, Campos, H, Chaves, PH, Djousse, L, Giles, GG, Gomez-Aracena, J, Hodge, AM, Hu, FB, Jansson, JH, Johansson, I, Khaw, KT, Koh, WP, Lemaitre, RN, Lind, L, Luben, RN, Rimm, EB, Riserus, U, Samieri, C, Franks, PW, Siscovick, DS, Stampfer, M, Steffen, LM, Steffen, BT, Tsai, MY, Van Dam, RM, Voutilainen, S, Willett, WC, Woodward, M, Mozaffarian, D and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCe) (2016) Omega-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Internal Medicine 176, 1155–1166.CrossRefGoogle ScholarPubMed
Dretsch, MN, Johnston, D, Bradley, RS, Macrae, H, Deuster, PA and Harris, WS (2014) Effects of omega-3 fatty acid supplementation on neurocognitive functioning and mood in deployed U.S. Soldiers: a pilot study. Military Medicine 179, 396–403.CrossRefGoogle ScholarPubMed
Farrell, ME, Kennedy, KM, Rodrigue, KM, Wig, G, Bischof, GN, Rieck, JR, Chen, X, Festini, SB, Devous, MD and Park, DC (2017) Association of longitudinal cognitive decline with amyloid burden in middle-aged and older adults: evidence for a dose-response relationship. JAMA Neurology 74, 830–838.CrossRefGoogle ScholarPubMed
Fernandes, R, Grootes, P, Nadeau, MJ and Nehlich, O (2015) Quantitative diet reconstruction of a Neolithic population using a Bayesian mixing model (FRUITS): the case study of Ostorf (Germany). American Journal of Physical Anthropology 158, 325–340.CrossRefGoogle Scholar
Flock, MR, Harris, WS and Kris-Etherton, PM (2013) Long-chain omega-3 fatty acids: time to establish a dietary reference intake. Nutrition Reviews 71, 692–707.CrossRefGoogle ScholarPubMed
Fontani, G, Corradeschi, F, Felici, A, Alfatti, F, Migliorini, S and Lodi, L (2005) Cognitive and physiological effects of omega-3 polyunsaturated fatty acid supplementation in healthy subjects. European Journal of Clinical Investigation 35, 691–699.CrossRefGoogle ScholarPubMed
Ginty, AT, Muldoon, MF, Kuan, DCH, Schirda, B, Kamark, TW, Jennings, JR, Manuck, SB and Gianaros, PJ (2017) Omega-3 supplementation and the neural correlates of negative affect and impulsivity: a double-blind, randomized, placebo-controlled trial in midlife adults. Psychosomatic Medicine 79, 549–556.CrossRefGoogle ScholarPubMed
Hibbeln, JR, Davis, JM, Steer, C, Emmett, P, Rogers, I, Williasm, C and Golding, J (2007) Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet 369, 578–585.CrossRefGoogle Scholar
Homack, SR (2007) Wechsler Abbreviated Scale of Intelligence (WASI). San Antonio, TX: Harcourt Brace & Company.Google Scholar
Jackson, PA, Deary, ME, Reay, JL, Scholey, AB and Kennedy, DO (2012 a) No effect of 12 weeks' supplementation with 1 g DHA-rich or EPA-rich fish oil on cognitive function or mood in healthy young adults aged 18–35 years. British Journal of Nutrition 107, 1232–1243.CrossRefGoogle ScholarPubMed
Jackson, PA, Reay, JL, Scholey, AB and Kennedy, DO (2012 b) DHA-rich oil modulates the cerebral haemodynamic response to cognitive tasks in healthy young adults: a near IR spectroscopy pilot study. British Journal of Nutrition 107, 1093–1098.CrossRefGoogle ScholarPubMed
Joordens, JC, Kuipers, RS, Wanink, JH and Muskiet, FA (2014) A fish is not a fish: patterns in fatty acid composition of aquatic food may have had implications for hominin evolution. Journal of Human Evolution 77, 107–116.CrossRefGoogle Scholar
Karr, JE, Grindstaff, TR and Alexander, JE (2012) Omega-3 polyunsaturated fatty acids and cognition in a college-aged population. Experimental and Clinical Psychopharmacology 20, 236–242.CrossRefGoogle Scholar
Kitajka, K, Puskas, LG, Zvara, A, Hackler, L, Barcelo-Coblijn, G, Yeo, YK and Farkas, T (2002) The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proceedings of the National Academy of Sciences of the United States of America 99, 2619–2624.CrossRefGoogle ScholarPubMed
Kitajak, K, Sinclair, AJ, Weisinger, RS, Weisinger, HS, Mathai, M, Jayasooriya, AP, Halver, JE and Puskas, LG (2004) Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proceedings of the National Academy of Sciences of the United States of America 101, 10931–10936.CrossRefGoogle Scholar
Kris-Etherton, PM, Harris, WS and Appel, LJ (2002) Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106, 2747–2757.CrossRefGoogle ScholarPubMed
Lauritzen, L, Brambilla, P, Mazzocchi, A, Harslof, LB, Ciappolino, V and Agostonie, C (2016) DHA effects in brain development and function. Nutrients 8, 6.CrossRefGoogle ScholarPubMed
Leckie, RL, Manuck, SB, Bhattacharjee, N, Muldoon, MF, Flory, JM and Erickson, KI (2014) Omega-3 fatty acids moderate effects of physical activity on cognitive function. Neuropsychologia 59, 103–111.CrossRefGoogle ScholarPubMed
Li, P, Stuart, EA and Allison, DB (2015) Multiple imputation: a flexible tool for handling missing data. Journal of the American Medical Associaton 314, 1966–1967.CrossRefGoogle ScholarPubMed
Lim, J, Oh, IK, Han, C, Huh, YJ, Jung, IK, Patkar, AA, Steffens, DC and Janb, BH (2013) Sensitivity of cognitive tests in four cognitive domains in discriminating MDD patients from healthy controls: a meta-analysis. International Psychogeriatrics 25, 1543–1557.CrossRefGoogle ScholarPubMed
Luchtman, DW and Song, C (2013) Cognitive enhancement by omega-3 fatty acids from child-hood to old age: findings from animal and clinical studies. Neuropharmacology 64, 550–565.CrossRefGoogle ScholarPubMed
McNamara, RK, Able, J, Jandacek, R, Rider, T, Tso, P, Eliasen, JC, Alfieri, D, Weber, W, Jarvis, K, Delbello, MP, Strakowski, SM and Adler, CM (2010) Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study. American Journal of Clinical Nutrition 91, 1060–1067.CrossRefGoogle ScholarPubMed
Moriguchi, T, Greiner, RS and Salem, N (2000) Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. Journal of Neurochemistry 75, 2563–2573.CrossRefGoogle ScholarPubMed
Muldoon, MF, Ryan, CM, Sheu, L, Yao, JK, Conklin, SM and Manuck, SB (2010) Serum phospholipid docosahexaenoic acid is associated with cognitive functioning during middle adulthood. Journal of Nutrition 140, 848–853.CrossRefGoogle ScholarPubMed
Muldoon, MF, Ryan, CM, Yao, JK, Conklin, SM and Manuck, SB (2014) Long-chain omega-3 fatty acids and optimization of cognitive performance. Military Medicine 179, 95–105.CrossRefGoogle ScholarPubMed
Muldoon, MF, Laderian, B, Kuan, DC, Sereika, SM, Marsland, AL and Manuck, SB (2016) Fish oil supplementation does not lower C-reactive protein or interleukin-6 levels in healthy adults. Journal of Internal Medicine 279, 98–109.CrossRefGoogle ScholarPubMed
O'Brien, JS, Fillerup, DL and Mead, JF (1964) Quantification and fatty acid and fatty aldehyde composition of ethanolamine, choline, and serine glycerophosphatides in human cerebral grey and white matter. Journal of Lipid Research 5, 329–338.CrossRefGoogle ScholarPubMed
Panikolaou, Y, Brooks, J, Reider, C and Fulgoni, VL (2014) U.S. Adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003–2008. Nutrition Journal 13, 31.CrossRefGoogle Scholar
Patenaude, B, Smith, SM, Kenndy, DN and Jenkinson, M (2011) A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage 56, 907–922.CrossRefGoogle ScholarPubMed
Puri, BK, Counsell, SJ, Hamilton, G, Richardson, AJ and Horrobin, DF (2001) Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover. International Journal of Clinical Practice 55, 560–563.Google ScholarPubMed
Rivest, L (1994) Statistical properties of Winsorized means for skewed distributions. Biometrika 81, 373–383.CrossRefGoogle Scholar
Rodrigue, KM, Kennedy, KM, Devous, MD, Rieck, JR, Hebrank, AC, Diaz-Arrastia, R, Mathews, D and Park, DC (2012) Beta-amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology 78, 387–395.CrossRefGoogle ScholarPubMed
Rogers, PJ, Appleton, KM, Kessler, D, Peters, TJ, Gunnell, D, Hayward, RC, Heatherley, SV, Christian, LM, McNaughton, SA and Ness, AR (2008) No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. British Journal of Nutrition 99, 421–431.CrossRefGoogle ScholarPubMed
Sala-Vila, A, Guasch-Ferre, M, Hu, FB, Sanchez-Tainta, A, Bullo, M, Serra-Mir, M, Lopez-Sabater, C, Sorli, JV, Aros, F, Fiol, M, Munoz, MA, Serra-Majem, L, Martinez, JA, Corella, D, Fita, M, Salas-Salvado, J, Martinez-Gonzalez, MA, Estruch, R, Ros, E and PREDIMED Investigators (2016) Dietary alpha-linolenic acid, marine omega-3 fatty acids, and mortality in a population with high fish consumption: findings from the PREvencion con DIeta MEDiterranea (PREDIMED) study. Journal of the American Heart Association 5, e002543.CrossRefGoogle Scholar
Singh, PP, Singh, M and Mastana, SS (2006) APOE distribution in world populations with new data from India and the UK. Annals of Human Biology 33, 279–308.CrossRefGoogle ScholarPubMed
Siscovick, DS, Barringer, TA, Fretts, AM, Wu, JH, Lichtenstein, AH, Costello, RB, Kris-Etherton, PM, Jacobson, TA, Engler, MB, Alger, HM, Appel, LJ, Moxaffarian, D and American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health, Council on Epidemiology and Prevention, Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology (2017) Omega-3 polyunsaturated fatty acid (Fish Oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation 135, e867–e884.CrossRefGoogle ScholarPubMed
Stonehouse, W, Conlon, CA, Podd, J, Hill, SR, Minihane, AM, Haskell, C and Kennedy, D (2013) DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. American Journal of Clinical Nutrition 97, 1134–1143.CrossRefGoogle ScholarPubMed
Van De Rest, O, Wang, Y, Barnes, LL, Tangney, C, Bennett, DA and Morris, MC (2016) APOE epsilon4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline. Neurology 86, 2063–2070.CrossRefGoogle ScholarPubMed
Wechseler, D (1997 a) Wechsler Adult Intelligence Scale – Third Edition: Administration and Scoring Manual. San Antonio, TX: Harcourt Brace & Company.Google Scholar
Wechsler, DB (1997 b) THE WMS-III Administration and Scoring Manual. San Antonio, TX: Harcourt Brace & Company.Google Scholar
Yurko-Mauro, K, Alexander, DD and Van Elswyk, ME (2015) Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One 10, e0120391.CrossRefGoogle ScholarPubMed
Zazzo, A, Munoz, O and Saliege, JF (2014) Diet and mobility in a late Neolithic population of coastal Oman inferred from radiocarbon dating and stable isotope analysis. American Journal of Physical Anthropology 153, 353–364.CrossRefGoogle Scholar
Zhang, Y, Chen, J, Qiu, J, Li, Y, Wang, J and Jiao, J (2016) Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. American Journal of Clinical Nutrition 103, 330–340.CrossRefGoogle ScholarPubMed
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