Effects of omega-3 fatty acid supplementation on cognitive functions and neural substrates: A voxel-based morphometry study in aged mice

Frontiers in Aging Neuroscience

Volumn 8, Issue MAR, 2016, Pages

  Cutuli, Debora ^a,b   Pagani, Marco ^c,d   Caporali, Paola ^a,b   Galbusera, Alberto ^c   Laricchiuta, Daniela ^a,b   Foti, Francesca ^a,b   Neri, Cristina ^a   Spalletta, Gianfranco ^a   Caltagirone, Carlo ^a,e   Petrosini, Laura ^a,b   Gozzi, Alessandro ^c  

^a IRCCS FONDAZIONE SANTA LUCIA   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c ISTITUTO ITALIANO DI TECNOLOGIA   (Italy)

^d UNIVERSITY OF TRENTO   (Italy)

^e UNIVERSITY OF ROME TOR VERGATA   (Italy)

Author keywords

Aging; Cognitive decline; Dietary supplementation; MRI; Omega 3 fatty acids; Voxel based morphometry

Indexed keywords

OMEGA 3 FATTY ACID;

AGED; AGING; ANIMAL EXPERIMENT; ANXIETY; ARTICLE; BRAIN ATROPHY; BRAIN SIZE; COGNITION; CONTROLLED STUDY; COPING BEHAVIOR; DIET SUPPLEMENTATION; DISCRIMINATION LEARNING; EMOTIONAL DISORDER; GRAY MATTER; HIPPOCAMPUS; MALE; MOUSE; NERVE CELL PLASTICITY; NERVE DEGENERATION; NONHUMAN; SOCIAL LEARNING; SPATIAL LEARNING; VOXEL BASED MORPHOMETRY;

EID: 84964650330     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2016.00038     Document Type: Article

References (88)

1. Ashburner, J., and Friston, K. J. (2000). Voxel-based morphometry-the methods. Neuroimage 11, 805-821. doi: 10.1006/nimg.2000.0582.
2. Avants, B. B., Tustison, N., and Song, G. (2009). Advanced normalization tools (ANTS). Insight J. 2, 1-35.
3. Bazan, N. G., Musto, A. E., and Knott, E. J. (2011). Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity. Mol. Neurobiol. 44, 216-222. doi: 10.1007/s12035-011-8200-6.
4. Beydoun, M. A., Kaufman, J. S., Satia, J. A., Rosamond, W., and Folsom, A. R. (2007). Plasma n-3 fatty acids and the risk of cognitive decline in older adults: the Atherosclerosis Risk in Communities Study. Am. J. Clin. Nutr. 85, 1103-1111.
5. Bowman, G. L., Dodge, H. H., Mattek, N., Barbey, A. K., Silbert, L. C., Shinto, L., et al. (2013). Plasma omega-3 PUFA and white matter mediated executive decline in older adults. Front. Aging Neurosci. 5:92. doi: 10.3389/fnagi.2013.00092.
6. Bowman, G. L., Silbert, L. C., Howieson, D., Dodge, H. H., Traber, M. G., Frei, B., et al. (2012). Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology 78, 241-249. doi: 10.1212/WNL.0b013e3182436598.
7. Calder, P. C. (2011). Fatty acids and inflammation: the cutting edge between food and pharma. Eur. J. Pharmacol. 668, S50-S58. doi: 10.1016/j.ejphar.2011.05.085.
8. Calviello, G., Palozza, P., Franceschelli, P., and Bartoli, G. M. (1997). Low-dose eicosapentaenoic or docosahexaenoic acid administration modifies fatty acid composition and does not affect susceptibility to oxidative stress in rat erythrocytes and tissues. Lipids 32, 1075-1083. doi: 10.1007/s11745-997-0139-4.
9. Carrié, I., Smirnova, M., Clément, M., De, J. D., Francès, H., and Bourre, J. M. (2002). Docosahexaenoic acid-rich phospholipid supplementation: effect on behavior, learning ability, and retinal function in control and n-3 polyunsaturated fatty acid deficient old mice. Nutr. Neurosci. 5, 43-52. doi: 10.1080/10284150290007074.
10. Chen, G., Chen, K. S., Knox, J., Inglis, J., Bernard, A., Martin, S. J., et al. (2000). A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975-979. doi: 10.1038/35046031.
11. Chiu, C. C., Su, K. P., Cheng, T. C., Liu, H. C., Chang, C. J., Dewey, M. E., et al. (2008). The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1538-1544. doi: 10.1016/j.pnpbp.2008.05.015.
12. Conklin, S. M., Gianaros, P. J., Brown, S. M., Yao, J. K., Hariri, A. R., Manuck, S. B., et al. (2007). Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults. Neurosci. Lett. 421, 209-212. doi: 10.1016/j.neulet.2007.04.086.
13. Costa, A. P., Vieira, C., Bohner, L. O., Silva, C. F., Santos, E. C., De Lima, T. C., et al. (2013). A proposal for refining the forced swim test in Swiss mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 45, 150-155. doi: 10.1016/j.pnpbp.2013.05.002.
14. Crawley, J., and Goodwin, F. K. (1980). Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol. Biochem. Behav. 13, 167-170. doi: 10.1016/0091-3057(80)90067-2.
15. Cunnane, S. C., Plourde, M., Pifferi, F., Bégin, M., Féart, C., and Barberger-Gateau, P. (2009). Fish, docosahexaenoic acid and Alzheimer's disease. Prog. Lipid Res. 48, 239-256. doi: 10.1016/j.plipres.2009.04.001.
16. Cutuli, D., De Bartolo, P., Caporali, P., Laricchiuta, D., Foti, F., Ronci, M., et al. (2014). n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice. Front. Aging. Neurosci. 6:220. doi: 10.3389/fnagi.2014.00220.
17. Cutuli, D., De Bartolo, P., Caporali, P., Tartaglione, A. M., Oddi, D., D'Amato, F. R., et al. (2013). Neuroprotective effects of donepezil against cholinergic depletion. Alzheimers Res. Ther. 5:50. doi: 10.1186/alzrt215.
18. Dangour, A. D., Allen, E., Elbourne, D., Fasey, N., Fletcher, A. E., Hardy, P., et al. (2010). Effect of 2-y nGêÆ3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am. J. Clin. Nutr. 91, 1725-1732. doi: 10.3945/ajcn.2009.29121.
19. Danthiir, V., Burns, N. R., Nettelbeck, T., Wilson, C., and Wittert, G. (2011). The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: a randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults. Nutr. J. 10:117. doi: 10.1186/1475-2891-10-117.
20. Denis, I., Potier, B., Heberden, C., and Vancassel, S. (2015). Omega-3 polyunsaturated fatty acids and brain aging. Curr. Opin. Clin. Nutr. Metab. Care 18, 139-146. doi: 10.1097/MCO.0000000000000141.
21. Denis, I., Potier, B., Vancassel, S., Heberden, C., and Lavialle, M. (2013). Omega-3 fatty acids and brain resistance to ageing and stress: body of evidence and possible mechanisms. Ageing Res. Rev. 12, 579-594. doi: 10.1016/j.arr.2013.01.007.
22. Dodero, L., Damiano, M., Galbusera, A., Bifone, A., Tsaftsaris, S. A., Scattoni, M. L., et al. (2013). Neuroimaging evidence of major morpho-anatomical and functional abnormalities in the BTBR T+TF/J mouse model of autism. PLoS ONE 8:e76655. doi: 10.1371/journal.pone.0076655.
23. Driscoll, I., Howard, S. R., Stone, J. C., Monfils, M. H., Tomanek, B., Brooks, W. M., et al. (2006). The aging hippocampus: a multi-level analysis in the rat. Neuroscience 139, 1173-1185. doi: 10.1016/j.neuroscience.2006.01.040.
24. Dullemeijer, C., Durga, J., Brouwer, I. A., van de Rest, O., Kok, F. J., Brummer, R. J., et al. (2007). n 3 fatty acid proportions in plasma and cognitive performance in older adults. Am. J. Clin. Nutr. 86, 1479-1485.
25. Dyall, S. C. (2015). Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front. Aging Neurosci. 7:52. doi: 10.3389/fnagi.2015.00052.
26. Erickson, K. I., Miller, D. L., and Roecklein, K. A. (2012). The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 18, 82-97. doi: 10.1177/1073858410397054.
27. Fedorova, I., and Salem, N. (2006). Omega-3 fatty acids and rodent behavior. Prostaglandins Leukot Essent. Fatty Acids 75, 271-289. doi: 10.1016/j.plefa.2006.07.006.
28. Folch, J., Lees, M., and Sloane Stanley, G. H. (1957). A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226, 497-509.
29. Freeman, M. P., Hibbeln, J. R., Wisner, K. L., Davis, J. M., Mischoulon, D., Peet, M., et al. (2006). Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J. Clin. Psychiatry 67, 1954-1967. doi: 10.4088/JCP.v67n1217.
30. Freund-Levi, Y., Eriksdotter-Jönhagen, M., Cederholm, T., Basun, H., Faxén-Irving, G., Garlind, A., et al. (2006). Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol. 63, 1402-1408. doi: 10.1001/archneur.63.10.1402.
31. Geleijnse, J. M., Giltay, E. J., and Kromhout, D. (2012). Effects of n-3 fatty acids on cognitive decline: a randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimer's Dement. 8, 278-287. doi: 10.1016/j.jalz.2011.06.002.
32. Gómez-Pinilla, F. (2008). Brain foods: the effects of nutrients on brain function. Nat. Rev. Neurosci. 9, 568-578. doi: 10.1038/nrn2421.
33. Hooijmans, C. R., Pasker-de Jong, P. C., de Vries, R. B., and Ritskes-Hoitinga, M. (2012). The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer's pathology in animal models of Alzheimer's disease: a systematic review and meta-analysis. J. Alzheimers Dis. 28, 191-209. doi: 10.3233/JAD-2011-111217.
34. Hoover, W., and Vertes, R. (2007). Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct. Funct. 212, 149-179. doi: 10.1007/s00429-007-0150-4.
35. Jernigan, T. L., Archibald, S. L., Fennema-Notestine, C., Gamst, A. C., Stout, J. C., Bonner, J., et al. (2001). Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol. Aging 22, 581-594. doi: 10.1016/S0197-4580(01)00217-2.
36. Jiang, L. H., Liang, Q. Y., and Shi, Y. (2012). Pure docosahexaenoic acid can improve depression behaviors and affect HPA axis in mice. Eur. Rev. Med. Pharmacol. Sci. 16, 1765-1773.
37. Keers, R., Pedroso, I., Breen, G., Aitchison, K. J., Nolan, P. M., Cichon, S., et al. (2012). Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours. PLoS ONE 7:e38263. doi: 10.1371/journal.pone.0038263.
38. Kelly, L., Grehan, B., Chiesa, A. D., O'Mara, S. M., Downer, E., Sahyoun, G., et al. (2011). The polyunsaturated fatty acids, EPA and DPA exert a protective effect in the hippocampus of the aged rat. Neurobiol. Aging 32:e1-e15. doi: 10.1016/j.neurobiolaging.2010.04.001.
39. Kotani, S., Sakaguchi, E., Warashina, S., Matsukawa, N., Ishikura, Y., Kiso, Y., et al. (2006). Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci. Res. 56, 159-164. doi: 10.1016/j.neures.2006.06.010.
40. Kröger, E., Verreault, R., Carmichael, P. H., Lindsay, J., Julien, P., Dewailly, E., et al. (2009). Omega-3 fatty acids and risk of dementia: the Canadian Study of Health and Aging. Am. J. Clin. Nutr. 90, 184-192. doi: 10.3945/ajcn.2008.26987.
41. Labrousse, V. F., Nadjar, A., Joffre, C., Costes, L., Aubert, A., Grégoire, S., et al. (2012). Short-term long chain omega 3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS ONE 7:e36861. doi: 10.1371/journal.pone.0036861.
42. Lang, U. E., and Borgwardt, S. (2013). Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol. Biochem. 31, 761-777. doi: 10.1159/000350094.
43. Luchtman, D. W., 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. doi: 10.1016/j.neuropharm.2012.07.019.
44. Lynch, A. M., Loane, D. J., Minogue, A. M., Clarke, R. M., Kilroy, D., Nally, R. E., et al. (2007). Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol. Aging 286, 845-855. doi: 10.1016/j.neurobiolaging.2006.04.006.
45. Maher, F. O., Martin, D. S., and Lynch, M. A. (2004). Increased IL-1beta in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase. Neurobiol. Aging 25, 795-806. doi: 10.1016/j.neurobiolaging.2003.08.007.
46. Martin, D. S., Lonergan, P. E., Boland, B., Fogarty, M. P., Brady, M., Horrobin, D. F., et al. (2002). Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J. Biol. Chem. 277, 34239-34246. doi: 10.1074/jbc. M205289200.
47. Maruszak, A., Pilarski, A., Murphy, T., Branch, N., and Thuret, S. (2014). Hippocampal neurogenesis in Alzheimer's disease: is there a role for dietary modulation? J. Alzheimers Dis. 38, 11-38. doi: 10.3233/JAD-131004.
48. Masliah, E., Crews, L., and Hansen, L. (2006). Synaptic remodeling during aging and in Alzheimer's disease. J. Alzheimers. Dis. 9, 91-99.
49. McNamara, R. K., and Liu, Y. (2011). Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder. J. Affect. Disord. 129, 359-363. doi: 10.1016/j.jad.2010.08.021.
50. Nadler, J. J., Moy, S. S., Dold, G., Trang, D., Simmons, N., Perez, A., et al. (2004). Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303-314. doi: 10.1111/j.1601-183X.2004.00071.x.
51. Nakamoto, K., Nishinaka, T., Mankura, M., Fujita-Hamabe, W., and Tokuyama, S. (2010). Antinociceptive effects of docosahexaenoic acid against various pain stimuli in mice. Biol. Pharm. Bull. 33, 1070-1072. doi: 10.1248/bpb.33.1070.
52. Oarada, M., Tsuzuki, T., Gonoi, T., Igarashi, M., Kamei, K., Nikawa, T., et al. (2008). Effects of dietary fish oil on lipid peroxidation and serum triacylglycerol levels in psychologically stressed mice. Nutrition 24, 67-75. doi: 10.1016/j.nut.2007.10.006.
53. Pagani, M., Damiano, M., Galbusera, A., Tsaftaris, S. A., and Gozzi, A. (2012). Registration-based volumetric labelling, voxel based morphometry and cortical thickness mapping of the mouse brain. J. Neurosci. Methods (in press).
54. Patrick, R. P., and Ames, B. N. (2015). Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 29, 2207-2222. doi: 10.1096/fj.14-268342.
55. Pottala, J. V., Yaffe, K., Robinson, J. G., Espeland, M. A., Wallace, R., and Harris, W. S. (2014). Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology 82, 435-442. doi: 10.1212/WNL.0000000000000080.
56. Puri, B. K., Counsell, S. J., Hamilton, G., Richardson, A. J., and Horrobin, D. F. (2001). Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover. Int. J. Clin. Pract. 55, 560-563.
57. Quinn, J. F., Raman, R., Thomas, R. G., Yurko-Mauro, K., Nelson, E. B., Van Dyck, C., et al. (2010). Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 304, 1903-1911. doi: 10.1001/jama.2010.1510.
58. Raji, C. A., Erickson, K. I., Lopez, O. L., Kuller, L. H., Gach, H. M., Thompson, P. M., et al. (2014). Regular fish consumption and age-related brain grey matter loss. Am. J. Prev. Med. 47, 444-451. doi: 10.1016/j.amepre.2014.05.037.
59. Rao, J. S., Ertley, R. N., DeMar, J. C. Jr., Rapoport, S. I., Bazinet, R. P., and Lee, H. J. (2007). Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Mol. Psychiatry 12, 151-157. doi: 10.1038/sj.mp.4001887.
60. Renault, J., and Aubert, A. (2006). Immunity and emotions: lipopolysaccharide increases defensive behaviours and potentiates despair in mice. Brain Behav. Immun. 20, 517-526. doi: 10.1016/j.bbi.2006.03.003.
61. Riedel, G., Kang, S. H., Choi, D. Y., and Platt, B. (2009). Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behav. Brain Res. 204, 217-225. doi: 10.1016/j.bbr.2009.06.012.
62. Ruehle, S., Remmers, F., Romo-Parra, H., Massa, F., Wickert, M., Wörtge, S., et al. (2013). Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions. J. Neurosci. 33, 10264-10277. doi: 10.1523/JNEUROSCI.4171-12.2013.
63. Samieri, C., Féart, C., Proust-Lima, C., Peuchant, E., Dartigues, J. F., Amieva, H., et al. (2011). ω-3 fatty acids and cognitive decline: modulation by ApoEe4 allele and depression. Neurobiol. Aging 32, e13-e22. doi: 10.1016/j.neurobiolaging.2010.03.020.
64. Samieri, C., Maillard, P., Crivello, F., Proust-Lima, C., Peuchant, E., Helmer, C., et al. (2012). Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe. Neurology 79, 2-650. doi: 10.1212/WNL.0b013e318264e394.
65. Sannino, T., Gozzi, A., Cerasa, A., Piras, F., Schegga, D., Manago, F., et al. (2015). Sexual dimorphisms in COMT modulation of cortical anatomy and behavior in mice and humans. Cereb. Cortex 25, 2529-2541. doi: 10.1093/cercor/bhu053.
66. Schipper, P., Kiliaan, A. J., and Homberg, J. R. (2011). A mixed polyunsaturated fatty acid diet normalizes hippocampal neurogenesis and reduces anxiety in serotonin transporter knockout rats. Behav. Pharmacol. 22, 324-334. doi: 10.1097/FBP.0b013e328347881b.
67. Sinn, N., Milte, C., and Howe, P. R. C. (2010). Oiling the brain: a review of randomized controlled trials of omega-3 fatty acids in psychopathology across the lifespan. Nutrients 2, 128-170. doi: 10.3390/nu2020128.
68. Steffens, D. C., Otey, E., Alexopoulos, G. S., Butters, M. A., Cuthbert, B., Ganguli, M., et al. (2006). Perspectives on depression, mild cognitive impairment, and cognitive decline. Arch. Gen. Psychiatry 63, 130-138. doi: 10.1001/archpsyc.63.2.130.
69. Su, K. P. (2009). Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a 'mind-body interface'? Neurosignals 17, 144-152. doi: 10.1159/000198167.
70. Sublette, M. E., Ellis, S. P., Geant, A. L., and Mann, J. J. (2011). Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 72, 1577-1584. doi: 10.4088/JCP.10m06634.
71. Tan, Z. S., Harris, W. S., Beiser, A. S., Au, R., Himali, J. J., Debette, S., et al. (2012). Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology 78, 658-664. doi: 10.1212/WNL.0b013e318249f6a9.
72. Thomas, C., and Baker, C. I. (2013). Teaching an adult brain new tricks: a critical review of evidence for training-dependent structural plasticity in humans. Neuroimage 73, 225-236. doi: 10.1016/j.neuroimage.2012.03.069.
73. Titova, O. E., Sjögren, P., Brooks, S. J., Kullberg, J., Ax, E., Kilander, L., et al. (2013). Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to grey matter volume and cognitive function in elderly. Age 35, 1495-1505. doi: 10.1007/s11357-012-9453-3.
74. Trépanier, M. O., Hopperton, K. E., Orr, S. K., and Bazinet, R. P. (2015). N-3 polyunsaturated fatty acids in animal models with neuroinflammation: an update. Eur. J. Pharmacol. 88, 97-103. doi: 10.1016/j.ejphar.2015.05.045.
75. van de Rest, O., Geleijnse, J. M., Kok, F. J., van Staveren, W. A., Dullemeijer, C., Olderikkert, M. G., et al. (2008). Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology 71, 430-438. doi: 10.1212/01.wnl.0000324268.45138.86.
76. Varteresian, T., and Lavretsky, H. (2014). Natural products and supplements for geriatric depression and cognitive disorders: an evaluation of the research. Curr. Psychiatry Rep. 16:456. doi: 10.1007/s11920-014-0456-x.
77. Videbech, P., and Ravnkilde, B. (2004). Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957-1966. doi: 10.1176/appi.ajp.161.11.1957.
78. Vinot, N., Jouin, M., Lhomme-Duchadeuil, A., Guesnet, P., Alessandri, J. M., Aujard, F., et al. (2011). Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate. PLoS ONE 6:e20491. doi: 10.1371/journal.pone.0020491.
79. Virtanen, J. K., Siscovick, D. S., Lemaitre, R. N., Longstreth, W. T., Spiegelman, D., Rimm, E. B., et al. (2013). Circulating omega-3 polyunsaturated fatty acids and subclinical brain abnormalities on MRI in older adults: the Cardiovascular Health Study. J. Am. Heart. Assoc. 2:e000305. doi: 10.1161/JAHA.113.000305.
80. Vu, N. Q., and Aizenstein, H. J. (2013). Depression in the elderly: brain correlates, neuropsychological findings, and role of vascular lesion load. Curr. Opin. Neurol. 26, 656-661. doi: 10.1097/WCO.0000000000000028.
81. Whalley, L. J., Deary, I. J., Starr, J. M., Wahle, K. W., Rance, K. A., Bourne, V. J., et al. (2008). n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am. J. Clin. Nutr. 87, 449-454.
82. Willis, L. M., Shukitt-Hale, B., and Joseph, J. A. (2009). Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain. Genes Nutr. 4, 309-314. doi: 10.1007/s12263-009-0141-6.
83. Winters, B. D., and Bussey, T. J. (2005). Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat. Eur. J. Neurosci. 21, 2263-2270. doi: 10.1111/j.1460-9568.2005.04055.x.
84. Witte, A. V., Kerti, L., Hermannstädter, H. M., Fiebach, J. B., Schreiber, S. J., Schuchardt, J. P., et al. (2014). Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb. Cortex 24, 3059-3068. doi: 10.1093/cercor/bht163.
85. Worsley, K. J., Evans, A. C., Marrett, S., and Neelin, P. (1992). A three-dimensional statistical analysis for CBF activation studies in human brain. J. Cereb. Blood Flow Metab. 12, 900-918. doi: 10.1038/jcbfm.1992.127.
86. Yehuda, S. (2012). Polyunsaturated fatty acids as putative cognitive enhancers. Med. Hypoth. 79, 456-461. doi: 10.1016/j.mehy.2012.06.021.
87. Yehuda, S., Rabinovitz, S., Carasso, R. L., and Mostofsky, D. I. (2002). The role of polyunsaturated fatty acids in restoring the aging neuronal membrane. Neurobiol. Aging 23, 843-853. doi: 10.1016/S0197-4580(02)00074-X.
88. Yurko-Mauro, K., McCarthy, D., Rom, D., Nelson, E. B., Ryan, A. S., Blackwell, A., et al. (2010). Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 6, 456-464. doi: 10.1016/j.jalz.2010.01.013