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The Relationship of Omega 3 Polyunsaturated Fatty Acids in Red Blood Cell Membranes with Cognitive Function and Brain Structure: A Review Focussed on Alzheimer’s Disease

  • Claudie HooperEmail author
  • P. De Souto Barreto
  • M. Pahor
  • M. Weiner
  • B. Vellas
Review
  • 34 Downloads

Abstract

Significant research attention has focussed on the identification of nutraceutical agents for the prevention of cognitive decline as a natural means of cognitive preservation in the elderly. There is some evidence for a reduction of brain omega 3 polyunsaturated fatty acids (n-3 PUFAs) in normal aging and in Alzheimer’s disease. n-3 PUFAs exhibit anti-inflammatory and anti-amyloidogenic properties as well as being able to reduce tau phosphorylation. Many observational studies have demonstrated a link between n-3 PUFAs and cognitive aging, and some, but not all, randomized controlled trials have demonstrated a benefit of n-3 PUFA supplementation on cognition, particularly in those subjects with mild cognitive impairment. The identification of a biomarker that reflects n-3 PUFA intake over time and consequent tissue levels is required. In this narrative review we discuss the evidence associating red blood cell membrane n-3 PUFAs with cognitive function and structural brain changes associated with Alzheimer’s disease.

Key words

Docosahexaenoic acid omega 3 polyunsaturated fatty acids cognitive decline Alzheimer’s disease red blood cell 

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References

  1. 1.
    von Strauss E, Viitanen M, De Ronchi D, Winblad B, Fratiglioni L. Aging and the occurrence of dementia: findings from a population-based cohort with a large sample of nonagenarians. Arch Neurol. 1999 May;56(5):587–92.CrossRefGoogle Scholar
  2. 2.
    Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci. 1991 Oct;12(10):383–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993 Aug 13;261(5123):921–3.CrossRefPubMedGoogle Scholar
  4. 4.
    Vellas B, Carrie I, Gillette-Guyonnet S, Touchon J, Dantoine T, Dartigues JF, et al. MAPT Study: A Multidomain approach for preventing Alzheimer’s disease: Design and baseline data. J Prev Alzheimers Dis. 2014 Jun;1(1):13–22.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Köbe T, Witte AV, Schnelle A, Lesemann A, Fabian S, Tesky VA, et al. Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment. NeuroImage. 2015 Oct 1Google Scholar
  6. 6.
    Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495–505.CrossRefPubMedGoogle Scholar
  7. 7.
    Rissanen T, Voutilainen S, Nyyssönen K, Lakka TA, Salonen JT. Fish oilderived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio ischaemic heart disease risk factor study. Circulation. 2000 Nov 28;102(22):2677–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Oda E, Hatada K, Katoh K, Kodama M, Nakamura Y, Aizawa Y. A casecontrol pilot study on n-3 polyunsaturated fatty acid as a negative risk factor for myocardial infarction. Int Heart J. 2005 Jul;46(4):583–91.CrossRefPubMedGoogle Scholar
  9. 9.
    Kyle DJ, Schaefer E, Patton G, Beiser A. Low serum docosahexaenoic acid is a significant risk factor for Alzheimer’s dementia. Lipids. 1999;34 Suppl:S245.CrossRefPubMedGoogle Scholar
  10. 10.
    Guixà-González R, Javanainen M, Gómez-Soler M, Cordobilla B, Domingo JC, Sanz F, et al. Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors. Sci Rep. 2016;6:19839.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    McGahon BM, Martin DS, Horrobin DF, Lynch MA. Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids. Neuroscience. 1999;94(1):305–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Lin Q, Ruuska SE, Shaw NS, Dong D, Noy N. Ligand selectivity of the peroxisome proliferator-activated receptor alpha. Biochemistry (Mosc). 1999 Jan 5;38(1):185–90.CrossRefGoogle Scholar
  13. 13.
    Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014 May 22;509(7501):503–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Freund Levi Y, Vedin I, Cederholm T, Basun H, Faxén Irving G, Eriksdotter M, et al. Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer’s disease: the OmegAD study. J Intern Med. 2014 Apr;275(4):428–36.CrossRefPubMedGoogle Scholar
  15. 15.
    Dyall SC. 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. 2015;7:52.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Song C, Shieh C-H, Wu Y-S, Kalueff A, Gaikwad S, Su K-P. The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer’s disease: Acting separately or synergistically? Prog Lipid Res. 2016 Jan 4;62:41–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Prasad MR, Lovell MA, Yatin M, Dhillon H, Markesbery WR. Regional membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res. 1998 Jan;23(1):81–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Söderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids. 1991 Jun;26(6):421–5.CrossRefPubMedGoogle Scholar
  19. 19.
    McNamara RK, Liu Y, Jandacek R, Rider T, Tso P. The aging human orbitofrontal cortex: decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-CoA desaturase activity. Prostaglandins Leukot Essent Fatty Acids. 2008 May;78(4–5):293–304.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ameur A, Enroth S, Johansson A, Zaboli G, Igl W, Johansson ACV, et al. Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids. Am J Hum Genet. 2012 May 4;90(5):809–20.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Niizeki T, Takeishi Y, Takabatake N, Shibata Y, Konta T, Kato T, et al. Circulating levels of heart-type fatty acid-binding protein in a general Japanese population: effects of age, gender, and physiologic characteristics. Circ J Off J Jpn Circ Soc. 2007 Sep;71(9):1452–7.Google Scholar
  22. 22.
    Pelsers MM, Chapelle JP, Knapen M, Vermeer C, Muijtjens AM, Hermens WT, et al. Influence of age and sex and day-to-day and within-day biological variation on plasma concentrations of fatty acid-binding protein and myoglobin in healthy subjects. Clin Chem. 1999 Mar;45(3):441–3.PubMedGoogle Scholar
  23. 23.
    Nourooz-Zadeh J, Liu EH, Yhlen B, Anggård EE, Halliwell B. F4-isoprostanes as specific marker of docosahexaenoic acid peroxidation in Alzheimer’s disease. J Neurochem. 1999 Feb;72(2):734–40.CrossRefPubMedGoogle Scholar
  24. 24.
    Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, et al. Lipid peroxidation in aging brain and Alzheimer’s disease. Free Radic Biol Med. 2002 Sep 1;33(5):620–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Bazan NG. Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection. Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):136–41.CrossRefPubMedGoogle Scholar
  26. 26.
    Cederholm T, Salem N, Palmblad J. ω-3 fatty acids in the prevention of cognitive decline in humans. Adv Nutr Bethesda Md. 2013 Nov;4(6):672–6.CrossRefGoogle Scholar
  27. 27.
    Mazereeuw G, Lanctôt KL, Chau SA, Swardfager W, Herrmann N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging. 2012 Jul;33(7):1482.e17–29.CrossRefGoogle Scholar
  28. 28.
    Minogue AM, Lynch AM, Loane DJ, Herron CE, Lynch MA. Modulation of amyloid-beta-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. J Neurochem. 2007 Nov;103(3):914–26.CrossRefPubMedGoogle Scholar
  29. 29.
    Ma Q-L, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci Off J Soc Neurosci. 2009 Jul 15;29(28):9078–89.CrossRefGoogle Scholar
  30. 30.
    Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, et al. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci Off J Soc Neurosci. 2007 Apr 18;27(16):4385–95.CrossRefGoogle Scholar
  31. 31.
    Lukiw WJ, Cui J-G, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid–derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest. 2005 Oct 1;115(10):2774–83.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Grimm MOW, Kuchenbecker J, Grösgen S, Burg VK, Hundsdörfer B, Rothhaar TL, et al. Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. J Biol Chem. 2011 Apr 22;286(16):14028–39.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Perez SE, Berg BM, Moore KA, He B, Counts SE, Fritz JJ, et al. DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects. J Neurosci Res. 2010 Apr;88(5):1026–40.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, et al. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci Off J Soc Neurosci. 2005 Mar 23;25(12):3032–40.CrossRefGoogle Scholar
  35. 35.
    Yang X, Sheng W, Sun GY, Lee JC-M. Effects of fatty acid unsaturation numbers on membrane fluidity and a-secretase-dependent amyloid precursor protein processing. Neurochem Int. 2011 Feb;58(3):321–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Keli SO, Feskens EJ, Kromhout D. Fish consumption and risk of stroke. The Zutphen Study. Stroke J Cereb Circ. 1994 Feb;25(2):328–32.CrossRefGoogle Scholar
  37. 37.
    McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol (Berl). 2013 Oct;126(4):479–97.CrossRefGoogle Scholar
  38. 38.
    Zhou J, Yu J-T, Wang H-F, Meng X-F, Tan C-C, Wang J, et al. Association between stroke and Alzheimer’s disease: systematic review and metaanalysis. J Alzheimers Dis JAD. 2015;43(2):479–89.CrossRefPubMedGoogle Scholar
  39. 39.
    de la Torre JC. How do heart disease and stroke become risk factors for Alzheimer’s disease? Neurol Res. 2006 Sep;28(6):637–44.CrossRefPubMedGoogle Scholar
  40. 40.
    Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors and dementia: how to move forward? Neurology. 2009 Jan 27;72(4):368–74.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hjorth E, Zhu M, Toro VC, Vedin I, Palmblad J, Cederholm T, et al. Omega-3 fatty acids enhance phagocytosis of Alzheimer’s disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J Alzheimers Dis JAD. 2013;35(4):697–713.CrossRefPubMedGoogle Scholar
  42. 42.
    Moon D-O, Kim K-C, Jin C-Y, Han M-H, Park C, Lee K-J, et al. Inhibitory effects of eicosapentaenoic acid on lipopolysaccharide-induced activation in BV2 microglia. Int Immunopharmacol. 2007 Feb;7(2):222–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Chang HY, Lee H-N, Kim W, Surh Y-J. Docosahexaenoic acid induces M2 macrophage polarization through peroxisome proliferator-activated receptor γ activation. Life Sci. 2015 Jan 1;120:39–47.CrossRefGoogle Scholar
  44. 44.
    Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010 Nov 12;107(10):1170–84.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhu M, Wang X, Hjorth E, Colas RA, Schroeder L, Granholm A-C, et al. Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis. Mol Neurobiol. 2016 May;53(4):2733–49.CrossRefPubMedGoogle Scholar
  46. 46.
    McGeer PL, McGeer EG. Inflammation of the brain in Alzheimer’s disease: implications for therapy. J Leukoc Biol. 1999 Apr;65(4):409–15.CrossRefPubMedGoogle Scholar
  47. 47.
    Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer’s disease: relevance to pathogenesis and therapy. Alzheimers Res Ther. 2010 Jan 22;2(1):1.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997 Jan;41(1):17–24.CrossRefPubMedGoogle Scholar
  49. 49.
    Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003 May 13;60(9):1495–500.CrossRefPubMedGoogle Scholar
  50. 50.
    Huang TL. Omega-3 fatty acids, cognitive decline, and Alzheimer’s disease: a critical review and evaluation of the literature. J Alzheimers Dis JAD. 2010;21(3):673–90.CrossRefPubMedGoogle Scholar
  51. 51.
    Sydenham E, Dangour AD, Lim W-S. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD005379.Google Scholar
  52. 52.
    Issa AM, Mojica WA, Morton SC, Traina S, Newberry SJ, Hilton LG, et al. The efficacy of omega-3 fatty acids on cognitive function in aging and dementia: a systematic review. Dement Geriatr Cogn Disord. 2006;21(2):88–96.CrossRefPubMedGoogle Scholar
  53. 53.
    Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH. Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids. 2000 Dec;35(12):1305–12.CrossRefPubMedGoogle Scholar
  54. 54.
    Corrigan FM, Van Rhijn AG, Ijomah G, McIntyre F, Skinner ER, Horrobin DF, et al. Tin and fatty acids in dementia. Prostaglandins Leukot Essent Fatty Acids. 1991 Aug;43(4):229–38.CrossRefPubMedGoogle Scholar
  55. 55.
    Arab L. Biomarkers of fat and fatty acid intake. J Nutr. 2003 Mar;133 Suppl 3:925S–932S.CrossRefPubMedGoogle Scholar
  56. 56.
    Harris WS, Sands SA, Windsor SL, Ali HA, Stevens TL, Magalski A, et al. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 2004 Sep 21;110(12):1645–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Heude B, Ducimetière P, Berr C, EVA Study. Cognitive decline and fatty acid composition of erythrocyte membranes—The EVA Study. Am J Clin Nutr. 2003 Apr;77(4):803–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Wang W, Shinto L, Connor WE, Quinn JF. Nutritional biomarkers in Alzheimer’s disease: the association between carotenoids, n-3 fatty acids, and dementia severity. J Alzheimers Dis JAD. 2008 Feb;13(1):31–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Chiu C-C, Su K-P, Cheng T-C, Liu H-C, Chang C-J, Dewey ME, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebocontrolled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1538–44.CrossRefPubMedGoogle Scholar
  60. 60.
    Whalley LJ, Fox HC, Wahle KW, Starr JM, Deary IJ. Cognitive aging, childhood intelligence, and the use of food supplements: possible involvement of n-3 fatty acids. Am J Clin Nutr. 2004 Dec;80(6):1650–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Chiu C-C, Frangou S, Chang C-J, Chiu W-C, Liu H-C, Sun I-W, et al. Associations between n-3 PUFA concentrations and cognitive function after recovery from late-life depression. Am J Clin Nutr. 2012 Feb;95(2):420–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Milte CM, Sinn N, Street SJ, Buckley JD, Coates AM, Howe PRC. Erythrocyte polyunsaturated fatty acid status, memory, cognition and mood in older adults with mild cognitive impairment and healthy controls. Prostaglandins Leukot Essent Fatty Acids. 2011 Jun;84(5–6):153–61.CrossRefPubMedGoogle Scholar
  63. 63.
    Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, et al. 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 Neurol. 2017 Mar 27Google Scholar
  64. 64.
    Lukaschek K, von Schacky C, Kruse J, Ladwig K-H. Cognitive Impairment Is Associated with a Low Omega-3 Index in the Elderly: Results from the KORA-Age Study. Dement Geriatr Cogn Disord. 2016;42(3–4):236–45.CrossRefPubMedGoogle Scholar
  65. 65.
    Whalley LJ, Deary IJ, Starr JM, Wahle KW, Rance KA, Bourne VJ, et al. n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr. 2008 Feb;87(2):449–54.CrossRefPubMedGoogle Scholar
  66. 66.
    Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology. 2014 Feb 4;82(5):435–42.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Tan ZS, Harris WS, Beiser AS, Au R, Himali JJ, Debette S, et al. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012 Feb 28;78(9):658–64.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ammann EM, Pottala JV, Harris WS, Espeland MA, Wallace R, Denburg NL, et al. ω-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA. Neurology. 2013 Oct 22;81(17):1484–91.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Danthiir V, Hosking D, Burns NR, Wilson C, Nettelbeck T, Calvaresi E, et al. Cognitive performance in older adults is inversely associated with fish consumption but not erythrocyte membrane n-3 fatty acids. J Nutr. 2014 Mar;144(3):311–20.CrossRefPubMedGoogle Scholar
  70. 70.
    Kröger E, Verreault R, Carmichael P-H, Lindsay J, Julien P, Dewailly E, et al. Omega-3 fatty acids and risk of dementia: the Canadian Study of Health and Aging. Am J Clin Nutr. 2009 Jul;90(1):184–92.CrossRefPubMedGoogle Scholar
  71. 71.
    Huang TL, Zandi PP, Tucker KL, Fitzpatrick AL, Kuller LH, Fried LP, et al. Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology. 2005 Nov 8;65(9):1409–14.CrossRefPubMedGoogle Scholar
  72. 72.
    Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, et al. Dietary patterns and risk of dementia: the Three-City cohort study. Neurology. 2007 Nov 13;69(20):1921–30.CrossRefPubMedGoogle Scholar
  73. 73.
    Plourde M, Vohl M-C, Vandal M, Couture P, Lemieux S, Cunnane SC. Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-alpha L162V polymorphism in men. Br J Nutr. 2009 Oct;102(8):1121–4.CrossRefPubMedGoogle Scholar
  74. 74.
    van de Rest O, Wang Y, Barnes LL, Tangney C, Bennett DA, Morris MC. APOE e4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline. Neurology. 2016 May 4Google Scholar

Copyright information

© Serdi and Springer-Verlag France SAS, part of Springer Nature 2017

Authors and Affiliations

  • Claudie Hooper
    • 1
    Email author
  • P. De Souto Barreto
    • 1
  • M. Pahor
    • 2
  • M. Weiner
    • 3
  • B. Vellas
    • 1
    • 4
  1. 1.Gérontopôle, Department of GeriatricsCHU Toulouse, Purpan University HospitalToulouseFrance
  2. 2.Department of Aging and Geriatric Research, Institute on Aging, College of MedicineUniversity of FloridaGainesvilleUSA
  3. 3.University of California San Francisco, School of MedicineSan FranciscoUSA
  4. 4.INSERM UMR 1027ToulouseFrance

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