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Licensed Unlicensed Requires Authentication Published by De Gruyter November 12, 2012

Aqueous humor glycation marker and plasma homocysteine in macular degeneration

  • Rima Obeid EMAIL logo , Kouris Ninios , Ursula Loew , Zisis Gatzioufas , Stephan Hoffmann , Berthold Seitz , Jurgen Geisel and Wolfgang Herrmann


Background: We investigated concentrations of total homocysteine (tHcy) in elderly people without and those with age-related macular degeneration (AMD). In addition, we tested the association between plasma tHcy and one glycation marker in aqueous humor.

Methods: People with cataract only (n=48), patients with dry AMD (n=38) and those with wet AMD (n=31) were studied. Blood concentrations of tHcy, and methylation and vitamin markers were measured in 116 blood samples. The concentrations of the extracellular soluble receptor for advanced glycated end products (esRAGE) were measured in 77 aqueous humor samples.

Results: Mean aqueous humor concentration of esRAGE and that of plasma tHcy did not differ significantly between the groups. Arterial hypertension but not eye disease explained the tHcy elevation in plasma in this study. In the cataract group, a significant negative correlation was found between plasma tHcy and that of esRAGE in aqueous humor (r=–0.483, p=0.006). In patients with dry AMD, the concentration of esRAGE in aqueous humor correlated negatively to tHcy and positively to serum folate.

Conclusions: Plasma tHcy levels were positively associated with hypertension, but not with AMD in this study. Higher esRAGE in aqueous humor was related to higher folate and lower tHcy in blood. Following studies may assess whether B-vitamins can protect against age-related ocular diseases by reducing glycation.

Corresponding author: Dr. Rima Obeid, Department of Clinical Chemistry and Laboratory Medicine, University Hospital of Saarland, Building 57, 66421 Homburg/Saar, Germany, Phone: +49 68411630701, Fax: +49 68411630703

The study was partly supported by a grant from the Homburger Forschungsförderungsprogramm (HOMFOR) 2008.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.


1. Schmidt KG, Bergert H, Funk RH. Neurodegenerative diseases of the retina and potential for protection and recovery. Curr Neuropharmacol 2008;6:164–78.10.2174/157015908784533851Search in Google Scholar

2. Feeney-Burns L, Eldred GE. The fate of the phagosome: conversion to ‘age pigment’ and impact in human retinal pigment epithelium. Trans Ophthalmol Soc UK 1983;103 (Pt 4):416–21.Search in Google Scholar

3. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122:598–614.10.1001/archopht.122.4.598Search in Google Scholar

4. Louie JL, Kapphahn RJ, Ferrington DA. Proteasome function and protein oxidation in the aged retina. Exp Eye Res 2002;75: 271–84.10.1006/exer.2002.2022Search in Google Scholar

5. Dentchev T, Milam AH, Lee VM, Trojanowski JQ, Dunaief JL. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol Vis 2003;9:184–90.Search in Google Scholar

6. Stitt AW. Advanced glycation: an important pathological event in diabetic and age related ocular disease. Br J Ophthalmol 2001;85:746–53.10.1136/bjo.85.6.746Search in Google Scholar

7. Du YS, Zhu H, Fu J, Yan SF, Roher A, Tourtellotte WW, et al. Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci USA 1997;94:5296–301.10.1073/pnas.94.10.5296Search in Google Scholar

8. Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 2003;370:1097–109.10.1042/bj20021371Search in Google Scholar

9. Harrison DA, Mullaney PB, Mesfer SA, Awad AH, Dhindsa H. Management of ophthalmic complications of homocystinuria. Ophthalmology 1998;105:1886–90.10.1016/S0161-6420(98)91035-1Search in Google Scholar

10. Cross HE, Jensen AD. Ocular manifestations in the Marfan syndrome and homocystinuria. Am J Ophthalmol 1973;75: 405–20.10.1016/0002-9394(73)91149-5Search in Google Scholar

11. Paoli D, Pierro L. Bilateral occlusion of the central retinal artery in a homocystinuric patient: the role of echography. Ophthalmologica 1998;212(Suppl 1):95–8.10.1159/000055440Search in Google Scholar PubMed

12. vd BW, Verbraak FD, Bos PJ. Homocystinuria presenting as central retinal artery occlusion and longstanding thromboembolic disease. Br J Ophthalmol 1990;74:696–7.10.1136/bjo.74.11.696Search in Google Scholar PubMed PubMed Central

13. Mulvihill A, O’Keeffe M, Yap S, Naughten E, Howard P, Lanigan B. Ocular axial length in homocystinuria patients with and without ocular changes: effects of early treatment and biochemical control. J AAPOS 2004;8:254–8.10.1016/j.jaapos.2004.01.010Search in Google Scholar PubMed

14. Rochtchina E, Wang JJ, Flood VM, Mitchell P. Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol 2007;143:344–6.10.1016/j.ajo.2006.08.032Search in Google Scholar PubMed

15. Nowak M, Swietochowska E, Wielkoszynski T, Marek B, Kos-Kudla B, Szapska B, et al. Homocysteine, vitamin B12, and folic acid in age-related macular degeneration. Eur J Ophthalmol 2005;15:764–7.10.1177/112067210501500617Search in Google Scholar

16. Heuberger RA, Fisher AI, Jacques PF, Klein R, Klein BE, Palta M, et al. Relation of blood homocysteine and its nutritional determinants to age-related maculopathy in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2002;76:897–902.10.1093/ajcn/76.4.897Search in Google Scholar PubMed

17. Coral K, Raman R, Rathi S, Rajesh M, Sulochana KN, Angayarkanni N, et al. Plasma homocysteine and total thiol content in patients with exudative age-related macular degeneration. Eye (Lond) 2006;20:203–7.10.1038/sj.eye.6701853Search in Google Scholar PubMed

18. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 2006;580:2994–3005.10.1016/j.febslet.2006.04.088Search in Google Scholar PubMed

19. Flicker L, Martins RN, Thomas J, Psych JA, Taddei K, Vasikaran SD, et al. B-vitamins reduce plasma levels of beta amyloid. Neurobiol Aging 2008;29:3.10.1016/j.neurobiolaging.2006.10.007Search in Google Scholar PubMed

20. Hasegawa T, Ukai W, Jo DG, Xu X, Mattson MP, Nakagawa M, et al. Homocysteic acid induces intraneuronal accumulation of neurotoxic Abeta42: implications for the pathogenesis of Alzheimer’s disease. J Neurosci Res 2005;80:869–76.10.1002/jnr.20514Search in Google Scholar PubMed

21. Irizarry MC, Gurol ME, Raju S, az-Arrastia R, Locascio JJ, Tennis M, et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology 2005;65:1402–8.10.1212/01.wnl.0000183063.99107.5cSearch in Google Scholar PubMed

22. Moore P, El-Sherbeny A, Roon P, Schoenlein PV, Ganapathy V, Smith SB. Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 2001;73:45–57.10.1006/exer.2001.1009Search in Google Scholar PubMed

23. Lee I, Lee H, Kim JM, Chae EH, Kim SJ, Chang N. Short-term hyperhomocysteinemia-induced oxidative stress activates retinal glial cells and increases vascular endothelial growth factor expression in rat retina. Biosci Biotechnol Biochem 2007;71:1203–10.10.1271/bbb.60657Search in Google Scholar PubMed

24. Kirsch SH, Knapp JP, Geisel J, Herrmann W, Obeid R. Simultaneous quantification of S-adenosyl methionine and S-adenosyl homocysteine in human plasma by stable-isotope dilution ultra performance liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877:3865–70.10.1016/j.jchromb.2009.09.039Search in Google Scholar PubMed

25. Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women’s Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med 2009;169:335–41.10.1001/archinternmed.2008.574Search in Google Scholar PubMed PubMed Central

26. Seddon JM, Gensler G, Klein ML, Milton RC. Evaluation of plasma homocysteine and risk of age-related macular degeneration. Am J Ophthalmol 2006;141:201–3.10.1016/j.ajo.2005.07.059Search in Google Scholar PubMed

27. Kamburoglu G, Gumus K, Kadayifcilar S, Eldem B. Plasma homocysteine, vitamin B12 and folate levels in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2006;244:565–9.10.1007/s00417-005-0108-2Search in Google Scholar PubMed

28. Wu KH, Tan AG, Rochtchina E, Favaloro EJ, Williams A, Mitchell P, et al. Circulating inflammatory markers and hemostatic factors in age-related maculopathy: a population-based case-control study. Invest Ophthalmol Vis Sci 2007;48:1983–8.10.1167/iovs.06-0223Search in Google Scholar PubMed

29. Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 2001;107:675–83.10.1172/JCI10588Search in Google Scholar PubMed PubMed Central

30. Hernanz A, De la FM, Navarro M, Frank A. Plasma aminothiol compounds, but not serum tumor necrosis factor receptor II and soluble receptor for advanced glycation end products, are related to the cognitive impairment in Alzheimer’s disease and mild cognitive impairment patients. Neuroimmunomodulation 2007;14:163–7.10.1159/000110641Search in Google Scholar PubMed

31. Franke S, Muller A, Sommer M, Busch M, Kientsch-Engel R, Stein G. Serum levels of total homocysteine, homocysteine metabolites and of advanced glycation end-products (AGEs) in patients after renal transplantation. Clin Nephrol 2003;59:88–97.10.5414/CNP59088Search in Google Scholar

32. Yokoi M, Yamagishi SI, Takeuchi M, Ohgami K, Okamoto T, Saito W, et al. Elevations of AGE and vascular endothelial growth factor with decreased total antioxidant status in the vitreous fluid of diabetic patients with retinopathy. Br J Ophthalmol 2005;89:673–5.10.1136/bjo.2004.055053Search in Google Scholar PubMed PubMed Central

33. Yamada Y, Ishibashi K, Ishibashi K, Bhutto IA, Tian J, Lutty GA, et al. The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas. Exp Eye Res 2006;82:840–8.10.1016/j.exer.2005.10.005Search in Google Scholar PubMed PubMed Central

34. Glenn JV, Stitt AW. The role of advanced glycation end products in retinal ageing and disease. Biochim Biophys Acta 2009;1790:1109–16.10.1016/j.bbagen.2009.04.016Search in Google Scholar PubMed

35. Viktorov IV, Aleksandrova OP, Alekseeva NY. Homocysteine toxicity in organotypic cultures of rat retina. Bull Exp Biol Med 2006;141:471–4.10.1007/s10517-006-0202-4Search in Google Scholar PubMed

36. Steele ML, Fuller S, Maczurek AE, Kersaitis C, Ooi L, Munch G. Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells. Cell Mol Neurobiol 2012 Jul 31 [Epub ahead of print].10.1007/s10571-012-9867-6Search in Google Scholar PubMed

37. da Cunha AA, Ferreira AG, Loureiro SO, da Cunha MJ, Schmitz F, Netto CA, et al. Chronic hyperhomocysteinemia increases inflammatory markers in hippocampus and serum of rats. Neurochem Res 2012;37:1660–9.10.1007/s11064-012-0769-2Search in Google Scholar PubMed

38. Chang L, Geng B, Yu F, Zhao J, Jiang H, Du J, et al. Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. Amino Acids 2008;34:573–85.10.1007/s00726-007-0011-8Search in Google Scholar PubMed

39. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 2008;322:587–90.10.1126/science.1162667Search in Google Scholar PubMed PubMed Central

40. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. J Am Med Assoc 2008;299:2027–36.10.1001/jama.299.17.2027Search in Google Scholar PubMed PubMed Central

41. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr 2008;87:517–33.10.1093/ajcn/87.3.517Search in Google Scholar PubMed

42. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010;170:1622–31.10.1001/archinternmed.2010.348Search in Google Scholar PubMed

43. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population [see comments]. J Am Med Assoc 1993;270:2693–8.10.1001/jama.1993.03510220049033Search in Google Scholar PubMed

Received: 2012-6-22
Accepted: 2012-10-9
Published Online: 2012-11-12
Published in Print: 2013-03-01

©2013 by Walter de Gruyter Berlin Boston

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