How we wish to be cited:
Brattström L. Homocysteine, vitamin B12, and folate in Parkinson´s disease treated by levodopa [evaluation]. Rondel 2005; 22. URL: http://www.rondellen.net

Homocysteine, vitamin B12, and folate in Parkinson´s disease treated by levodopa

Figure legend Lars Brattström has contributed to The Rondel previously (evaluation07_eng.htm). He is neurologist at The Department of Internal Medicine, of Kalmar County Hospital. Furthermore, he is a pioneer of modern homocysteine research. For Swedish readers, he has made a review of Parkinson´s disease, homocysteine, levodopa, vitamin B12 and folate. (evaluation22_swe.htm). For global readers, an abstract and list of references are published below. In leisure, if any, Brattström is a dovoted fisherman, at left demonstrating a haul, a Baltic salmon. E-mail: lars.brattstrom@ltkalmar.se

Many studies have shown that levodopa treatment in Parkinson´s disease patients is associated with increased plasma levels of total homocysteine (tHcy), an indicator of vitamin B12 and folate deficiency. I fact, in competition with several essential cerebral transmethylation reactions, levodopa consumes large amounts of methyl groups for its methylation to 3-O-methyldopa, methyl groups that have to be synthesised by vitamin B12- and folate-dependent metabolism. The increase in tHcy can be interpreted as a marker of insufficient methyl group synthesis for covering both the methylation of levodopa and endogenous compounds. By this competitive mechanism, levodopa may be toxic leading to hypomethylation of myeline, receptor proteins, DNA, membrane phospholipids, and catecholamines. This may explain why cerebral symptoms of vitamin B12 and folate deficiency as depressed mood and cognitive decline are common in Parkinsons disease. Moreover, homocysteine itself may be toxic by contribution in processes causing vascular disease and neural damage. More research on this topic is warranted.

References

1. Rosenblatt DS, Fenton WA. Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, editors. The Metabolic & Molecular Bases of Inherited Disease. 8^th ed. New York: McGraw-Hill; 2001.p.3897-933.

2. Mudd HS, Levy HL, Kraus JP. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, editors. The Metabolic & Molecular Bases of Inherited Disease. 8^th ed. New York: McGraw-Hill; 2001.p.2007-56.

3. Brattström L, Zhang Y, Hurtig M, Refsum H, Östensson S, Fransson L, Jonés K, Landgren F, Brudin L, Ueland PM. A common methylenetetrahydrofolate reductase gene mutation and logevity. Atherosclerosis 1998;141:315-9.

4. Brattström L, Wilcken DE, Öhrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 2000;101:2520-6.

5. Hultdin J. Laurells klinisk kemi i praktisk medicin (ed. Nilsson-Ehle P) 8:e upplagan 2003;645-652.

6. Refsum H, Smith AD, Ueland PM, Nexö E, Clarke R, McPartlin J, Johnston C, Engbaek F, Schneede J, McPartlin C, Scott JM. Facts and recommendations about total homocysteine determinations: An expert opinion. Clin Chem 2004;50:3-32.

7. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate and homocysteine. Hematology (Am Soc Heamtol Educ Program) 2003;:62-81.

8. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I: Usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34:90-8.

9. Daly D, Miller JW, Nadeau MR, Selhub J. The effect of L-dopa administration and folate deficiency on plasma homocysteine concentrations in rats. J Nutr Biochem 1997;8:634-40.

10. Wurtman RJ, Rose CM, Matthysse S, Stephenson J, Baldessarini R. L-dihydroxyphenylalanin: Effect on S-adenosylmethionine in brain. Science 1970;169:395-7.

11. Ordonez LA, Wurtman RJ. Folic acid and methyl group metabolism in rat brain: effects of L-dopa. Arch Biochem Biophys 1974;160:372-6

12. Da Prada M, Borgulya J, Napolitano A, Zurcher G. Improved therapy of Parkinsons disease with tolcapone, a central and peripheral COMT inhibitor with an S-adenosylmethionine-sparing effect. Clin Neuropharm 1994;17(suppl 3):S26-S37.

13. Miller JW, Shukitt-Hale B, Villalobos-Molina R, Nardeau MR, Selhub J, Joseph JA. Effect of L-dopa and the catechol-O-methyltransferase inhibitor Ro41-0960 on sulphur amino acid metabolism in rats. Clin Neuropharm 1997;20:55-66.

14. Cheng H, Gomes-Trolin C, Aquilonius SM, Steinberg A, Löfberg C, Ekblom J, Oreland L. Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adensylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinsons disease. Exprem Neurol 1997;145:580-5.

15. Surtees R, Hyland K. L-3,4-dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans. J Neurol Neurosurg Psych 1990;53:569-72.

16. Mudd SH, Pool JR. Labile methyl balances for normal humans on various dietary regimes. Metabolism 1975;24:721-35.

17. Allain P, Le Bouil A, Cordillet E, Le Quay, Bagheri H, Montastruc JL. Sulfate and cysteine levels in the plasma of patients with Parkinsons disease. Neuro Toxicol 1995;16:527-30.

18. Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Przuntek H et al. Elevated plasma levels of homocystine in Parkinsons disease. Eur Neurol 1998;40:225-7.

19. Yasui K, Kowa H, Nakaso K, Takeshima T, Nakashima K. Plasma homocysteine and MTHFR C677T genotype in levodopatreated patients with PD. Neurology 2000;55:437-40.

20. Brattstrom L. Plasma homocysteine and MTHFR C677T genotype in levodopatreated patients with PD. Neurology 2001;56:281

21. Muller T, Woitalla D, Hauptmann B, Fowler B, Kuhn W. Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinsons disease. Neurosci Letters 2001;308:54-6.

22. Blandini F, Fancellu R, Martignoni E, Mangiagalli A, Pacchetti C, Samuele A, Nappi G. Plasma homocysteine and L-dopa metabolism in patients with Parkinsons disease. Clin Chem 2001;47:1102-4.

23. Widner B, Leblhuber F, Frick B, Laich A, Artner-Dworzak E. Moderate hyperhomocysteinemia and immune activation in Parkinsons disease. J Neural Transm 2002;109:1445-52.

24. 3-OMD and homocysteine plasma levels in parkinsonian patients. J Neural Transm 2002;109:175-79.

25. Rogers J, Sanchez-Saffon A, Frol AB, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease. Arch Neurol 2003;60:59-64.

26. Miller JW, Selhub J, Nadeau MR, Thomas CA, Feldman RG, Wolf PA. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology 2003;60:1125-9.

27. Yasui K, Nakaso K, Kowa H, Takeshima T, Nakashima K. Levodopa-induced hyperhomocysteinemia in Parkinsons disease. Acta Neurol Scand 2003;108:66-7.

28. Woitalla D, Kuhn W, Muller T. MTHFR C677T polymorphism, folic acid and hyperhomocysteinemia in levodopa treated patients with Parkinsons disease. J Neural Transm 2004;(Supp 68):15-20.

29. O´Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB Jr, Bottiglieri T, Diaz-Arrastia R. Elevated plasma homocysteine level in patients with Parkinsons disease: motor, affective and cognitive associations. Arch Neurol 2004;61:865-8.

30. Özkan A, Colak Ö, Kutlu C, Ertan M, Özkan A. Plasma homocysteine levels in Pergolide-treated Parkinsons disease patients. Clin Neuropharmacol 2004;27:163-65.

31.Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, De Mari M, Livrea P. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinsons disease patients. Mov Dis 2005 in press.

32. Religa D, Czyzewski K, Styczynska M, Peplonska B, Chodakowska-Zebrowska M, Stepien K, Winblad B, Barcikowska M. Hyperhomocysteinemia in Parkinsons disease. Eur J Neurol 2004;11(Suppl. 2):10-11.

33. Nissinen E, Nissinen H, Larjonmaa H, Vaananen A, Helkamaa T, Reenila I, Rauhala P. The COMT inhibitor, entacapone, reduces levodopa-induced elevation in plasma homocysteine in healthy adult rats. J Neurol Transm 2004; (Epub ahead of print).

34. Carrieri PB, Indaco, A, Gentile S, Troisi E, Campanella G. S-adenosylmethionine treatment of depression in patients with Parkinsons disease. Curr Therap Res 1990;48:154-60.

35. Di Rocco A, Rodgers J, Brown R, Werner P, Bottiglieri T. S-adenosylmethionine improves depression in patients with Parkinsons disease in an open-label clinical trial. Mov Dis 2000;15:1225-29.

36. Gasparini M, Fabrizio E, Bonifati V, Meco G. Cognitive improvement during tolcapone treatment in Parkinsons disease. J Neural Transm 1997;104:887-894.

37. Ravaglia G, Forti P, Maioli F, Muscari A, Sacchetti L, Arnone G, Nativio V Talerico T, Mariani E. Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr 2003;77:668-73.

38. Budge M, de Jager C, Hogervorst C, Smith AD. Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people. J Am Geriatr Soc 2002;50:2014-18.

39. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D´Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimers disease. N Engl J Med 2002;346:476-83

40. Di Rocco A, Werner P. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology 2004;62:676-7.

41. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurogenerative disorders. Trends Neurosci 2003;26:137-46.

42. Duan W, Landenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP. Dietary folate deficiency and elevated homocysteine levels edanger dopaminergic neurons in models of Parkinsons disease. J Neurochem 2002;80:101-10.

43. Miller JW. Homocysteine, folate deficiency, and Parkinsons disease. Nutr Rev 2002;60:410-13

44. O´Suilleabhain P, Diaz-Arrastia R. Levodopa elevates homocysteine: is this a problem? Arch Neurol 2004;61:633-4.

45. Muller T, Hefter H, Hueber, Jost WH, Leenders K, Odin P, Schwartz J. Is levodopa toxic? J Neurol 2004;251 (Suppl. 6):VI/44-VI/46.

46. Postuma R, Lang A. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004;63:886-91.

Published March 3, 2005