HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Correspondence to:

ARTICLES: J. W. Miller, J. Selhub, M. R. Nadeau, C. A. Thomas, R. G. Feldman, and P. A. Wolf Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status Neurology 2003; 60: 1125-1129 [Abstract] [Full text] [PDF]

Correspondence: Submit a response to this article

Correspondence published:

Reply to Both Letters to the Editor

Joshua W Miller   (11 August 2003)

Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status

Katharina Schroecksnadel, Friedrich Leblhuber and Dietmar Fuchs   (11 August 2003)

Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status

Alessandro DiRocco, Peter Werner   (11 August 2003)

Reply to Both Letters to the Editor 11 August 2003
Joshua W Miller, UC Davis Medical Center Department of Medical Pathology 4645 Second Avenue Research III, Room 3200A Sacramento, CA 95817 Send Correspondence to journal: Re: Reply to Both Letters to the Editor jwmiller{at}ucdavis.edu Joshua W Miller	I thank Drs. Di Rocco and Werner for their interest in our article describing the effect of L-Dopa on plasma homocysteine levels in PD patients [1]. I concur with their statement that L-Dopa is expected to not only affect plasma homocysteine levels, but also disrupt methylation reactions by decreasing intracellular S-adenosylmethionine levels. In this regard I refer to the early work of Wurtman et al. (among others) which demonstrated that L-Dopa affects both methyl group metabolism and norepinephrine metabolism in rats [2, 3]. I also refer to our more recent rat study in which we demonstrated significant effects of L-Dopa on intracellular S-adenosylmethionine and S-adenosylhomocysteine concentrations in discrete brain regions [4]. Taken together, these animal studies strongly suggest that L-Dopa toxicity, at least in part, can result from disruption of key methylation reactions in the brain, as asserted by Drs. Di Rocco and Werner. We conclude that B vitamin supplementation (folate, vitamin B12, and vitamin B6) may be beneficial for L-Dopa-treated PD patients [1]. In addition to lowering plasma homocysteine, such supplements would be expected to raise intracellular S- adenosylmethionine and lower intracellular S-adenosylhomocysteine levels, thus protecting against L-Dopa-related toxicity. B vitamin supplements may be important for L-Dopa-treated PD patients with polymorphisms that significantly affect the activity of enzymes involved in one-carbon metabolism (e.g. methylenetetrahydrofolate reductase, methionine synthase). I agree that rigorous investigations are now warranted to assess the utility of innocuous B vitamin supplements in protecting against vascular disease and dementia in these patients. The hypothesis of Schroecksnadel et al. that hyperhomocysteinemia in PD patients is a consequence of immune activation is intriguing. However, their hypothesis is not supported by our data. Although the L-Dopa-treated PD patients in our study [1] had longer disease duration than the patients not treated with L-Dopa, there was no correlation between disease duration and homocysteine levels within either the L-Dopa-treated or the non-L-Dopa -treated groups. This is inconsistent with their hypothesis. Our hypothesis, in contrast, is supported by our rat studies showing that folate deficiency accentuates the effect of L-Dopa on plasma homocysteine levels [5] and that a catechol-O-methyltransferase inhibitor prevents L- Dopa-induced hyperhomocysteinemia [4]. References: 1.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; 60:1125-1129. 2.Chalmers JP, Baldessarini RJ, Wurtman RJ. Effects of L-dopa on norepinephrine metabolism in the brain. Proc Natl Acad Sci 1971;68:662- 666. 3.Ordonez LA, Wurtman RJ. Methylation of exogenous 3,4- dihydroxyphenylalanine (L-Dopa) - effects on methyl group metabolism. Biochem Pharmacol 1973;22:134-137. 4.Miller JW, Shukitt-Hale B, Villalobos-Molina R, Nadeau MR, Selhub J, Joseph JA. Effect of L-dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats. Clin Neuropharmacol 1997;20:55-66. 5.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;8:634-640.
Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status 11 August 2003
Katharina Schroecksnadel, Institute of Medical Chemistry and Biochemistry University of Innsbruck Fritz-Pregl-Streasse 3 Innsbruck, A-6020 Austria, Friedrich Leblhuber and Dietmar Fuchs Send Correspondence to journal: Re: Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status Dietmar.Fuchs{at}uibk.ac.at Katharina Schroecksnadel, et al.	We read with interest the article by Miller et. al. on L-dopa administration to induce homocysteine accumulation in patients with Parkinson�s disease. [1] The observed difference in homocysteine concentrations between patients with and without L-dopa treatment was attributed to a direct effect of L-dopa. However, this does not provide an adequate explanation for the fact that low B-vitamin concentration, which exists in both groups to a similar extent, lead to much higher homocysteine concentrations in patients under treatment. Rather the observed difference in homocysteine concentrations between patients seems to be associated with the significantly longer disease duration in L-dopa-treated patients. Earlier we described elevated homocysteine concentrations in patients with late stage Parkinson�s disease under L-dopa-treatment, and hyperhomocysteinemia coincided with lowered B-vitamin concentrations. [2] In our study, hyperhomocysteinemia in late stage of Parkinson�s disease was also related to higher concentrations of immune activation marker neopterin. [2] Immune activation and oxidative stress are considered to be involved in the pathogenesis of neurodegenerative diseases in general, and signs of immune activation parallel the progression of Parkinson�s disease. [2, 3] Immune activation could also be responsible for the accumulation of homocysteine in the patients because homocysteine was found to accumulate in supernatants of activated peripheral blood mononuclear cells. [4] Interestingly, when comparing data of the study by Miller et al. [1] it is obvious that there was no relationship between higher homocysteine and lower vitamin concentrations in the untreated group as compared with the patients receiving L-dopa. Considering that the treated group was older [1] and that later stages of Parkinson�s disease were found to present with significantly elevated production of neopterin and degradation of tryptophan, [2, 3] immune activation may be responsible for the increase of homocysteine rather than L-dopa therapy. Interestingly, an association between higher neopterin concentrations and hyperhomocysteinemia has also been described in various groups of patients and in healthy controls; none of them was treated with L-dopa. [5] References: 1. 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; 60:1125-1129. 2. Widner B, Leblhuber F, Frick B, Laich A, Artner-Dworzak E, Fuchs D. Moderate hyperhomocysteinaemia and immune activation in Parkinson's disease. J Neural Transm 2002; 109:1445-1452. 3. Widner B, Leblhuber F, Fuchs D. Increased neopterin production and tryptophan degradation in advanced Parkinson�s disease. J Neural Transm 2002;109:181-189. 4. Schroecksnadel K, Frick B, Winkler C, Leblhuber F, Wirleitner B, Fuchs D. Hyperhomocysteinemia and immune activation. Clin Exp Immunol (in press). 5. Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to oxidative depletion of folate rather than insufficient dietary intake. Clin Chem Lab Med 2001;39:691- 694.
Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status 11 August 2003
Alessandro DiRocco, Albert Einstein College of Medicine and Beth Israel Medical Center PACC-10 Union Square East #2-R New York, NY 10003, Peter Werner Send Correspondence to journal: Re: Effect of L-dopa on plasma homocysteine in PD patients: Relationship to B-vitamin status adirocco{at}aecom.yu.edu Alessandro DiRocco, et al.	We read with interest the article by Miller et al. describing the effect of L-Dopa on plasma homocysteine in Parkinson�fs disease [1]. We welcome the attention that this important metabolic phenomenon now receives, as we think that L-Dopa induced hyperhomocystenemia in PD is indicative of a broader metabolic alteration of the trans-methyl pathway with potential clinical consequences that extend beyond vascular disease and dementia. As reported by the authors [1], the increase in homocysteine is due to L-Dopa O-methylation, a reaction catalyzed by catechol-O- methyltransferase (COMT). This reaction consumes the methyl donor S- Adenosylmethionine, the principal methyl-group donor in the brain, and leads to increased production of (demethylated) S-Adenosylhomocysteine, and, ultimately, homocysteine. Increased O-methylation however, cannot only lead to hyperhomocystenemia, but can also cause a depletion of S- Adenosylmethionine, inducing a state of relative hypomethylation. In addition to COMT-dependent O-methylation of catecholamines, S- Adenosylmethionine is the methylating agent in vital metabolic reactions, including the synthesis of phosphatidylcholine and creatine, the methylation of phospholipids and of proteins, including N- and carboxyl- methylation of proteins, essential for the proper function of receptors configuration and permeability of ion channels [2]. Of immediate clinical relevance is the fact that S-Adenosylmethionine depletion has been associated with depression, common in patients with Parkinson�fs disease [3]. Lastly, our own work has shown that S-Adenosylmethionine and its precursors prevent or ameliorate L-Dopa neurotoxicity in primary mesencephalic cultures. Protection of dopaminergic neurons was abolished by COMT-inhibitors, suggesting that it was COMT mediated [4]. We also would like to note that hyperhomocystenemia has been reported not only in subjects with the (677C��T) methylenetetrahydrofolate reductase polymorphism, but also with a (D919G) mutation of the methionine synthase gene, substituting aspartate for glycine [5]. The prevalence of homozygosity of this mutation is high, with 10% of the overall population affected, and this mutation is associated with significantly decreased methionine synthase activity and elevated levels of plasma homocysteine. The effect of this mutation on homocysteine and other intermediaries of the trans-methyl pathway are likely to be of relevance for Parkinson�fs disease, and deserve attention. We believe that particularly in genetically vulnerable individuals, L -Dopa-associated hyperhomocysteinemia, while being a potential risk factor for vascular disease and dementia, may be a marker of broader L-Dopa induced or unmasked metabolic disorder that may have important clinical implications, and deserve further rigorous investigations. References: 1) 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;60:1125-1129 2) Clarke S. Protein methylation. Curr Opin Cell Biol 1993;5:977- 983. 3) Bottiglieri T, Hyland K. S-adenosyl-methionine levels in psychiatric and neurologic disorders. Acta Neurol Scand 1994;(S154):19- 26. 4) P. Werner, A. Di Rocco, A. Prikhojan, N. Rempel, T. Bottiglieri, S. Bressman, M.Yahr. COMT-dependnet protection of dopaminergic neurons by methionine, dimethionine, and S-adenosylmethionine (SAM-e) against L-Dopa toxicity in vitro: Implications for Parkinson�fs disease treatment. Brain Research 2001;893:278-281. 5) Cai H, Wang X, Colagiuri S, Wilcken DE. Methionine synthase D919G mutation in type 2 diabetes and its relation to vascular events. Diabetes Care 1998;10:1774-1775.