Neurology -- Correspondence for Postuma et al., 66 (12) 1941-1943

Correspondence published:

Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: A randomized controlled study: Alessandro Di Rocco, Peter Werner, Ph.D. (31 October 2006)

Reply from the Authors: Ronald B. Postuma, Anthony E. Lang (31 October 2006)

Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: A randomized controlled study 31 October 2006

Alessandro Di Rocco,
New York University School of Medicine
650 First Avenue, New York, NY 10016,
Peter Werner, Ph.D.
Send Correspondence to journal:
Re: Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: A randomized controlled study

alessandro.dirocco{at}med.nyu.edu Alessandro Di Rocco, et al.

Clinical studies addressing metabolic consequences of L-Dopa treatment are of great importance to develop sophisticated therapeutic strategies for Parkinson’s disease (PD). Postuma et al [1] report that treatment of patients with PD with folate and vitamin B12, but not with the catechol-O-methyltransferase (COMT) inhibitor entacapone, lead to a reduction of L-Dopa induced elevation of plasma homocysteine. [1]
It should be considered whether the study allowed a sufficient time to observe a metabolic correction and whether a longer treatment period would have produced a more pronounced differences between treatment groups. It is also likely that patients who had been treated with L-Dopa for a longer period of time had a more profound metabolic change requiring a longer treatment period than those who were newly started on the drug. Furthermore, we wonder whether there was a nutritional bias in the population studied, as the baseline vitamin B12 levels in all treatment groups were in the lower range of normal.
These findings highlight a complex change in one-carbon cycle in both L-dopa treated and L-Dopa naïve patients with PD, of which hyperhomocystenemia is however only one of a more complex set of metabolic consequences. It would helpful to know how the plasma and whole blood levels of S-adenosylmethionine (SAM), the metabolite of the one-carbon cycle directly affected by increased demand due to L-Dopa treatment.
In the one-carbon cycle, homocysteine removal and methionine /SAM recycling depend on B vitamin status. Homocysteine transsulfuration to cysteine requires pyridoxal phosphate (B6), while recycling of methionine through methionine synthase requires cobalamin (B12) and the folic acid one-carbon pool as its methyl-group donor. [2] Hyperhomocysteinemia is an indicator of broader metabolic changes occurring in response to COMT O- Methylation of L-Dopa. Another immediate consequence is the depletion of the methyl donor SAM. Although O- methylation in itself is neuroprotective [3], SAM depletion will cause multiple neurochemical changes in the CNS, including reduced synthesis of phosphatidylcholine and creatine, lowered methylation of phospholipids, and N- and carboxyl- methylation of membrane proteins regulating receptor configuration and ion channels permeability. [2,3,4] In addition, the risk of developing PD is significantly increased by polymorphisms in key enzymes of one-carbon metabolism. [5]
The long-term consequences of disease and treatment-induced alteration of one-carbon metabolism remain unclear but growing evidence suggests they can lead to a broader effect on disease manifestations and progression than those attributable to hyperhomocystenemia alone.
References
1. Postuma RB, Espay AJ, Zadikoff C, et al. Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology. 2006 27;66:1941-1943.
2. 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.
3. Werner P, Di Rocco A, Prikhojan A, et al. COMT-dependent protection of dopaminergic neurons by methionine, dimethionine, and S- adenosylmethionine (SAM-e) against L-Dopa toxicity in vitro: implications for Parkinson’s disease treatment. Brain Res 2001; 893: 278–281.
4. Mattson MP. Methylation and acetylation in nervous system development and neurodegenerative disorders. Ageing Res Rev 2003; 2:329-342.
5. de Lau LM, Koudstaal PJ, Van Meurs JB, et al. Methylenetetrahydrofolate reductase C677T genotype and PD. Ann Neurol 2005; 58:972-973.
Disclosure: The authors report no conflicts of interest.

Reply from the Authors 31 October 2006

Ronald B. Postuma,
Department of Neurology, Montreal General Hospital
L7-305 1650 Cedar Ave., Montreal, Quebec, Canada H3G 1A4,
Anthony E. Lang
Send Correspondence to journal:
Re: Reply from the Authors

ron.postuma{at}muhc.mcgill.ca Ronald B. Postuma, et al.

We thank Drs. Di Rocco and Werner for their interest in our article. It is possible that longer treatment with vitamins, entacapone, or both may have resulted in a larger decrease in homocysteine levels than we observed. To support this, we found some trend towards a further decrease in homocysteine between weeks 3 and 6 in the vitamin-treated group, although the majority of the decline occurred in the first three weeks.
On the other hand, we cannot find any evidence that there was a decline in vitamin treatment efficacy in patients who were on long-term levodopa treatment. In these patients, baseline homocysteine levels were somewhat higher than in newly-treated patients (12.9 +/- 4.0 vs. 10.0 +/- 3.07) - this likely reflects higher levodopa dose in the long-term treated group, as there was a significant correlation between levodopa dose and baseline homocysteine (r=0.449, p=0.0165). However, the decline in homocysteine level was greater in patients who had received long-term treatment (-2.05 +/- 3.03 vs. -0.98 +/- 2.03), suggesting that duration of metabolic abnormality did not negatively impact response to vitamin therapy.
“Borderline” vitamin B12 levels have been reported by other groups in similar studies. [6,7] The reason for this is unclear, but may perhaps reflect dietary changes in patients with PD or even altered methylation status as a risk factor for disease. Whether these levels are low enough to have impacted significantly on our findings is debatable, particularly since the B12 levels in our patients were still in the low normal range.
We concur that other metabolic consequences of altered methylation, including S-adenosylmethionine (SAM) depletion may be important in any potential levodopa toxicity. Even if homocysteine may not be the only potentially toxic agent, it is a good marker for methylation status and was the primary marker in all large-scale epidemiologic studies that suggested a connection between homocysteine metabolism and vascular disease. [8,9] This is the main reason why we selected this measurement as the primary outcome. However, measurement of SAM, S-adenosylhomocysteine (SAH), and other markers would also be of interest in future studies.
References
6. O'Suilleabhain PE, Bottiglieri T, Dewey RB Jr., Sharma S, az- Arrastia R. Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease. Mov Disord 2004;19:1403-1408.
7. Valkovic P, Benetin J, Blazicek P, Valkovicova L, Gmitterova K, Kukumberg P. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients. Parkinsonism Relat Disord 2005;11:253-256.
8. Postuma RB, Lang AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004;63:886-891.
9. Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C- ->T polymorphism, and risk of ischemic stroke: Results of a meta- analysis. Neurology 2002;59:529-536.
Disclosure: The authors report no conflicts of interest.