Elevated plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with dyskinesias.

BACKGROUND: Elevated plasma homocysteine (Hcy) concentrations are associated with increased risk of systemic vascular diseases, Alzheimer's disease and vascular dementia. Several cross-sectional reports and two prospective clinical studies have recently reported elevated plasma Hcy levels in L-dopa-treated Parkinson's disease (PD) patients and Hcy has been proposed as a possible mediator for the development of long-term L-dopa motor complications (such as wearing off and on-off phenomena, and dyskinesias). The aim of the study was to elucidate a possible role of L-dopa-related hyperhomocysteinemia in the development of dyskinesias. METHODS: In this cross-sectional study we compared Hcy, B(12) and folate levels in 53 PD patients treated with L-dopa (29 with dyskinesias, 24 without dyskinesias). RESULTS: Mean plasma Hcy levels were higher in the group of PD patients with dyskinesias (19 vs. 15.4 micromol/L; T: 2.12; p=0.04). After taking into account potential confounding factors, analysis of the data revealed that the occurrence of dyskinesias progressively increased with plasma Hcy levels (relative risk 1.2, 95% CI 1.015-1.4; p=0.03). CONCLUSIONS: Our results raise the possibility that Hcy plays a role in the development of dyskinesias, through its toxic effects on both dopaminergic neurons and non-substantia nigra, non-dopaminergic neurons.

Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions.

Elevated plasma homocysteine (Hcy) concentrations are associated with Alzheimer's disease and vascular dementia. Several recent reports have indicated that L-dopa treatment is an acquired cause of hyperhomo-cysteinemia. Despite the fact that a large proportion of Parkinson's disease (PD) patients develop cognitive dysfunctions or dementia, particularly in the late stages of the illness and after long-term L-dopa treatment, the relationship between Hcy and dementia in PD has not been fully investigated. The aim of this study was to evaluate plasma Hcy levels in a group of L-dopa-treated PD patients with cognitive impairment and to elucidate a possible role of Hcy in the development of cognitive dysfunctions in PD. We compared Hcy, vitamin B12 and folate levels in 35 parkinsonian patients treated with L-dopa (14 with cognitive dysfunctions, 21 without cognitive impairment). Analysis of the data revealed that mean Hcy levels were significantly higher in the group with cognitive dysfunctions (21.2+/-7.4 vs. 15.8+/-4.4 micromol/L; p=0.0001), while there was no difference in age, sex, B12 and folate levels. In addition, logistic regression analysis showed that the risk of cognitive dysfunction progressively increased according to Hcy levels after correction for age, sex and B-vitamin status (odds ratio, 19.1; 95% CI, 1.5-241.4; p=0.02). Our results raise the possibility of a relationship between Hcy levels and cognitive dysfunctions in this group of L-dopa-treated PD patients. However, prospective studies on large cohorts of patients should be performed to clarify such an association.

Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients.

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment, and dementia. Elevated plasma concentrations of Hcy have been found recently in Parkinson's disease (PD) patients treated with levodopa, suggesting that levodopa is a cause of hyperhomocysteinemia (HHcy). The mechanism underlying HHcy in PD is the O-methylation of levodopa catalyzed by catechol-O-methyltransferase (COMT) that produces S-adenosylhomocysteine, which is hydrolyzed rapidly to Hcy. COMT inhibitors (COMT-I) are used currently in the treatment of PD; however, no study has assessed the effects of COMT-I administration on Hcy concentrations in PD patients. We compared plasma levels of Hcy, B12, and folate in 26 PD patients treated with levodopa, 20 PD patients treated with levodopa + COMT-I, and 32 controls. No significant differences were found in vitamin B12 levels, whereas folate concentrations were significantly lower in the levodopa-treated group. Plasma Hcy was increased significantly in the two groups of PD patients and was significantly lower in the group treated with levodopa + COMT-I. Statistical analysis showed that the difference in mean Hcy levels observed among PD patients was related to the addition of COMT-I, rather than to folate concentrations. We conclude that levodopa treatment increases plasma Hcy and the addition of COMT-I effectively reduces HHcy.