Elevated homocysteine levels in Parkinson's Disease: is there anything besides L-dopa treatment?

Background: Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have been linked to the pathogenesis of neurodegenerative disorders. Several studies observed elevated plasma Hcy levels in Parkinson's Disease (PD) patients treated with L-dopa, compared to healthy controls and to patients with other neurodegenetative disorders. Objective: We performed an overview of published evidences assessing the possible correlations between Hcy levels and the incidence or pathogenesis of PD. Methods: A Medline literature search was performed to identify all available studies on Hcy and the incidence or pathophysiology of PD up to 30/09/2009. Results: 30 studies were included in this overview (20 studies on humans, 10 experimental studies). The relationship between metilentetrahydrofolate-reductase genotype (the most common genetic cause of hyperhomocysteinemia) and the development of PD was contradictory. Dietary patterns and B-vitamins levels (important determinants of Hcy levels) were associated with a not-significant increased risk of PD in three prospective studies. Investigations on plasma and cerebro-spinalfluid Hcy concentrations in L-dopa naive PD patients gave conflicting results; some studies observed increased Hcy levels in L-dopa naive PD patients compared to controls, while others found no difference. In vitro, Hcy caused dose-dependent depletion of dopaminergic mesencephalic neurons, by numerous pathogenetic mechanisms. In vivo brain administration of Hcy induced motor and behavioural changes, similar to those observed in animal models of PD. Conclusions: Based on the available data, the possibility that the hyperhomocysteinemia may contribute to the pathogenesis of PD remains uncertain. L-dopa treatment represents the major determinant of the hyperhomocysteinemia observed in PD.