Hyperhomocysteinemia recurrence in levodopa-treated ParkinsonÕs disease patients V. Belcastro a, *, L. Pierguidi a, *, A. Castrioto a , C. Menichetti a , G. Gorgone b , R. Ientile c , F. Pisani d , A. Rossi a , P. Calabresi a and N. Tambasco a a Neurology Clinic, University of Perugia, S. Maria della Misericordia Hospital, Perugia and IRCCS Fondazione Santa Lucia, Rome; b Neurologia Clinica, Universita ` Campus Biomedico di Roma, Rome; c Dipartimento di Biochimica, Fisiologia e Scienze della Nutrizione, University of Messina, Messina; and d Neurology Clinic, University of Messina, Messina, Italy Keywords: folate, hyperhomocyste- inemia, levodopa, ParkinsonÕs disease Received 26 June 2009 Accepted 2 November 2009 Background: Patients with ParkinsonÕs disease (PD) and chronically treated with L-DOPA exhibit, in a percentage of 10–30%, supra-physiological levels of plasma total homocysteinemia (tHcy). In this study, we have investigated, in a group of hyper-homocysteinemic PD patients, the time of hyper-tHcy recurrence after dis- continuation of 1-month folate supplementation given to normalize plasma tHcy levels. Methods: Plasma tHcy, cobalamin and folate were assayed before and after 1-month folate supplementation (5 mg/day), and after 2 and 4 months after folate discontin- uation in 29 PD patients (16M/13F, mean age 69.4 ± 6.9 years) stabilized on a mean L-DOPA dose of 509.4 ± 312.1 mg/day. Results: After folate supplementation, plasma tHcy levels fell within the normal range in all patients. At the 2-month control after folate discontinuation, plasma tHcy remained within physiological values in 25 out of 29 patients. Conversely, 4 months after folate discontinuation, all patients exhibited hyper-tHcy. Conclusions: One-month intake of 5 mg/day folate normalizes plasma tHcy levels in all hyper-homocysteinemic PD patients. Following folate discontinuation, hyper-tHcy recurs in all patients within 4 months. Knowledge of this time interval is useful to optimize pulses of folate therapy in hyper-homocysteinemic patients with PD. Introduction Supra-physiological plasma total (t) homocysteine (Hcy) levels have been associated to an increased risk for coronary artery disease, atherosclerosis, cognitive impairment, depression and diskinesia in patients with Parkinson disease (PD) [1–5]. A percentage of 10–30% of PD patients exhibits hyper-homocysteinemia (hyper- tHcy). Amongst the various variables analyzed, including for example smoke, alcohol consumption, advanced age and others, genetic factors and L-DOPA therapy have been indicated as causative factors of hyper-tHcy [6–8]. Amongst genetic factors, common single-nucleotide polymorphisms in methylenetetrahy- drofolate reductase gene (C677T MTHFR polymor- phism) have been extensively studied. Mutations of the MTHFR gene, in fact, implicate reduction in the activity of MTHFR, the main enzyme in the Hcy- methionine conversion [9]. L-DOPA is metabolised via O-methylation by catechol-O-methyl-transferase (COMT) using S-adenosyl-L-methionine as substrate, the main methyl group donor in the brain. Thus, L-DOPA metabolism consumes methyl groups needed for Hcy conversion to methionine and may ultimately lead to hyper-Hcy [6,7]. A common practice to normalize hyper-tHcy in PD patients is treatment with folate alone or associated with other B vitamins [10–12]. Guidelines on this treatment, however, including, for example, folate dose, duration of treatment and pulses, are not available in the literature, and folate is largely prescribed on empirical basis. The present study has been carried out to investigate in L-DOPA-treated PD patients, the time interval of hyper-tHcy recurrence once folate is dis- continued. Information on this parameter might help to optimize folate therapy pulses over time. Correspondence: V. Belcastro, MD, Clinica Neurologica, Universita` degli Studi di Perugia, Ospedale Santa Maria della Misericordia – S.Andrea delle Fratte, 06156 Perugia, Italy (tel.: +39-075-578.4230; fax: +39-075-578.4229; e-mail: vincenzobelcastro@libero.it). *These authors equally contributed to the work. Ó 2009 The Author(s) Journal compilation Ó 2009 EFNS 661 European Journal of Neurology 2010, 17: 661–665 doi:10.1111/j.1468-1331.2009.02894.x