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Association With Vascular Disease

John D. Rogers, MD; Anna Sanchez-Saffon, BA; Alan B. Frol, PhD; Ramon Diaz-Arrastia, MD, PhD

Arch Neurol. 2003;60:59-64.

Background  Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B₁₂. However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels.

Objectives  To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B₁₂ have in levodopa-induced hyperhomocysteinemia.

Design/Methods  Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or ² test.

Results  Mean ± SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 ± 6.2 µmol/L), compared with levodopa-naïve patients (12.2 ± 4.2 µmol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (17.7 µmol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P= .04).

Conclusions  Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B₁₂ levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.

From the Yarmen Center for Parkinson's Disease, Department of Neurology, Beth Israel Medical Center, New York, NY (Dr Rogers and Ms Sanchez-Saffon); and the Division of Neuropsychology, Departments of Psychiatry (Dr Frol) and Neurology (Dr Diaz-Arrastia), The University of Texas Southwestern Medical Center, Dallas.

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