Cerebrospinal fluid homovanillic acid in the DATATOP study on Parkinson's disease. Parkinson Study Group

Abstract

Objectives: To determine whether cerebrospinal fluid (CSF) homovanillic acid (HVA) concentration in subjects with early, mild Parkinson's disease (PD) treated with the monoamine oxidase type B inhibitor selegiline hydrochloride differs from that of control subjects receiving placebo. Our hypothesis is that if selegiline offers neuroprotection in such patients, the HVA levels should not decrease over time as much as in those receiving placebo. A second objective was to define the kinetics of recovery of HVA concentration after discontinuation of selegiline therapy.

Design: During the controlled clinical trial DATATOP (deprenyl [selegiline] and tocopherol antioxidative therapy of parkinsonism) (which examined the effects of selegiline and tocopherol in 800 subjects with early, untreated PD), the CSF HVA concentration was measured at baseline and again 4 weeks after the study end point (need for levodopa therapy) was reached and medications were withdrawn (n = 265). Based on an interim analysis, the lumbar puncture protocol was modified, such that subjects who reached the study end point were randomly assigned an interval of 0 days or 2, 6, or 8 weeks between discontinuation of selegiline therapy and the lumbar puncture (n = 215).

Setting: In the hospital, after overnight bed rest and fasting.

Patients: The 800 subjects with early, mild PD who participated in the DATATOP controlled clinical trial.

Intervention: The four treatment arms were (1) selegiline-placebo and tocopherol-placebo, (2) selegiline-placebo and active tocopherol (2000 IU/d), (3) active selegiline hydrochloride (10 mg/d) and tocopherol-placebo, and (4) active selegiline hydrochloride (10 mg/d) and active tocopherol (2000 IU/d).

Main outcome measure: Cerebrospinal fluid HVA concentrations.

Results: The CSF HVA concentration at baseline did not correlate with disease duration or severity; the mean (+/- SD) HVA concentration was 34.7 +/- 17.0 ng/mL. In the 265 subjects who underwent analysis 4 weeks after the study end point was reached and medications were withdrawn, the decline in HVA concentration was significantly greater in subjects assigned to receive selegiline (9.2 +/- 12.7 ng/mL) than in subjects not receiving selegiline (3.2 +/- 14.4 ng/mL), indicating persistent monoamine oxidase (MAO) inhibition by selegiline. Tocopherol had no effect. Results from the modified protocol revealed that HVA concentration increased with time to approximately the same levels as determined in controls by 60 days but showed no clear final plateau level. At 0 days, HVA concentration was reduced from baseline by less than one third, indicating only partial inhibition of MAO activity by selegiline.

Conclusions: Measurements of CSF HVA concentrations (1) indicate the long duration of MAO inhibition by selegiline, (2) have limited utility as a marker of severity or progression in PD, (3) indicate that selegiline does not provide sufficient MAO inhibition to test adequately the oxidative stress hypothesis of the cause of PD, and (4) lend no support for a protective role of selegiline in slowing the progression of PD.