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Cerebrospinal Fluid Homovanillic Acid in the DATATOP Study on Parkinson's Disease
Parkinson Study Group
Arch Neurol. 1995;52(3):237-245.
Abstract
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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at baseline and again 4 weeks after the study end point (need for levodopa therapy) was reached and medications were withdrawn (n=265).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 In the 265 subjects who underwent analysis 4 weeks after the study end point was reached and medications were withdrawn, the decline in HVA concentration was significantly greater in subjects assigned to receive selegiline (9.2±12.7 ng/mL) than in subjects not receiving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.
Footnotes
Accepted for publication October 10, 1994.
This investigation was supported primarily by US Public Health Service grant NS 24778 from the National Institute of Neurological Disorders and Stroke and by the General Clinical Research Centers Program of the National Institutes of Health at Columbia University (grant RR00645), the University of Virginia (grant RR00847), the University of Pennsylvania (grant RR00040), the University of Iowa (grant RR00059), Ohio State University (grant RR00034), Massachusetts General Hospital (grant RR01066), the University of Rochester (NY) (grant RR00044), Brown University (grant RR02038), Oregon Health Sciences University (grant RR00334), Baylor College of Medicine (grant RR00350), the University of California-San Diego (grant RR00827), The Johns Hopkins University (grant RR00035), the University of Michigan (grant RR00042), and Washington University (grant RR00036); the Parkinson's Disease Foundation at Columbia-Presbyterian Medical Center, New York, NY; the National Parkinson Foundation, Miami, Fla; the Parkinson Foundation of Canada, Toronto, Ontario; the United Parkinson Foundation, Chicago, 111; the American Parkinson's Disease Association, New York, NY; and the University of Rochester (NY).
The HVA determinations were performed by Matthew Galloway, PhD, Lafayette Clinic, Detroit, Mich.
Reprint requests to the Neurological Institute, 710 W 168th St, New York, NY 10032-3784 (Stanley Fahn, MD).
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