Brain Imaging to Assess the Effects of Dopamine Agonists on Progression of Parkinson Disease

To the Editor: Dr Marek and colleagues¹ reported that patients with Parkinson disease (PD) who were treated with pramipexole for 22 to 46 months had evidence of less dopamine neuron degeneration (as assessed by single-photon computed tomography [SPECT]) than did patients who were treated with levodopa for a similar period.

It is unclear whether these results simply reflect the pharmacological effects of pramipexole on dopamine transporter (DAT) expression, or the ability of DAT to sequester the radiologic marker 2β-carboxymethoxy-3β(4-iodophenyl)tropane (β-CIT). If pramipexole simply increased DAT expression in surviving nerve terminals, imaging could falsely indicate more surviving neurons. Pramipexole alteration of DAT function might have a similar influence. Drugs that bind to dopaminergic receptors have significant effects on DAT phosphorylation, functions, expression, and turnover.² Dopamine agonists and levodopa can influence DAT synthesis and degradation, with D1- and D2-linked second messenger systems often affecting DAT expression in opposite ways.² Dopamine generated from levodopa stimulates both classes of receptors, while pramipexole spares D1 receptors.³

The authors found no difference in β-CIT uptake at 10 weeks among a small subsample (7 who received pramipexole and 6 who received levodopa) of their patients, which argues against simple pramipexole upregulation of DAT. However, this raises 2 additional questions. First, what was the mean dose of pramipexole in these 7 patients at 10 weeks, and did this correspond to the mean dosage at 2 to 4 years? Low pramipexole doses may not influence DAT activity, so the authors should provide some assurance that the doses were similar in this 10-week assessment to later assessments. Second, does failure to detect changes at 10 weeks rule out the possibility of pramipexole influencing DAT expression and thus confounding the results? Little is known about chronic effects of drugs on DAT expression, as most animal studies have assessed only short-term effects. Some drug responses develop slowly, as in the examples of tardive dyskinesia, tachyphylaxis after months of hypnotic medications, and levodopa-dyskinesias in otherwise stable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–parkinsonism that developed only after months of levodopa treatment.⁴

We have investigated the short-term effect of dopamine agonist therapy on β-CIT SPECT imaging,⁵ and reported a trend toward increased uptake after 6 weeks of pergolide treatment. This approached statistical significance with a small sample size (n = 12) and raised concerns about possible direct pharmacologic impact of dopamine agonist therapy on β-CIT uptake.

The study by Marek et al¹ allows appropriate speculation that dopamine agonists may slow progression of PD. However, given the uncertainties, it may be premature to argue for a major change in clinical practice at this time.