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Comment & Response
June 29, 2020

Dopamine Metabolite Biomarkers and Testing for Disease Modification in Parkinson Disease

Author Affiliations
  • 1Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan
  • 2Henry Ford Hospital, Detroit, Michigan
JAMA Neurol. Published online June 29, 2020. doi:10.1001/jamaneurol.2020.1928

To the Editor In their randomized, placebo-controlled clinical trial of nilotinib in patients with Parkinson disease (PD), Pagan and colleagues1 reported dopamine metabolite data as “exploratory biomarkers.” They describe these biochemical findings as providing support for studying nilotinib as a potential disease-modifying therapy. The reasons for their conclusions are largely based on changes in cerebrospinal fluid (CSF) homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations (which, from my understanding of the data in Figure 2 A and B in the article, suggest that outlier effects might explain the reported differences between nilotinib and placebo treatment groups). Furthermore, the study’s methods and assumptions contradict what is known about dopamine metabolism in PD. For example, the authors report that changes seen in plasma dopamine metabolites offer further evidence for nilotinib’s effect on PD. However, measurement of dopamine metabolism in the bloodstream is not relevant to the pathophysiology of PD, for which the dopaminergic lesion is predominantly situated in the nigrostriatal pathway. Even CSF HVA concentration is a poor correlate of either PD severity or progression2 (although indexing the concentration of CSF HVA to that of xanthine improves its use as a biomarker3). In CSF obtained by lumbar puncture, HVA concentration almost doubles during sequential collection from the 1st to the 23rd milliliter.4 Unless CSF is sampled in serial aliquots in patients undergoing bed rest, the measured concentration of HVA will be subject to variability governed by the dimensions of the sac surrounding the spinal cord.

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