CSF xanthine, homovanillic acid, and their ratio as biomarkers of Parkinson's disease

Abstract

Diminished nigrostriatal dopaminergic neurotransmission is a biochemical hallmark of Parkinson's disease. Despite this, a reliable trait biomarker of sporadic Parkinson's disease has not emerged from measurements of cerebrospinal fluid dopamine metabolites. Previous studies have highlighted strong neurochemical relationships between dopamine and various purine compounds. In this study, we analyzed cerebrospinal fluid concentrations of homovanillic acid (the major catabolite of dopamine) and the purine compound xanthine for a comparison of 217 unmedicated Parkinson's disease subjects and 26 healthy controls. These compounds were highly correlated for both the Parkinson's disease subjects (r=0.68) and for controls (r=0.73; both groups, p<0.001). While neither homovanillic acid nor xanthine concentrations differentiated Parkinson's disease from controls, their ratio did. For controls, the mean [xanthine]/[homovanillic acid] quotient was 13.1±5.5 as compared to the Parkinson's disease value of 17.4±6.7 at an initial lumbar CSF collection (p=0.0017), and 19.7±8.7 (p<0.001) at a second CSF collection up to 24 months later. The [xanthine]/[homovanillic acid] ratio in the Parkinson's disease subjects differed as a function of disease severity, as measured by the sum of Unified Parkinson's Disease Rating Scale Activities of Daily Living and Motor Exam ratings. The [xanthine]/[homovanillic acid] ratio also increased between the first and second CSF collections, suggesting that this quotient provides both a state and trait biomarker of Parkinson's disease. These observations add to other neurochemical evidence that links purine metabolism to Parkinson's disease.

Fig. 1

Schematic pathways of purine metabolism. Inter-relationships of purine metabolism are shown, illustrating that xanthine is the last intermediate before urate (the end-product of purine degradation in man).

Fig. 2

Cerebrospinal fluid concentrations of xanthine, homovanillic acid, and their ratio in Parkinson’s disease subjects and controls. Box-and-whisker diagrams for control values and changes found for Parkinson’s disease (PD) subjects between the first and second cerebrospinal fluid (CSF) collections. CSF xanthine (XAN) and homovanillic acid (HVA) nanomolar concentrations and their ratios in healthy control and PD subjects (see Sections 2.1 and 2.2). The first CSF collection for the PD subjects was carried out in an unmedicated state. Data from the second CSF collection is sub-divided into subjects who either received or else did not receive selegiline (see Tables 4a and 4b). The shaded boxes indicate boundaries of the upper and lower quartiles of the data, while the upper and lower horizontal bars in each graph (“whiskers”) indicate the range of data. Circles in shaded boxes represent mean values, and the horizontal lines near the middle of each box indicate median values.