Biomarker repurposing: Therapeutic drug monitoring of serum theophylline offers a potential diagnostic biomarker of Parkinson's disease

Abstract

Caffeine has been considered a neuroprotective agent against Parkinson's disease (PD). Recent metabolomic analysis showed that levels of caffeine and its metabolites were decreased in sera from patients with PD compared with those from healthy controls. We focused on theophylline, which is one of the primary caffeine metabolites, as a candidate biomarker of PD because: (1) its serum level can be measured in hospital laboratories by standardized immunoassay kits for therapeutic drug monitoring and (2) because it is less markedly affected by caffeine intake. This was a pilot study to measure the levels of theophylline in sera of 31 patients with PD and 33 age-matched disease controls using an immunoassay kit. We confirmed the previous finding of significantly lower levels of serum theophylline in the PD group compared with control group (PD: 0.07±0.09 μg/mL, control: 0.18±0.24 μg/mL, p<0.05). Using such an approach of applying known medical biomarkers for neurodegenerative diseases may allow us to skip the process from the discovery phase to clinical application, and subsequently shorten the period of time necessary for biomarker development.

Fig 1. Theophylline levels in sera of the PD and control groups.

Fig 1(A) Scatter plot showing the levels of serum theophylline in the control (n = 33) and PD (n = 31) groups. Bars indicate median values. The levels of theophylline in the PD group were significantly lower than those in the control group (P = 0.0383). Fig 1(B) ROC curve showing serum levels of theophylline to discriminate PD patients from controls. The AUC value was 0.65.

Fig 2. Serum levels of theophylline in PD patients with and without motor complications.

Scatter plot showing levels of serum theophylline in patients with PD with (n = 6) and without (n = 25) motor complications. The levels of serum theophylline in patients with motor complications were lower than in those without them, although the difference was not significant (p = 0.42).

Fig 3. Concept of biomarker repurposing.

The process of biomarker development is shown. Biomarker repurposing, the novel application of existing biomarkers for other purposes, enables the skipping of the development of quantification and standardization processes [27, 28].