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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 ?g/mL, control: 0.18±0.24 ?g/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.

SUBMITTER: Ohmichi T

PROVIDER: S-EPMC6059449 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Ohmichi Takuma T Kasai Takashi T Kosaka Tadashi T Shikata Keisuke K Tatebe Harutsugu H Ishii Ryotaro R Shinomoto Makiko M Mizuno Toshiki T Tokuda Takahiko T

PloS one 20180725 7

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 an ...[more]

PMID: 30044870

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Project description:BackgroundIn lymphangioleiomyomatosis (LAM), tuberous sclerosis gene mutations activate the mechanistic target of the rapamycin pathway, resulting in vascular endothelial growth factor-D (VEGF-D) overproduction. While the utility of serum VEGF-D testing for the diagnosis of LAM is outlined in ATS/JRS LAM Guidelines, the assay has not been fully validated for Asian populations. Our aims were to validate serum VEGF-D testing in Japan, by directly comparing measurements in Japan and the U.S., determining the diagnostic cut-off for serum VEGF-D levels among the Japanese women with typical thin walled cystic change on CT, and determining the performance of VEGF-D as a prognostic biomarker.Subjects and methodsWe determined serum VEGF-D levels from 108 LAM patients, 14 disease controls, and 51 healthy volunteers from the Japanese population. Measurements of 61 LAM patients were compared to those from the principal VEGF-D laboratory in the U.S at Cincinnati Children's Hospital Medical Center. We correlated baseline serum VEGF-D levels with baseline and longitudinal clinical data to determine how pregnancy, sirolimus or gonadotrophin-releasing hormone (GnRH) agonists influence serum VEGF-D levels.ResultsSerum VEGF-D measurements in Japan and the U.S. were very similar. Baseline serum VEGF-D levels effectively distinguished LAM from other diseases and healthy volunteers at a cut-off level of 645 pg/ml and were diagnostically specific at 800 pg/ml, consistent with the recommendations of the ATS/JRS LAM Guidelines. Baseline serum VEGF-D correlated negatively with the DLco baseline % predicted and with the annual decrease in DLco % predicted. There was no significant association between baseline serum VEGF-D level and the outcomes of death or transplant. Serum VEGF-D levels markedly decreased during treatment with sirolimus, but not with GnRH analogues. Serum VEGF-D levels of most LAM patients did not increase over time, and neither pregnancy nor menopause significantly modulated serum VEGF-D levels.ConclusionsSerum VEGF-D is a useful diagnostic and therapeutic biomarker for LAM. Satisfactory precision and international inter-laboratory agreement of the clinical assay support VEGF-D recommendations in the ATS/JRS LAM Guidelines for the Japanese population.

Dataset Information

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

Publications

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

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