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Serum Caffeine and Metabolites Are Reliable Biomarkers of Early Parkinson Disease Motoki Fujimaki, Shinji Saiki, Yuanzhe Li, Et Al

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Serum Caffeine and Metabolites Are Reliable Biomarkers of Early Parkinson Disease Motoki Fujimaki, Shinji Saiki, Yuanzhe Li, Et Al Published Ahead of Print on January 3, 2018 as 10.1212/WNL.0000000000004888 ARTICLE OPEN ACCESS CLASS OF EVIDENCE Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease Motoki Fujimaki, MD, Shinji Saiki, MD, PhD, Yuanzhe Li, PhD, Naoko Kaga, PhD, Hikari Taka, PhD, Correspondence Taku Hatano, MD, PhD, Kei-Ichi Ishikawa, MD, PhD, Yutaka Oji, MD, Akio Mori, MD, Ayami Okuzumi, MD, Dr. Saiki Takahiro Koinuma, MD, Shin-Ichi Ueno, MD, Yoko Imamichi, BS, Takashi Ueno, PhD, Yoshiki Miura, PhD, [email protected] Manabu Funayama, PhD, and Nobutaka Hattori, MD, PhD or Dr. Hattori [email protected] Neurology® 2018;90:e1-8. doi:10.1212/WNL.0000000000004888 Abstract MORE ONLINE Objective ff Class of evidence To investigate the kinetics and metabolism of ca eine in serum from patients with Parkinson Criteria for rating – disease (PD) and controls using liquid chromatography mass spectrometry. therapeutic and diagnostic studies Methods NPub.org/coe Levels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age- matched healthy controls were examined by liquid chromatography–mass spectrometry. RELATED ARTICLE Mutations in caffeine-associated genes were screened by direct sequencing. Editorial Results Caffeine and Parkinson Serum levels of caffeine and 9 of its downstream metabolites were significantly decreased even disease: A possible in patients with early PD, unrelated to total caffeine intake or disease severity. No significant diagnostic and pathogenic genetic variations in CYP1A2 or CYP2E1, encoding cytochrome P450 enzymes primarily breakthrough involved in metabolizing caffeine in humans, were detected compared with controls. Likewise, Page XXX caffeine concentrations in patients with PD with motor complications were significantly de- creased compared with those without motor complications. No associations between disease severity and single nucleotide variants of the ADORA2A gene encoding adenosine 2A receptor were detected, implying a dissociation of receptor sensitivity changes and phenotype. The profile of serum caffeine and metabolite levels was identified as a potential diagnostic biomarker by receiver operating characteristic curve analysis. Conclusion Absolute lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine previously revealed by epidemiologic and experimental studies. Classification of evidence This study provides Class III evidence that decreased serum levels of caffeine and its metab- olites identify patients with PD. From the Department of Neurology (M.F., S.S., Y.L., T.H., K.-I.I., Y.O., A.M., A.O., T.K., S.-I.U., Y.I., M.F., N.H.), Research Institute for Diseases of Old Age (M.F., N.H.), and Laboratory of Proteomics and Biomolecular Science (N.K., H.T., T.U., Y.M.), Juntendo University School of Medicine, Tokyo, Japan. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e1 Glossary A2A-R = adenosine 2A receptor; AUC = area under the curve; CYP1A2 = cytochrome P450 family 1 subfamily A member 2; CYP2E1 = cytochrome P450 family 2 subfamily E member 1; ExAC = Exome Aggregation Consortium; H&Y = Hoehn & Yahr; LC-MS = liquid chromatography–mass spectrometry; LED = levodopa equivalent dose; MIBG = 123I-metaiodobenzylgua- nidine; MMSE = Mini-Mental State Examination; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD = Parkinson disease; ROC = receiver operating characteristic; SIFT = sorting intolerant from tolerant; SNV = single nucleotide variation; UPDRS = Unified Parkinson’s Disease Rating Scale. Parkinson disease (PD) is a neurodegenerative disease char- Juntendo University Hospital. Patients were eligible for acterized by motor and nonmotor symptoms.1 There have inclusion if they were diagnosed with idiopathic PD based been several reports suggesting an inverse association be- on Movement Disorders Society criteria, with no dementia tween daily caffeine consumption and a reduced risk of de- (with a Mini-Mental State Examination [MMSE] score veloping PD in men, and in women not taking hormone ≥24).1 Hoehn & Yahr (H&Y) stages and Unified Parkin- replacement therapy.2,3 Caffeine can protect against nigral son’s Disease Rating Scale motor section (UPDRS-III) neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6- scores were defined during the “on” phase for practical and tetrahydropyridine (MPTP)–induced PD mouse model.4,5 ethical reasons. Levodopa equivalent doses (LEDs) were Likewise, the caffeine metabolites paraxanthine and theoph- calculated based on a previous report.19 We assessed caf- ylline similarly attenuate MPTP neurotoxicity.6 However, feine concentrations as 60 mg per cup of coffee, 30 mg per changes in the entire caffeine metabolic pathway in patients cup of tea, and 20 mg per cup of green tea, using the Food with PD remain unclear. Society Commission of Japan guidelines.20 No participant had a history of cancer, aspiration pneumonia, or collagen Clinically, caffeine appears to improve motor symptoms by vascular diseases. – antagonizing adenosine 2A receptors (A2A-Rs).7 9 One of the biological effects of caffeine is the nonselective antagonism of In addition to the cohort for serum caffeine metabolism A2A-Rs, which is encoded by the A2A-R gene (ADORA2A). analysis, we recruited an additional 51 healthy controls (25 Caffeine is primarily metabolized by 2 cytochrome P450 men) (total controls = 82) and 67 patients with PD (33 men) enzymes, cytochrome P450 family 1 subfamily A member 2 (total patients with PD = 176) for gene analysis. (CYP1A2) and cytochrome P450 family 2 subfamily E – member 1 (CYP2E1).10 12 No associations between Standard protocol approvals, registrations, ADORA2A and CYP1A2 gene variants and polymorphisms and patient consents – and PD onset frequencies have been detected,13 15 but the This study protocol complied with the Declaration of Hel- association of caffeine with motor fluctuations has not been sinki and was approved by the ethics committee of Juntendo addressed. University (2012157). Written informed consent was given by all participants. The development of blood-based biomarkers for PD is of high priority because of the easy sample collection pro- Sample collection cedure.16 Four caffeine metabolites have been identified as Blood samples were collected at the outpatient department biomarkers for de novo PD progression using gas of Juntendo University Hospital between December 2013 chromatography–mass spectrometry and liquid and February 2014. Following overnight fasting (12–14 chromatography–mass spectrometry (LC-MS).17 We have hours), a serum sample was obtained using 7 mL EDTA- also reported decreased serum levels of caffeine and 4 2Na blood spits (PN7; SRL, Tokyo, Japan) followed by 2–3 downstream metabolites in patients with PD receiving inversions. The samples then rested for 30–60 minutes at antiparkinsonian treatment.18 Here we analyzed serum 4°C followed by centrifugation for 15 minutes at ×3,000g. caffeine and metabolite concentrations and variations in The serum was separated into collection tubes and stored caffeine-associated genes. in liquid nitrogen until analysis. Sample preparation Methods Analyzers were blinded to all serum samples and partic- ipants’ information. We used the same methodology for the Participants sample preparation as the one employed in a previous We recruited 31 healthy controls (13 men) and 108 study.21 Briefly, 100 μL of serum was immediately plunged patients with PD without dementia (58 men) (table 1). All into 400 μL acetonitrile with 200 pmol of caffeine-(tri- 13 13 15 participants with PD had been treated at Juntendo Uni- methyl- C3); 3-methylxanthine-2,4,5,6- C4, 1,3,9- N3; ’ 13 15 versity Hospital. Control participants were the patients 7-methylxanthine-2,4,5,6- C4, 1,3- N2; paraxanthine-d3; 13 15 spouses and patients with asymptomatic brain ischemia at and theophylline-2- C-1, 3- N2 were purchased from e2 Neurology | Volume 90, Number 5 | January 30, 2018 Neurology.org/N variants was assessed using the sorting intolerant from Table 1 Demographic characteristics of participants tolerant (SIFT) method.22 The frequencies of each variant Patients p were evaluated using the Exome Aggregation Consortium Controls with PD Valuea (ExAC) database (http://exac.broadinstitute.org/). — Number 31 108 Cardiac 123I-metaiodobenzylguanidine Male:female 13:18 58:50 0.245b scintigraphy 123 Age, y, mean ± SD 63.3 ± 11.5 67.1 ± 9.95 0.184 All patients with PD underwent cardiac I- metaiodobenzylguanidine (MIBG) scintigraphy to assess Duration, y, mean ± SD — 6.49 ± 5.66 — any cardiac sympathetic denervation in the heart. We used the 23 H&Y stage, mean ± SD — 2.13 ± 0.90 — same methodology as the one employed in a previous study. ± — — UPDRS-III, mean SD 13.6 ± 10.1 Statistical analysis Coffee intake, cups/d, n 6+; 0 6+; 1 — When a value was under the limit of detection, we assigned it 4–5; 1 4–5; 3 half the minimum value of its compound. Wilcoxon tests were used to compare all individual analyses between controls and 1–3; 26 1–3; 79 patients with PD. The Steel test, a nonparametric, multiple 0; 4 0; 25 comparison test, was used to compare patients stratified by H&Y stage (I, II, III, and IV) and controls. Receiver operating Total caffeine 115.81 ± 69.22 107.50 ± 67.27 0.556 consumption, characteristic (ROC) analysis was carried out using JMP12 mg/d, mean ± SD (SAS Institute Japan, Chuo-Ku), and the optimal cutoff values and area under the curve (AUC) were calculated using You- Abbreviations: H&Y = Hoehn & Yahr; PD = Parkinson disease; UPDRS = 24 Unified Parkinson’s Disease Rating Scale.
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