Examination of Caffeine Metabolism Changes and Parkinson's Disease Symptom Correlation Based on Metabolite-Related Gene Analysis

• Project/Area Number: 17K07797
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Food science
• Research Institution: Tokiwa University
• Principal Investigator: SUMIYOSHI KATSUHIKO 常磐大学, 人間科学部, 准教授 (10445471)
• Co-Investigator(Kenkyū-buntansha): 斉木 臣二 順天堂大学, 医学部, 先任准教授 (00339996) ; 波田野 琢 順天堂大学, 大学院医学研究科, 准教授 (60338390)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: カフェイン / パーキンソン病 / 代謝 / カフェイン代謝 / 神経科学

Outline of Final Research Achievements

The purpose of this study is to use liquid chromatography (LC-MS) to describe the caffeine metabolism pathway in PD patient / control group serum for caffeine, which is epidemiologically effective in suppressing the onset of Parkinson's disease (PD).　 By examining the involvement in molecular pathology and identifying therapeutic target molecules, we found that PD patients had lower serum caffeine and its downstream metabolites compared to the control group．Verify its usefulness as a marker．We also searched for mutations and polymorphisms in PD patients with genes involved in abnormalities in the caffeine metabolic pathway, and verified the mechanism.　 Low levels of caffeine and caffeine metabolite profiles suggested a promising diagnostic biomarker for early PD.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病（PD）有病率は、わが国で 2 番目に多い神経変性疾患で、50 歳以降の発症が多い。発症 10 年以内に 40％の症例が認知症を呈するとされ、アルツハイマー型認知症などの他の認知症との共通病態も予測されている。10－20 年に及ぶ長期にわたり運動機能障害を呈するため、医療・介護的負担が大きく、現時点での治療は対症療法にとどまり根本的治療法はない。本研究の目的は疫学的にPD発症抑制効果があるとされるカフェインについて、 PD 患者のカフェイン代謝経路を、液体クロマトグラフィー(LC-MS)を用いて検討することにより、分子病態への関与を解明し治療標的分子を同定することである。

Research Products

• [Journal Article] Current Status of Telemedicine for Parkinson’s Disease in Japan: A Single-Center Cross-Sectional Questionnaire Survey (2022)
  • Author(s): Ogawa Mayuko、Oyama Genko、Sekimoto Satoko、Hatano Taku、Hattori Nobutaka
  • Journal Title: Journal of Movement Disorders Volume: 15 Issue: 1 Pages: 58-61
  • DOI: 10.14802/jmd.21096
  • Peer Reviewed / Open Access
• [Journal Article] α-Synuclein Seeding Assay Using RT-QuIC. (2021)
  • Author(s): Okuzumi Ayami、Hatano Taku、Fukuhara Takeshi、Ueno Shinichi、Nukina Nobuyuki、Imai Yuzuru、Hattori Nobutaka
  • Journal Title: Methods Mol Biol. Volume: 2322 Pages: 3-16
  • DOI: 10.1007/978-1-0716-1495-2_1
  • ISBN: 9781071614945, 9781071614952
  • Peer Reviewed
• [Journal Article] Diffusion MRI Captures White Matter Microstructure Alterations in PRKN Disease (2021)
  • Author(s): Koinuma Takahiro、Hatano Taku、Kamagata Koji、Andica Christina、Mori Akio、Ogawa Takashi、Takeshige-Amano Haruka、Uchida Wataru、Saiki Shinji、Okuzumi Ayami、Ueno Shin-Ichi、Oji Yutaka、Saito Yuya、Hori Masaaki、Aoki Shigeki、Hattori Nobutaka
  • Journal Title: Journal of Parkinson's Disease Volume: - Issue: 3 Pages: 1-15
  • DOI: 10.3233/jpd-202495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intrajejunal Infusion of Levodopa/Carbidopa for Advanced Parkinson's Disease: A Systematic Review (2021)
  • Author(s): Tsunemi Taiji、Oyama Genko、Saiki Shinji、Hatano Taku、Fukae Jiro、Shimo Yasushi、Hattori Nobutaka
  • Journal Title: Movement Disorders Volume: 36 Issue: 8 Pages: 1759-1771
  • DOI: 10.1002/mds.28595
  • Peer Reviewed
• [Journal Article] Reply: <i>PSAP</i> variants in Parkinson’s disease: a large cohort study in Chinese mainland population (2021)
  • Author(s): Oji Yutaka、Hatano Taku、Funayama Manabu、Hattori Nobutaka
  • Journal Title: Brain Volume: 144 Issue: 3 Pages: e26-e26
  • DOI: 10.1093/brain/awaa393
  • Peer Reviewed
• [Journal Article] MR Biomarkers of Degenerative Brain Disorders Derived From Diffusion Imaging (2020)
  • Author(s): Andica C, Kamagata K, Hatano T, Saito Y, Ogaki K, Hattori N, Aoki S.
  • Journal Title: J Magn Reson Imaging Volume: 52 Pages: 1620-1636
  • Peer Reviewed
• [Journal Article] Astrocytic 3-Repeat Tau Pathologies in Progressive Supranuclear Palsy (2020)
  • Author(s): Taniguchi D, Takanashi M, Hatano T, Kishikawa S, Shimonaka S, Motoi Y, Yao T, Hattori N.
  • Journal Title: J Neuropathol Exp Neurol. Volume: 79 Pages: 1015-1018
  • Peer Reviewed
• [Journal Article] Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease (2020)
  • Author(s): Yamaguchi A, Ishikawa KI, Inoshita T, Shiba-Fukushima K, Saiki S, Hatano T, Mori A, Oji Y, Okuzumi A, Li Y, Funayama M, Imai Y, Hattori N, Akamatsu W.
  • Journal Title: Stem Cell Reports Volume: 14 Pages: 1060-1075
  • Peer Reviewed
• [Journal Article] Shared Metabolic Profile of Caffeine in Parkinsonian Disorders (2020)
  • Author(s): Takeshige-Amano H, Saiki S, Fujimaki M, Ueno SI, Li Y, Hatano T, Ishikawa KI, Oji Y, Mori A, Okuzumi A, Tsunemi T, Daida K, Ishiguro Y, Imamichi Y, Nanmo H, Nojiri S, Funayama M, Hattori N.
  • Journal Title: Mov Disord Volume: 35 Pages: 1438-1447
• [Journal Article] Neurocognitive and psychiatric disorders-related axonal degeneration in Parkinson's disease (2020)
  • Author(s): Andica C, Kamagata K, Hatano T, Saito Y, Uchida W, Ogawa T, Takeshige-Amano H, Hagiwara A, Murata S, Oyama G, Shimo Y, Umemura A, Akashi T, Wada A, Kumamaru KK, Hori M, Hattori N, Aoki S.
  • Journal Title: J Neurosci Res Volume: 98 Pages: 936-949
• [Journal Article] Evaluation of white matter microstructure in patients with Parkinson's disease using microscopic fractional anisotropy (2020)
  • Author(s): Ikenouchi Y, Kamagata K, Andica C, Hatano T, Ogawa T, Takeshige-Amano H, Kamiya K, Wada A, Suzuki M, Fujita S, Hagiwara A, Irie R, Hori M, Oyama G, Shimo Y, Umemura A, Hattori N, Aoki S.
  • Journal Title: Neuroradiology. Volume: 62(2) Issue: 2 Pages: 197-203
  • DOI: 10.1007/s00234-019-02301-1
  • Peer Reviewed
• [Journal Article] A metabolic profile of polyamines in parkinson disease: A promising biomarker (2019)
  • Author(s): Saiki Shinji、Sasazawa Yukiko、Fujimaki Motoki、Kamagata Koji、Kaga Naoko、Taka Hikari、Li Yuanzhe、Souma Sanae、Hatano Taku、Imamichi Yoko、Furuya Norihiko、Mori Akio、Oji Yutaka、Ueno Shin‐Ichi、Nojiri Shuko、Miura Yoshiki、Ueno Takashi、Funayama Manabu、Aoki Shigeki、Hattori Nobutaka
  • Journal Title: Annals of Neurology Volume: 86 Issue: 2 Pages: 251-263
  • DOI: 10.1002/ana.25516
  • Peer Reviewed / Open Access
• [Journal Article] Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. (2019)
  • Author(s): Mori A, Hatano T, Inoshita T, Shiba-Fukushima K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui C, Yamashita C, Miki Y, Yamamoto K, Hirabayashi T, Murakami M, Takahashi Y, Shindou H, Nonaka T, Hasegawa M, Okuzumi A, Imai Y, Hattori N.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116(41) Issue: 41 Pages: 20689-20699
  • DOI: 10.1073/pnas.1902958116
  • NAID: 120007132272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pembrolizumab-related systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: a case report. (2019)
  • Author(s): Kamo H, Hatano T, Kanai K, Aoki N, Kamiyama D, Yokoyama K, Takanashi M, Yamashita Y, Shimo Y, Hattori N.
  • Journal Title: BMC Neurol. Volume: 19(1) Issue: 1 Pages: 184-184
  • DOI: 10.1186/s12883-019-1416-1
  • Peer Reviewed / Open Access
• [Journal Article] Free-Water Imaging in White and Gray Matter in Parkinson's Disease. (2019)
  • Author(s): Andica C, Kamagata K, Hatano T, Saito A, Uchida W, Ogawa T, Takeshige-Amano H, Zalesky A, Wada A, Suzuki M, Hagiwara A, Irie R, Hori M, Kumamaru KK, Oyama G, Shimo Y, Umemura A, Pantelis C, Hattori N, Aoki S.
  • Journal Title: Cells Volume: 8(8) Issue: 12 Pages: 839-839
  • DOI: 10.1007/s00234-019-02279-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasma metabolite biomarkers for multiple system atrophy and progressive supranuclear palsy (2019)
  • Author(s): Mori Akio、Ishikawa Kei-Ichi、Saiki Shinji、Hatano Taku、Oji Yutaka、Okuzumi Ayami、Fujimaki Motoki、Koinuma Takahiro、Ueno Shin-Ichi、Imamichi Yoko、Hattori Nobutaka
  • Journal Title: PLOS ONE Volume: 14 Issue: 9 Pages: e0223113-e0223113
  • DOI: 10.1371/journal.pone.0223113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p150glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery. (2019)
  • Author(s): Ishikawa-KI, Saiki S, Furuya N, Imamichi Y, Tsuboi Y, Hattori N
  • Journal Title: Neuroscience Letters Volume: 690 Pages: 181-187
  • DOI: 10.1016/j.neulet.2018.10.036
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomics‐based identification of metabolic alterations in PARK2 (2019)
  • Author(s): Okuzumi Ayami、Hatano Taku、Ueno Shin‐Ichi、Ogawa Takashi、Saiki Shinji、Mori Akio、Koinuma Takahiro、Oji Yutaka、Ishikawa Kei‐Ichi、Fujimaki Motoki、Sato Shigeto、Ramamoorthy Sivapriya、Mohney Robert P.、Hattori Nobutaka
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 6 Issue: 3 Pages: 525-536
  • DOI: 10.1002/acn3.724
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Randomized Crossover Pilot Study of Telemedicine Delivered via iPads in Parkinson’s Disease (2019)
  • Author(s): Sekimoto Satoko、Oyama Genko、Hatano Taku、Sasaki Fuyuko、Nakamura Ryota、Jo Takayuki、Shimo Yasushi、Hattori Nobutaka
  • Journal Title: Parkinson's Disease Volume: 2019 Pages: 1-7
  • DOI: 10.1155/2019/9403295
  • Peer Reviewed / Open Access
• [Journal Article] Correlation of Nutritional Indices on Admission to the Coronary Intensive Care Unit with the Development of Delirium (2018)
  • Author(s): Sugita Yurina、Miyazaki Tetsuro、Shimada Kazunori、Shimizu Megumi、Kunimoto Mitsuhiro、Ouchi Shohei、Aikawa Tatsuro、Kadoguchi Tomoyasu、Kawaguchi Yuko、Shiozawa Tomoyuki、Takasu Kiyoshi、Hiki Masaru、Takahashi Shuhei、Sumiyoshi Katsuhiko、Iwata Hiroshi、Daida Hiroyuki
  • Journal Title: Nutrients Volume: 10 Issue: 11 Pages: 1712-1712
  • DOI: 10.3390/nu10111712
  • Peer Reviewed / Open Access
• [Journal Article] Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease (2018)
  • Author(s): Ren Qian、Ma Min、Yang Jun、Nonaka Risa、Yamaguchi Akihiro、Ishikawa Kei-ichi、Kobayashi Kenta、Murayama Shigeo、Hwang Sung Hee、Saiki Shinji、Akamatsu Wado、Hattori Nobutaka、Hammock Bruce D.、Hashimoto Kenji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 25
  • DOI: 10.1073/pnas.1802179115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy. (2018)
  • Author(s): Furuya N, Kakuta S, Sumiyoshi K, Ando M, Nonaka R, Suzuki A, Kazuno S, Saiki S, Hattori N.
  • Journal Title: EMBO Reports Volume: 19 Issue: 12
  • DOI: 10.15252/embr.201846363
  • Peer Reviewed / Open Access
• [Journal Article] Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson's Disease. (2018)
  • Author(s): Ueno SI, Saiki S, Fujimaki M, Takeshige-Amano H, Hatano T, Oyama G, Ishikawa KI, Yamguchi A, Nojiri S, Akamatsu W, Hattori N.
  • Journal Title: Cells Volume: 8 Issue: 1 Pages: 14-14
  • DOI: 10.3390/cells8010014
  • Peer Reviewed / Open Access
• [Journal Article] Neurite orientation dispersion and density imaging of the nigrostriatal pathway in Parkinson's disease: Retrograde degeneration observed by tract-profile analysis. (2018)
  • Author(s): Andica C, Kamagata K, Hatano T, Okuzumi A, Saito A, Nakazawa M, Ueda R, Motoi Y, Kamiya K, Suzuki M, Hori M, Kumamaru KK, Hattori N, Aoki S.
  • Journal Title: Parkinsonism & Related Disorders Volume: 18 Pages: 30112-30113
  • DOI: 10.1016/j.parkreldis.2018.02.046
  • Peer Reviewed / Open Access
• [Journal Article] Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease (2018)
  • Author(s): Taniguchi Daisuke、Hatano Taku、Kamagata Koji、Okuzumi Ayami、Oji Yutaka、Mori Akio、Hori Masaaki、Aoki Shigeki、Hattori Nobutaka
  • Journal Title: Movement Disorders Volume: 33 Issue: 9 Pages: 1488-1492
  • DOI: 10.1002/mds.27365
  • Peer Reviewed / Open Access
• [Journal Article] GCH1 mutations in dopa-responsive dystonia and Parkinson's disease. (2018)
  • Author(s): Yoshino H, Nishioka K, Li Y, Oji Y, Oyama G, Hatano T, Machida Y, Shimo Y, Hayashida A, Ikeda A, Mogushi K, Shibagaki Y, Hosaka A, Iwanaga H, Fujitake J, Ohi T, Miyazaki D, Sekijima Y, Oki M, Kusaka H, Fujimoto KI Ugawa Y, Funayama M, Hattori N.
  • Journal Title: Journal of Neurology Volume: 265(8) Issue: 8 Pages: 1860-1870
  • DOI: 10.1007/s00415-018-8930-8
  • Peer Reviewed / Open Access
• [Journal Article] Randomized, double-blind, multicenter trial of hydrogen water for Parkinson's disease (2018)
  • Author(s): Yoritaka Asako、Ohtsuka Chigumi、Maeda Tetsuya、Hirayama Masaaki、Abe Takashi、Watanabe Hirohisa、Saiki Hidemoto、Oyama Genko、Fukae Jiro、Shimo Yasushi、Hatano Taku、Hattori Nobutaka、et al
  • Journal Title: Movement Disorders Volume: 33 Issue: 9 Pages: 1505-1507
  • DOI: 10.1002/mds.27472
  • Peer Reviewed / Open Access
• [Journal Article] Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice. (2018)
  • Author(s): Sato S, Uchihara T, Fukuda T, Noda S, Kondo H, Saiki S, Komatsu M, Uchiyama Y, Tanaka K, Hattori N.
  • Journal Title: Sci Rep. Volume: ８ Issue: 1 Pages: 2813-2813
  • DOI: 10.1038/s41598-018-21325-w
  • Peer Reviewed / Open Access
• [Journal Article] Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. (2018)
  • Author(s): Fujimaki M, Saiki S, Li Y, Kaga N, Taka H, Hatano T, Ishikawa KI, Oji Y, Mori A, Okuzumi A, Koinuma T, Ueno SI, Imamichi Y, Ueno T, Miura Y, Funayama M, Hattori N.
  • Journal Title: Neurology. Volume: 90 Issue: 5 Pages: 1-8
  • DOI: 10.1212/wnl.0000000000004888
  • Peer Reviewed / Open Access
• [Journal Article] Depressive symptoms in Parkinson's disease are related to decreased left hippocampal volume: correlation with the 15-item shortened version of the Geriatric Depression Scale. (2018)
  • Author(s): Goto M, Kamagata K, Hatano T, Hattori N, Abe O, Aoki S, Hori M, Gomi T.
  • Journal Title: Acta Radiologica Volume: 59 Issue: 3 Pages: 341-345
  • DOI: 10.1177/0284185117719100
  • Peer Reviewed / Open Access
• [Journal Article] Immunocytochemical Monitoring of PINK1/Parkin-Mediated Mitophagy in Cultured Cells. (2017)
  • Author(s): Fujimaki, M., Saiki, S., Sasazawa, Y., Ishikawa, KI., Imamichi, Y., Sumiyoshi, K &, Hattori, N.
  • Journal Title: Methods Mol Biol. Volume: 印刷中 Pages: 19-27
  • DOI: 10.1007/7651_2017_20
  • ISBN: 9781493977499, 9781493977505
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Connectome analysis with diffusion MRI in idiopathic Parkinson's disease: Evaluation using multi-shell, multi-tissue, constrained spherical deconvolution. (2017)
  • Author(s): Kamagata K, Zalesky A, Hatano T, Di Biase MA, El Samad O, Saiki S, Shimoji K, Kumamaru KK, Kamiya K, Hori M, Hattori N, Aoki S, Pantelis C.
  • Journal Title: Neuroimage Clinical Volume: 17 Pages: 518-529
  • DOI: 10.1016/j.nicl.2017.11.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased long-chain acylcarnitines from insufficient β-oxidation as potential early diagnostic markers for Parkinson's disease. (2017)
  • Author(s): Saiki S, Hatano T, Fujimaki M, Ishikawa K, Mori A, Oji Y, Okuzumi A, Fukuhara T, Koinuma T, Nagumo M, Furuya N, Nojiri S, Amo T, Yamashiro K, Hattori N.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 7328-7328
  • DOI: 10.1038/s41598-017-06767-y
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial-Associated Membranes in Parkinson's Disease. (2017)
  • Author(s): Hattori N, Arano T, Hatano T, Mori A, Imai Y.
  • Journal Title: Advances in Experimental Medicine and Biology Volume: 997 Pages: 157-169
  • Peer Reviewed / Open Access
• [Journal Article] The Risk Factors for the Wearing-off Phenomenon in Parkinson&apos;s Disease in Japan: A Cross-sectional, Multicenter Study (2017)
  • Author(s): Ouma S, Fukae J, Fujioka S, Yamamoto S, Hatano T, Yoritaka A, Okuma Y, Kashihara K, Hattori N, Tsuboi Y.
  • Journal Title: Internal Medicine Volume: 56 Issue: 15 Pages: 1961-1966
  • DOI: 10.2169/internalmedicine.56.7667
  • NAID: 130005876433
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Book] 動物/疾患モデルの作製技術・病態解析・評価手法 第9章第3節 (2017)
  • Author(s): 住吉克彦、中川 嘉、島野 仁
  • Publisher: 技術情報協会