{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T21:49:10Z","timestamp":1783979350004,"version":"3.55.0"},"reference-count":58,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19ak0101112h0001"],"award-info":[{"award-number":["19ak0101112h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JPMJMS2024"],"award-info":[{"award-number":["JPMJMS2024"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H04843"],"award-info":[{"award-number":["15H04843"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H02744"],"award-info":[{"award-number":["18H02744"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18KK0242"],"award-info":[{"award-number":["18KK0242"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18KT0027"],"award-info":[{"award-number":["18KT0027"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22H02986"],"award-info":[{"award-number":["22H02986"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K19512"],"award-info":[{"award-number":["22K19512"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Parkinson's disease (PD) is a common neurodegenerative disease characterized by initial involvement of the olfactory bulb\/amygdala or autonomic nerves followed by nigral degeneration. Although autonomic innervation strictly regulates multiorgan systems, including endocrine functions, circulation, and digestion, how dysautonomia in PD affects systemic metabolism has not been identified. In this study, we tried to estimate the pathogenic linkage of PD by nuclear medicine techniques, trans\u2010omic analysis of blood samples, and cultured cell experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thyroid mediastinum ratio of <jats:sup>123<\/jats:sup>I\u2010metaiodobenzylguanidine (MIBG) scintigraphy was measured in 1,158 patients with PD. Furthermore, serum exosome miRNA transcriptome analysis and plasma metabolome analysis followed by trans\u2010omic analysis were performed in patients with de novo PD and age\u2010matched healthy control persons. Additionally, thyroid hormone was administered to skeletal muscle and liver derived cells to evaluate the effect of hypothyroidism for these organs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sympathetic denervation of thyroid correlating with its cardiac denervation was confirmed in 1,158 patients with PD by MIBG scintigraphy. Among patients with drug\u2010na\u00efve PD, comprehensive metabolome analysis revealed decreased levels of thyroxine and insufficient fatty acid \u03b2\u2010oxidation, which positively correlate with one another. Likewise, both plasma metabolome data and transcriptome data of circulating exosomal miRNAs, revealed specific enrichment of the peroxisome proliferator\u2010activated receptor (PPAR\u03b1) axis. Finally, association of thyroid hormone with PPAR\u03b1\u2010dependent \u03b2\u2010oxidation regulation was confirmed by in vitro experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings suggest that interorgan communications between the thyroid and liver are disorganized in the early stage of PD, which would be a sensitive diagnostic biomarker for PD. ANN NEUROL 2023;93:303\u2013316<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26510","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T08:24:56Z","timestamp":1663748696000},"page":"303-316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Systemic Metabolic Alteration Dependent on the Thyroid\u2010Liver Axis in Early <scp>PD<\/scp>"],"prefix":"10.1002","volume":"93","author":[{"given":"Kengo","family":"Miyamoto","sequence":"first","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9732-8488","authenticated-orcid":false,"given":"Shinji","family":"Saiki","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"School of Information and Data Sciences Nagasaki University  Nagasaki Japan"},{"name":"Laboratory for Bioinformatics Research RIKEN Center for Biosystems Dynamics Research  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayami","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"},{"name":"Aging Biology in Health and Disease Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatou","family":"Iseki","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin\u2010Ichi","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Shiina","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsushi","family":"Kataura","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kamagata","sequence":"additional","affiliation":[{"name":"Department of Radiology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Imamichi","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Sasazawa","sequence":"additional","affiliation":[{"name":"Research Institute for Diseases of Old Age Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Fujimaki","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wado","family":"Akamatsu","sequence":"additional","affiliation":[{"name":"Center for Genomic and Regenerative Medicine Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutaka","family":"Hattori","sequence":"additional","affiliation":[{"name":"Department of Neurology Juntendo University Graduate School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00218-X"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2015.09.027"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26510"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-016-1667-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.62"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa238"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000948"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00219-2"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.034"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06767-y"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo7030042"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25516"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2013"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/B978-0-444-53491-0.00004-3","volume-title":"Handbook of Clinical Neurology Autonomic Nervous System","author":"Engeland WC","year":"2013"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(88)90334-X"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-94-4-959"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00292.2004"},{"key":"e_1_2_8_19_1","first-page":"1775","article-title":"Cardiac and extracardiac sympathetic denervation in Parkinson's disease with orthostatic hypotension and in pure autonomic failure","volume":"46","author":"Tipre DN","year":"2005","journal-title":"J Nucl Med"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02984609"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10286-013-0204-z"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105626"},{"key":"e_1_2_8_23_1","first-page":"446","volume-title":"Harrison's Principles of Internal Medicine, 20e","author":"Jameson JL","year":"2018"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6977"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01500"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1808855115"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26424"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.11.061"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-015-7780-x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2012-304436"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-7-2-149"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.1979.tb03028.x"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.12.001"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21365"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1141"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv403"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2021.11.020"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00438"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.695007"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00249-y"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr499"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.10"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2008.01.017"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3039"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm302"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2006.00032.x"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-022-00289-y"},{"key":"e_1_2_8_48_1","first-page":"9","volume-title":"The Thyroid: A Fundamental and Clinical Text 11th","author":"Werner SC","year":"2020"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03350368"},{"key":"e_1_2_8_50_1","first-page":"191","article-title":"Innervation of the thyroid. A study of the rat using retrograde tracing and immunocytochemistry","volume":"37","author":"Sundler F","year":"1989","journal-title":"Acta Histochem Suppl"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12350-015-0142-3"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.58.8.1247"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26048"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-212570"},{"key":"e_1_2_8_55_1","first-page":"446","volume-title":"The Thyroid: A Fundamental and Clinical Text 11th","author":"Werner SC","year":"2020"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-49876-6"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176243"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-2087-y"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.183"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26510","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.26510","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26510","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26510","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T04:36:44Z","timestamp":1692333404000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.26510"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,4]]},"references-count":58,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/ana.26510"],"URL":"https:\/\/doi.org\/10.1002\/ana.26510","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,4]]},"assertion":[{"value":"2022-06-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}