{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:09:21Z","timestamp":1777522161936,"version":"3.51.4"},"posted":{"date-parts":[[2026,3,13]]},"group-title":"Neurology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Severe putamen dopamine depletion in Parkinson disease (PD) has been attributed to nigrostriatal denervation; however, there are also functional abnormalities in extant terminals (the \u201csick-but-not-dead\u201d phenomenon). Rates of intra-neuronal processes of synthesis, storage, and metabolism of dopamine complexly influence releasable dopamine stores but have not yet been systematically estimated.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Post-mortem empirical data were available about putamen tissue contents of 7 reactants, including the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). We constructed kinetic models depicting reactions related to putamen dopamine content, the simplest model consisting of 7 reactions and the most complete model 18 reactions among 10 intra-neuronal reactants. We used the post-mortem data, in vivo results of\n                    <jats:sup>18<\/jats:sup>\n                    F-DOPA positron emission tomography (PET), and the models to estimate rates of the intra-neuronal processes and rank their contributions to control-PD differences.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    There was about a 98% decrease in putamen tissue dopamine in PD. The concentration ratio of DOPAL\/DA was about 9 times control. Applying the simplest kinetic model, vesicular sequestration was estimated to be decreased by 98.5% (0.073 vs. 4.91 nmol\/min). About 3-fold greater in vivo \u201cwashout\u201d of putamen\n                    <jats:sup>18<\/jats:sup>\n                    F-DOPA-derived radioactivity compared to controls also indicated attenuated vesicular storage in PD. According to the complete model, control-PD differences in intra-neuronal reaction rates were, in descending order, vesicular uptake \u2248 vesicular leakage &gt; exocytotic release \u2248 neuronal reuptake &gt; L-aromatic-amino-acid decarboxylase activity \u2248 tyrosine hydroxylase activity &gt; other reactions.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>Empirical post-mortem and in vivo data and application of kinetic models provide convergent quantitative evidence for a substantial vesicular storage defect in residual dopaminergic terminals in PD, a potential target for disease-modifying treatment or prevention strategies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Trial Registration<\/jats:title>\n                  <jats:p>None<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>BRIEF SUMMARY<\/jats:title>\n                  <jats:p>We estimated rates of reactions involved with synthesis, storage, release, reuptake, and metabolism of dopamine in the putamen in Parkinson disease and found that the main intra-neuronal functional abnormality separating Parkinson disease from controls was attenuated vesicular sequestration, implicating decreased vesicular uptake via the vesicular monoamine transporter and increased vesicular leakiness as key determinants of putamen dopamine deficiency in PD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.12.26348277","type":"posted-content","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:15:28Z","timestamp":1773425728000},"source":"Crossref","is-referenced-by-count":1,"title":["Putamen dopamine synthesis, vesicular storage, and metabolism in Parkinson disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5709-9940","authenticated-orcid":false,"given":"David S.","family":"Goldstein","sequence":"first","affiliation":[{"name":"Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026031701151159000_2026.03.12.26348277v1.1","first-page":"1236","article-title":"Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system","volume":"38","year":"1960","journal-title":"Wien Klin Wochenschr"},{"key":"2026031701151159000_2026.03.12.26348277v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198804073181402"},{"key":"2026031701151159000_2026.03.12.26348277v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2010.03246.x"},{"key":"2026031701151159000_2026.03.12.26348277v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1971.03190260019005"},{"key":"2026031701151159000_2026.03.12.26348277v1.5","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3934\/Neuroscience.2023017","article-title":"Depletion of dopamine in Parkinson\u2019s disease and relevant therapeutic options: A review of the literature","volume":"10","year":"2023","journal-title":"AIMS Neurosci"},{"key":"2026031701151159000_2026.03.12.26348277v1.6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.parkreldis.2016.12.011","article-title":"Determinants of denervation-independent depletion of putamen dopamine in Parkinson\u2019s disease and multiple system atrophy","volume":"35","year":"2017","journal-title":"Parkinsonism Relat Disord"},{"key":"2026031701151159000_2026.03.12.26348277v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5456-13.2014"},{"key":"2026031701151159000_2026.03.12.26348277v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt192"},{"key":"2026031701151159000_2026.03.12.26348277v1.9","first-page":"e130441","article-title":"Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases","volume":"5","year":"2019","journal-title":"JCI Insight"},{"key":"2026031701151159000_2026.03.12.26348277v1.10","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/jnc.12766","article-title":"A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson disease","volume":"131","year":"2014","journal-title":"J Neurochem"},{"key":"2026031701151159000_2026.03.12.26348277v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12345"},{"key":"2026031701151159000_2026.03.12.26348277v1.12","doi-asserted-by":"crossref","first-page":"e024411","DOI":"10.1161\/JAHA.121.024411","article-title":"Modeling the Progression of Cardiac Catecholamine Deficiency in Lewy Body Diseases","volume":"11","year":"2022","journal-title":"J Am Heart Assoc"},{"key":"2026031701151159000_2026.03.12.26348277v1.13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40035-022-00289-y","article-title":"Pathophysiological significance of increased alpha-synuclein deposition in sympathetic nerves in Parkinson\u2019s disease: a post-mortem observational study","volume":"11","year":"2022","journal-title":"Transl Neurodegener"},{"key":"2026031701151159000_2026.03.12.26348277v1.14","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1002\/mds.29820","article-title":"Persistent GDNF Expression 45 Months after Putaminal Infusion of AAV2-GDNF in a Patient with Parkinson\u2019s Disease","volume":"39","year":"2024","journal-title":"Mov Disord"},{"key":"2026031701151159000_2026.03.12.26348277v1.15","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1296.027"},{"key":"2026031701151159000_2026.03.12.26348277v1.16","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.93.9.1667"},{"key":"2026031701151159000_2026.03.12.26348277v1.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1991.tb02580.x"},{"key":"2026031701151159000_2026.03.12.26348277v1.18","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/BF03160027","article-title":"Autoradiographic study on dopamine uptake sites and their correlation with dopamine levels and their striata from patients with Parkinson disease, Alzheimer disease, and neurologically normal controls","volume":"18","year":"1993","journal-title":"Mol Chem Neuropathol"},{"key":"2026031701151159000_2026.03.12.26348277v1.19","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.47.3.718"},{"key":"2026031701151159000_2026.03.12.26348277v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0173(90)90015-G"},{"key":"2026031701151159000_2026.03.12.26348277v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2018.08.034"},{"key":"2026031701151159000_2026.03.12.26348277v1.22","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-01-00442.1994"},{"key":"2026031701151159000_2026.03.12.26348277v1.23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1894-10.2010"},{"key":"2026031701151159000_2026.03.12.26348277v1.24","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00027.2007"},{"key":"2026031701151159000_2026.03.12.26348277v1.25","doi-asserted-by":"publisher","DOI":"10.1007\/BF01250085"},{"key":"2026031701151159000_2026.03.12.26348277v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2006.07.018"},{"key":"2026031701151159000_2026.03.12.26348277v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02309-X"},{"key":"2026031701151159000_2026.03.12.26348277v1.28","doi-asserted-by":"publisher","DOI":"10.1021\/tx800405v"},{"key":"2026031701151159000_2026.03.12.26348277v1.29","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3389\/fnmol.2018.00467","article-title":"Dopamine Autoxidation Is Controlled by Acidic pH","volume":"11","year":"2018","journal-title":"Front Mol Neurosci"},{"key":"2026031701151159000_2026.03.12.26348277v1.30","doi-asserted-by":"publisher","DOI":"10.1007\/s10337-012-2229-1"},{"key":"2026031701151159000_2026.03.12.26348277v1.31","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0303-9"},{"key":"2026031701151159000_2026.03.12.26348277v1.32","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.248492"},{"key":"2026031701151159000_2026.03.12.26348277v1.33","doi-asserted-by":"crossref","unstructured":"Ito S , Tanaka H , Ojika M , Wakamatsu K , Sugumaran M . Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity. Int J Mol Sci 2021;22.","DOI":"10.3390\/ijms222111751"},{"key":"2026031701151159000_2026.03.12.26348277v1.34","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1021\/acs.chemrestox.5b00528","article-title":"Antioxidant-mediated modulation of protein reactivity for 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite","volume":"29","year":"2016","journal-title":"Chem Res Toxicol"},{"key":"2026031701151159000_2026.03.12.26348277v1.35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.249532"},{"key":"2026031701151159000_2026.03.12.26348277v1.36","doi-asserted-by":"publisher","DOI":"10.1021\/tx9000557"},{"key":"2026031701151159000_2026.03.12.26348277v1.37","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/j.1530-0277.1986.tb05087.x","article-title":"Human aldehyde dehydrogenase: kinetic identification of the isozyme for which biogenic aldehydes and acetaldehyde compete","volume":"10","year":"1986","journal-title":"Alcoholism: Clinical and Experimental Research"},{"key":"2026031701151159000_2026.03.12.26348277v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(90)90064-9"},{"key":"2026031701151159000_2026.03.12.26348277v1.39","doi-asserted-by":"publisher","DOI":"10.1124\/pr.59.2.1"},{"key":"2026031701151159000_2026.03.12.26348277v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)93832-9"},{"key":"2026031701151159000_2026.03.12.26348277v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2010.12.017"},{"key":"2026031701151159000_2026.03.12.26348277v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2008.04.011"},{"key":"2026031701151159000_2026.03.12.26348277v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2015.07.009"},{"key":"2026031701151159000_2026.03.12.26348277v1.44","first-page":"964","article-title":"6-[Fluorine-18]fluorodopamine pharmacokinetics and dosimetry in humans","volume":"35","year":"1994","journal-title":"J Nucl Med"},{"key":"2026031701151159000_2026.03.12.26348277v1.45","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-13-05835.2003"},{"key":"2026031701151159000_2026.03.12.26348277v1.46","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.631556"},{"key":"2026031701151159000_2026.03.12.26348277v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2396(199706)26:2<194::AID-SYN10>3.0.CO;2-Y"},{"key":"2026031701151159000_2026.03.12.26348277v1.48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-12-04588.1998"},{"key":"2026031701151159000_2026.03.12.26348277v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.033"},{"key":"2026031701151159000_2026.03.12.26348277v1.50","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1982.tb11490.x"},{"key":"2026031701151159000_2026.03.12.26348277v1.51","doi-asserted-by":"crossref","unstructured":"Khashab R , Gutman-Sharabi N , Shabtai Z , et al. Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson\u2019s Disease. Int J Mol Sci 2023;24.","DOI":"10.3390\/ijms241512522"},{"key":"2026031701151159000_2026.03.12.26348277v1.52","doi-asserted-by":"crossref","unstructured":"Landau R , Halperin R , Sullivan P , et al. The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson\u2019s disease. Dis Model Mech 2022;15.","DOI":"10.1242\/dmm.049082"},{"key":"2026031701151159000_2026.03.12.26348277v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2014.09.016"},{"key":"2026031701151159000_2026.03.12.26348277v1.54","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0378-4347(93)80310-Z","article-title":"Confirmation of a dopamine metabolite in parkinsonian brain tissue by gas chromatography-mass spectrometry","volume":"614","year":"1993","journal-title":"J Chromatogr"},{"key":"2026031701151159000_2026.03.12.26348277v1.55","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15432"},{"key":"2026031701151159000_2026.03.12.26348277v1.56","doi-asserted-by":"publisher","DOI":"10.1021\/tx5002223"},{"key":"2026031701151159000_2026.03.12.26348277v1.57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031522"},{"key":"2026031701151159000_2026.03.12.26348277v1.58","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0319-07.2007"},{"key":"2026031701151159000_2026.03.12.26348277v1.59","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1495-09.2009"},{"key":"2026031701151159000_2026.03.12.26348277v1.60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015251"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.12.26348277","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:28:52Z","timestamp":1773764932000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.03.12.26348277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":60,"URL":"https:\/\/doi.org\/10.64898\/2026.03.12.26348277","relation":{},"subject":[],"published":{"date-parts":[[2026,3,13]]},"subtype":"preprint"}}