{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:55:03Z","timestamp":1787018103265,"version":"build-2736575974"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,6,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Lewy body diseases (LBDs) feature deficiency of the sympathetic neurotransmitter norepinephrine in the left ventricular myocardium and sympathetic intra\u2010neuronal deposition of the protein alpha\u2010synuclein (\u03b1S). LBDs therefore are autonomic synucleinopathies. Computational modeling has revealed multiple functional abnormalities in residual myocardial sympathetic noradrenergic nerves in LBDs, including decreased norepinephrine synthesis, vesicular storage, and recycling. We report an extended model that enables predictions about the progression of LBDs and effects of genetic predispositions and treatments on that progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      The model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4\u2010dihydroxyphenylacetaldehyde. We tested the model by its ability to predict longitudinal empirical data based on cardiac sympathetic neuroimaging, effects of genetic variations related to particular intra\u2010neuronal reactions, treatment by monoamine oxidase inhibition to decrease 3,4\u2010dihydroxyphenylacetaldehyde production, and post\u2010mortem myocardial tissue contents of catecholamines and \u03b1S. The new model generated a triphasic decline in myocardial norepinephrine content. This pattern was confirmed by empirical data from serial cardiac\n                      <jats:sup>18<\/jats:sup>\n                      F\u2010dopamine positron emission tomographic scanning in patients with LBDs. The model also correctly predicted empirical data about effects of genetic variants and monoamine oxidase inhibition and about myocardial levels of catecholamines and \u03b1S.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">The present computational model predicts a triphasic decline in myocardial norepinephrine content as LBDs progress. According to the model, disease\u2010modifying interventions begun at the transition from the first to the second phase delay the onset of symptomatic disease. Computational modeling coupled with biomarkers of preclinical autonomic synucleinopathy may enable early detection and more effective treatment of LBDs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.121.024411","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T07:07:52Z","timestamp":1653635272000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Modeling the Progression of Cardiac Catecholamine Deficiency in Lewy Body Diseases"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5709-9940","authenticated-orcid":false,"given":"David S.","family":"Goldstein","sequence":"first","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-5889","authenticated-orcid":false,"given":"Mark J.","family":"Pekker","sequence":"additional","affiliation":[{"name":"Mathematical Sciences University of Alabama at Huntsville Huntsville AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patti","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Isonaka","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehonatan","family":"Sharabi","sequence":"additional","affiliation":[{"name":"Tel Aviv University Sackler Faculty of Medicine and Chaim Sheba Medical CenterTel HaShomer Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198804073181402"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199703063361004"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2017.09.033"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.130441"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45803"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep40699"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410180109"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.62.3.378"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115999"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2014.06.006"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/1055-8330(95)90016-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2011.03.013"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.248492"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(93)80310-Z"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.24513"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2019.09.014"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2008.01.010"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0809335"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26724"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cam.2013.10.034"},{"key":"e_1_3_2_23_2","unstructured":"Bindel D Govaerts W Hughes J Kuznetsov YA Pekker M Veldman D. 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