Abstract | BACKGROUND: Lewy body diseases, a family of aging-related neurodegenerative disorders, entail loss of the catecholamine dopamine in the nigrostriatal system and equally severe deficiency of the closely related catecholamine norepinephrine in the heart. The myocardial noradrenergic lesion is associated with major non-motor symptoms and decreased survival. Numerous mechanisms determine norepinephrine stores, and which of these are altered in Lewy body diseases has not been examined in an integrated way. We used a computational modeling approach to assess comprehensively pathways of cardiac norepinephrine synthesis, storage, release, reuptake, and metabolism in Lewy body diseases. Application of a novel kinetic model identified a pattern of dysfunctional steps contributing to norepinephrine deficiency. We then tested predictions from the model in a new cohort of Parkinson disease patients. METHODS: Rate constants were calculated for 17 reactions determining intra-neuronal norepinephrine stores. Model predictions were tested by measuring post-mortem apical ventricular concentrations and concentration ratios of catechols in controls and patients with Parkinson disease. RESULTS: CONCLUSION: TRIAL REGISTRATION: This study was not a clinical trial. FUNDING: The research reported here was supported by the Division of Intramural Research, NINDS.
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Authors | David S Goldstein, Mark J Pekker, Graeme Eisenhofer, Yehonatan Sharabi |
Journal | JCI insight
(JCI Insight)
Vol. 5
(07 23 2019)
ISSN: 2379-3708 [Electronic] United States |
PMID | 31335324
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Topics |
- Abnormalities, Multiple
(metabolism)
- Aged
- Computer Simulation
- Humans
- Lewy Body Disease
(metabolism)
- Male
- Middle Aged
- Myocardium
(metabolism)
- Parkinson Disease
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