Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases

David S. Goldstein, Mark J. Pekker, Graeme Eisenhofer, Yehonatan Sharabi

Research output: Contribution to journalArticlepeer-review

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 nonmotor 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 potentially 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 intraneuronal norepinephrine stores. Model predictions were tested by measuring postmortem apical ventricular concentrations and concentration ratios of catechols in controls and patients with Parkinson disease. RESULTS. The model identified low rate constants for 3 types of processes in the Lewy body group: catecholamine biosynthesis via tyrosine hydroxylase and aromatic l-amino acid decarboxylase, vesicular storage of dopamine and norepinephrine, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter. Postmortem catechols and catechol ratios confirmed this triad of model-predicted functional abnormalities. CONCLUSION. Denervation-independent impairments of neurotransmitter biosynthesis, vesicular sequestration, and norepinephrine recycling contribute to the myocardial norepinephrine deficiency attending Lewy body diseases. A proportion of cardiac sympathetic nerves are "sick but not dead," suggesting targeted disease modification strategies might retard clinical progression.

Original languageEnglish
Article numbere130441
JournalJCI insight
Volume4
Issue number16
DOIs
StatePublished - 22 Aug 2019

Fingerprint

Dive into the research topics of 'Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases'. Together they form a unique fingerprint.

Cite this