David S Goldstein1, Mark J Pekker2, Graeme Eisenhofer3, Yehonatan Sharabi4. 1. Autonomic Medicine Section (formerly Clinical Neurocardiology Section), Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland, USA. 2. Mathematical Sciences, University of Alabama at Huntsville, Huntsville, Alabama, USA. 3. Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine, Technische Universität Dresden, Dresden, Germany. 4. Tel Aviv University Sackler Faculty of Medicine and Chaim Sheba Medical Center, Tel HaShomer, Israel.
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: The model identified low rate constants for three types of processes in the Lewy body group-catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, vesicular storage of dopamine and norepinephrine, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter. Post-mortem 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. TRIAL REGISTRATION: This study was not a clinical trial. FUNDING: The research reported here was supported by the Division of Intramural Research, NINDS.
BACKGROUND:Lewy body diseases, a family of aging-related neurodegenerative disorders, entail loss of the catecholaminedopamine in the nigrostriatal system and equally severe deficiency of the closely related catecholaminenorepinephrine 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 diseasepatients. 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: The model identified low rate constants for three types of processes in the Lewy body group-catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, vesicular storage of dopamine and norepinephrine, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter. Post-mortem 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. TRIAL REGISTRATION: This study was not a clinical trial. FUNDING: The research reported here was supported by the Division of Intramural Research, NINDS.
Authors: Dennis W Dickson; Hiroshige Fujishiro; Anthony DelleDonne; Joshua Menke; Zeshan Ahmed; Kevin J Klos; Keith A Josephs; Roberta Frigerio; Melinda Burnett; Joseph E Parisi; J Eric Ahlskog Journal: Acta Neuropathol Date: 2008-02-09 Impact factor: 17.088