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.
Mathematical Sciences, University of Alabama at Huntsville, Huntsville, Alabama, USA.
JCI Insight. 2019 Jul 23;5(16):130441. doi: 10.1172/jci.insight.130441.
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.
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.
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.
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.
This study was not a clinical trial.
The research reported here was supported by the Division of Intramural Research, NINDS.
路易体病是一类与衰老相关的神经退行性疾病，涉及黑质纹状体系统中儿茶酚胺多巴胺的丧失，以及心脏中密切相关的儿茶酚胺去甲肾上腺素同样严重的缺乏。心肌去甲肾上腺素病变与主要的非运动症状和存活率降低有关。许多机制决定了去甲肾上腺素的储存，而这些机制在路易体病中是如何改变的尚未得到综合检查。我们使用计算建模方法来全面评估路易体病中心肌去甲肾上腺素合成、储存、释放、再摄取和代谢的途径。应用一种新的动力学模型确定了导致去甲肾上腺素缺乏的功能失调步骤的模式。然后，我们在一个新的帕金森病患者队列中测试了该模型的预测。
计算了 17 个反应确定神经元内去甲肾上腺素储存的速率常数。通过测量对照组和帕金森病患者的死后心尖室浓度和儿茶酚浓度比来测试模型预测。
该模型确定了路易体组中三种类型的过程的低速率常数-酪氨酸羟化酶和 L-芳香族-氨基酸脱羧酶介导的儿茶酚胺生物合成、多巴胺和去甲肾上腺素的囊泡储存，以及细胞膜去甲肾上腺素转运蛋白介导的神经元去甲肾上腺素再摄取。死后儿茶酚和儿茶酚比证实了该模型预测的三种功能异常。
神经递质生物合成、囊泡隔离和去甲肾上腺素再循环的去神经独立损伤导致了路易体病中心肌去甲肾上腺素缺乏。一部分心脏交感神经是“病态但未死亡”，这表明有针对性的疾病修饰策略可能会延缓临床进展。
本研究不是临床试验。
本报告所述的研究由 NINDS 内部研究司资助。
