Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, United States.
Chaim Sheba Medical Center and Tel Aviv University Sackler Faculty of Medicine, Israel.
Brain Res. 2019 Jan 1;1702:74-84. doi: 10.1016/j.brainres.2017.09.033. Epub 2017 Oct 10.
This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson's disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, "dying back" sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL.
这篇综述介绍了路易体病中心脏自主神经去神经支配的最新进展。路易体病家族包括帕金森病（PD）、单纯自主神经衰竭（PAF）和路易体痴呆（DLB）。这三种疾病都存在蛋白α-突触核蛋白的神经元内细胞质沉积。多系统萎缩（MSA），其帕金森形式可能难以与直立性低血压的 PD 区分，涉及含有α-突触核蛋白的神经胶质细胞质包涵体。到目前为止，有令人信服的神经影像学、神经病理学和神经化学证据表明路易体病存在心脏自主神经去神经支配。除了去神经支配外，残留终末中的儿茶酚胺储存减少。变性以向心性、逆行、“退行性”的顺序发展。在整个突触核蛋白病中，壳核和心脏儿茶酚胺能病变似乎彼此独立发生，而 PD 的非运动方面（例如，嗅觉丧失、痴呆、REM 行为障碍、OH）则相互关联，也与心脏自主神经去神经支配相关。心脏自主神经去神经支配可能是遗传性 PD 中突触核蛋白病引起的。根据儿茶酚醛假说，多巴胺的中间代谢产物 3,4-二羟基苯乙酮（DOPAL）引起或促成儿茶酚胺神经元死亡，特别是通过与α-突触核蛋白等蛋白相互作用。DOPAL 会自发氧化为 DOPAL-醌，这可能会将α-突触核蛋白转化为其毒性寡聚形式。减少 DOPAL 的产生和氧化可能会减缓神经退行性过程。随着时间的推移跟踪心脏自主神经支配可能是针对 DOPAL 的原理性实验治疗试验的基础。
