Orimo Satoshi, Uchihara Toshiki, Nakamura Ayako, Mori Fumiaki, Kakita Akiyoshi, Wakabayashi Koichi, Takahashi Hitoshi
Department of Neurology, Kanto Central Hospital, 6-25-1 Kami-Yoga, Setagaya-ku, 158-8531 Tokyo, Japan..
Brain. 2008 Mar;131(Pt 3):642-50. doi: 10.1093/brain/awm302. Epub 2007 Dec 13.
Degeneration of the cardiac sympathetic nerve occurs in both Parkinson's disease (PD) and dementia with Lewy bodies and begins early in the disease progression of PD, accounting for reduced cardiac uptake of meta-iodobenzylguanidine even in the early stages of Lewy body disease (LBD). We previously demonstrated that degeneration of the distal axons of the cardiac sympathetic nerve precedes loss of their mother neurons in the paravertebral sympathetic ganglia, suggesting distal dominant degeneration of the cardiac sympathetic nerve in PD. Because alpha-synuclein is one of the key molecules in the pathogenesis of this disease, we further investigated how alpha-synuclein aggregates are involved in this distal-dominant degeneration. Both cardiac tissues and paravertebral sympathetic ganglia were obtained for comparison from 20 patients with incidental Lewy body disease (ILBD), 10 with PD, 20 with multiple system atrophy (MSA) and 10 control subjects. Immunohistochemical analysis was performed using antibodies against tyrosine hydroxylase (TH) as a marker for sympathetic nerves, phosphorylated neurofilament as a marker for axons and phosphorylated alpha-synuclein for pathological deposits. We found that (i) alpha-synuclein aggregates in the epicardial nerve fascicles, namely the distal axons of the cardiac sympathetic nerve, were much more abundant in ILBD with preserved TH-ir axons than in this disease with decreased TH-ir axons and PD; (ii) alpha-synuclein aggregates in the epicardial nerve fascicles were closely related to the disappearance of TH-ir axons; (iii) in ILBD with preserved TH-ir axons, alpha-synuclein aggregates were consistently more abundant in the epicardial nerve fascicles than in the paravertebral sympathetic ganglia; (iv) this distal-dominant accumulation of alpha-synuclein aggregates was reversed in ILBD with decreased TH-ir axons and PD, which both showed fewer of these axons but more abundant alpha-synuclein aggregates in the paravertebral sympathetic ganglia and (v) MSA was completely different from ILBD and PD based on the preservation of TH-ir axons and the scarcity of alpha-synuclein aggregates in either the cardiac tissues or the paravertebral sympathetic ganglia. These findings indicate that accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that heralds centripetal degeneration of the cardiac sympathetic nerve in PD, which sharply contrasts with slight changes in MSA. This chronological and dynamic relationship between alpha-synuclein aggregates and distal-dominant degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.
心脏交感神经退变在帕金森病（PD）和路易体痴呆中均有发生，且在PD疾病进展早期就已出现，这也是导致即使在路易体病（LBD）早期阶段间碘苄胍心脏摄取减少的原因。我们之前证实，心脏交感神经远端轴突的退变先于椎旁交感神经节中其母神经元的丢失，提示PD中心脏交感神经存在远端优势性退变。由于α-突触核蛋白是该疾病发病机制中的关键分子之一，我们进一步研究了α-突触核蛋白聚集体如何参与这种远端优势性退变。从20例偶然性路易体病（ILBD）患者、10例PD患者、20例多系统萎缩（MSA）患者和10例对照受试者中获取心脏组织和椎旁交感神经节进行比较。使用抗酪氨酸羟化酶（TH）抗体作为交感神经标志物、抗磷酸化神经丝抗体作为轴突标志物以及抗磷酸化α-突触核蛋白抗体检测病理沉积物进行免疫组织化学分析。我们发现：（i）在心外膜神经束（即心脏交感神经的远端轴突）中，α-突触核蛋白聚集体在TH免疫反应性轴突保留的ILBD中比在TH免疫反应性轴突减少的该疾病及PD中更为丰富；（ii）心外膜神经束中的α-突触核蛋白聚集体与TH免疫反应性轴突的消失密切相关；（iii）在TH免疫反应性轴突保留的ILBD中，心外膜神经束中的α-突触核蛋白聚集体始终比椎旁交感神经节中更丰富；（iv）在TH免疫反应性轴突减少的ILBD和PD中，α-突触核蛋白聚集体的这种远端优势性积累发生逆转，这两种疾病在椎旁交感神经节中显示这些轴突较少但α-突触核蛋白聚集体更丰富；（v）基于TH免疫反应性轴突保留情况以及心脏组织或椎旁交感神经节中α-突触核蛋白聚集体的稀缺性，MSA与ILBD和PD完全不同。这些发现表明，心脏交感神经系统远端轴突中α-突触核蛋白聚集体的积累先于椎旁交感神经节中神经元胞体或神经突的积累，预示着PD中心脏交感神经的向心性退变，这与MSA中的轻微变化形成鲜明对比。α-突触核蛋白聚集体与心脏交感神经系统远端优势性退变之间的这种时间顺序和动态关系可能代表了PD中常见退变过程的病理机制。
