α-突触核蛋白和多巴胺转运体在快眼动睡眠期行为障碍神经变性机制中的研究

Clinical studies have confirmed that rapid eye movement sleep behavior disorder (RBD) is a robust risk factor of neurodegeneration, which now is considered as the early stage of α-synucleinopathy. Up to now, the mechanism of α-synuclein underlying the pathogenesis of RBD has not been investigated. According to Braak staging and non-motor symptoms (eg. olfactory dysfunction and constipation) presenting at the early stage of neurodegeneration, we hypothesize that peripheral nervous system (PNS) involved in α-synucleinopathy, which may be key mechanisms of neurodegeneration in RBD. In this proposed study, we aim to compare the differences in concentration of α-synuclein in salivary, aggregation of phosphorylated α-synuclein in colonic mucosa, and dopamine transporter (DAT) imaging between RBD cases and healthy controls. The correlation between α-synuclein in PNS and DAT will verify whether α-synuclein in PNS is a predictor of neurodegeneration related pathophysiology in central nervous system (CNS). In addition, we also analyze the correlations among α-synuclein, DAT, and other biomarkers of neurodegeneration in patients with RBD. We also investigate the longitudinal association between these indicators of pathology and changes of biomarkers of neurodegeneration after 2 years. The completion of this proposed study has great implications in understanding the role of α-synuclein in mechanisms underlying neurodegeneration in RBD. These findings also help to seek for the valuable biomarkers, to monitoring disease progression, and to develop novel intervention strategy of preventing neurodegeneration in RBD patients.

临床随访研究发现快眼动睡眠期行为障碍（RBD）有发展为神经变性疾病的风险，推测是α-突触核蛋白（α-Syn）病的早期阶段。但目前并没有关于RBD 的α-Syn病理机制的研究。结合Braak的病理分期和神经变性早期非运动症状（如嗅觉减退、便秘）的出现，我们推测周围神经系统α-Syn的病理改变是研究RBD神经变性机制的契入点。通过病例对照研究，检测α-Syn在唾液的表达和在结肠的异常聚集，并通过SPECT评估脑多巴胺转运体功能，明确外周α-Syn的检测是否可以预测RBD中枢的病理改变。同时分析α-Syn、多巴胺转运功能与临床神经变性指标的关系，纵向观察2年后这些病理改变的进展以及与神经变性临床指标的关系。本研究有望通过阐明RBD病理机制寻找到神经变性的生物标记物，为监测病情进展、早期干预、增加神经保护机会提供科学依据。

快眼动睡眠期行为障碍（Rapid eye movement sleep behavior disorder, RBD）有发展为神经变性疾病的风险，被认为是α-突触核蛋白病的早期阶段，因此探讨RBD神经变性的机制、寻找预测RBD向神经变性疾病发展的生物学标记物成为热点问题。我们建立RBD队列，通过病例对照研究，评估一系列非运动症状与神经变性的关系、检测α-突触核蛋白在唾液和血液的异常聚集。研究发现便秘、嗅觉减退、日间过度嗜睡是RBD神经变性的预测因子，α-突触核蛋白的异常表达是RBD神经变性的生物化学标记物。通过对该队列的研究，我们还发现早发型RBD的临床特征及向神经变性疾病的转归与典型RBD不一致；抗抑郁药导致RBD出现，可能只是触发了RBD症状，抑郁本身也是RBD向神经变性疾病发展的预测因子。通过与一般人群比较，RBD患者只有在发展为神经变性疾病后死亡风险才增高，周期性肢体运动障碍是RBD死亡的预测因子。综上，该研究发现了一些可预测RBD发展为神经变性疾病的临床和生化标记物，明确了RBD神经变性的病理机制，为临床判断预后、早期干预、增加神经保护机会提供了充足的依据。