基于多巴胺通路的左旋多巴诱导异动症相关脑网络机制研究

Levodopa-induced dyskinesias (LID) is a common motor complication in Parkinson’s disease (PD) patients receiving levodopa treatment. However, its pathogenesis remains unclear and there is no effective treatment as well as effective means to predict the occurrence of LID. Our previous studies and the latest literature have found that dopamine pathway related genes and brain structural and functional abnormalities in dopamine pathway are closely associated with LID. But the brain network base for LID is unclear and how genetic factors regulating the changes of brain network in LID remains unknown. With the dopamine pathway-based imaging genetics techniques, we recruited PD patients with peak-dose dyskinesias as research subjects, clinical data exactly matched PD patients without LID and healthy people as controls. The clinical data, genetic and neuroimaging information were comprehensively collected; gene polymorphisms participating in encoding dopamine decomposition, transport and receptor were genotyped; the multi-gene interaction models established by the multivariate statistical methods were used to investigate the intrinsic association between the clinical phenotype, imaging features and gene polymorphisms. This research will clarify the specific role of dopamine pathway in the pathogenesis of LID, reveal the brain network base for LID, obtain imaging genetics markers for LID and establish risk prediction models for the occurrence of LID.

左旋多巴诱导异动症（LID）是帕金森病（PD）患者接受左旋多巴治疗后常见的运动并发症，其发病机制不明，尚无有效治疗措施，且缺乏有效手段来预测LID发生。我们的前期研究和最新文献均发现多巴胺通路相关基因及相关脑区结构与功能异常与LID的发生密切相关。但形成LID的脑网络基础尚不明确，且遗传学因素是如何调控LID脑网络改变仍未知。本项目旨在利用基于多巴胺通路水平的影像遗传学方法，率先选择有LID（剂峰异动）的PD患者为研究对象，以临床资料严格匹配的无LID的PD患者和健康人群为对照，全面采集临床资料、遗传学和神经影像学信息；选取参与编码多巴胺分解、转运以及受体相关基因多态性位点，运用多因素统计方法建立多基因交互作用模型，探讨临床表型、影像学特征与基因多态性间的内在关联，阐明多巴胺通路在LID发病中的具体作用，揭示LID的脑网络基础，获得LID的影像遗传学标记物，建立预测LID发生的风险模型。

左旋多巴诱导异动症是帕金森病（PD）患者接受左旋多巴治疗后常见的运动并发症，其发病机制不明。本研究使用VBM技术发现PD双相异动患者存在中央前回灰质体积增加，并且与异动症的严重程度呈正相关。本研究使用交互功能连接发现额内侧上回的功能异常与PD双相异动的发病紧密关联，且与异动症的严重程度密切相关。本研究使用DTI技术发现，在存在异动症的PD患者中，全脑拓扑结构连 接过于优化。还发现过度强化的基底节-丘脑-皮质结构连接在异动症的存在中起着重要作用。本研究使用VMHC技术发现PD伴异动症患者存在额叶下皮质及辅助运动前区两侧大脑半球间功能连接失调，且失调严重程度与异动症严重程度密切相关，提示对运动环路抑制控制的不协调可能是PD异动症的神经基础。以上一系列神经影像研究的结果初步揭示了PD异动症的脑网络机制，为PD异动症的识别提供了客观的神经影像标志物，还为PD异动症的神经调控治疗提供了潜在靶点。