LRRK2-PD进展的免疫相关影像标志物研究

Abnormal activation of immune system is an important pathogenesis of Parkinson's disease (PD), but the mechanism of how inflammation impact on dopaminergic degeneration is still unclear. Leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset PD, and is highly associated with the immune and inflammatory system. Previous study has showed increased serum inflammatory factors in LRRK2 non-manifesting carriers and LRRK2-PD, and activation of microglia in the brain of LRRK2-mice models. However, there is a lack of evidence between the increase of inflammatory profile and disease progression. We hypothesize that in LRRK2 carriers blood T lymphocytes activate under stimulation and release inflammatory factors including IL-17A and IFN-γ, which activate of microglia in the brain, causing dopaminergic disruption. In this study, we first compare the ratio of T cells and Th1/Th2/Th17 cells and the level of serum inflammatory factors, and the standard uptake ratio of brain [18F]-PBR06 PET/MR between 30 LRRK2 non-manifesting carriers, 15 LRRK2-PD, and 15 healthy controls. The aim of the first study is to evaluate the association between [18F]-PBR06 uptake, peripheral inflammation and dopaminergic degeneration. After that we follow the LRRK2 non-manifesting carriers for 24 months with [18F]-PBR06 PET/MR, [18F]-FP-DTBZ PET/MR and clinical interview. The aim of the follow-up study is to evaluate the accordance between brain microglia activation and future dopaminergic denervation.

免疫炎症异常激活是帕金森病（PD）重要发病机制，但致多巴胺能神经元受损的过程尚不明确，前驱期高危人群和在体无创免疫标志物的稀缺是限制因素。LRRK2为PD最常见高危基因，与免疫炎症机制密切相关，其携带者可能存在外周血T淋巴细胞激活及中枢小胶质细胞激活过程，导致多巴胺能神经元缺失，但与疾病进展的关系不清。本研究拟通过分析脑18-kDa转位蛋白靶向分子探针[18F]-PBR06能否检测到LRRK2未发病携带者和LRRK2-PD脑小胶质细胞激活、及其与外周 T淋巴细胞激活和脑多巴胺能神经元受损的关系，探索其作为免疫相关影像标志物对PD早期预警的指示价值；同时纵向评估[18F]-PBR06显像能否预测LRRK2未发病携带者脑多巴胺能神经元受损变化、进入PD前驱期。从而建立在体无创显示LRRK2-PD进展的免疫标志物，对PD的早诊早治和进一步开展早期干预、精准治疗研究具有重大意义。

帕金森病是最常见的神经退行性运动障碍疾病。免疫系统异常激活是其重要发病机制，但是外周免疫系统改变、中枢小胶质细胞激活及多巴胺能神经元受损间的关系不清。LRRK2基因是帕金森病最常见的高危基因，与免疫炎症机制密切相关。本研究使用脑18-kDa转位蛋白靶向分子探针[18F]-PBR06、单胺囊泡转运体靶向分子探针[18F]-FP-DTBZ和正电子发射计算机断层扫描技术在体显像帕金森病患者脑小胶质细胞激活程度及多巴胺能神经元完整性。本研究发现，帕金森病患者早期出现壳核小胶质细胞激活，外周血促炎Th1淋巴细胞比例、细胞因子IL17A、IL10水平升高，且基线壳核小胶质细胞激活程度可预测随访期患者认知水平，支持“在PD发病过程中存在外周炎症免疫系统持续过度活跃，T淋巴细胞激活、IL-17A等炎症因子表达增加，中枢神经系统小胶质细胞持续活化，多巴胺能神经受损”的过程，验证了[18F]-PBR06作为免疫相关影像标志物对PD预后的指示价值。此外，本研究显示LRRK2基因携带PD存在后壳核多巴胺能缺失及细胞因子水平升高。因此，本研究项目从中枢-外周免疫炎症改变出发，探索了相应机制，建立了在体无创脑小胶质细胞激活及多巴胺能神经元受损标志物，对PD的早诊早治和进一步开展早期干预、精准治疗研究具有重大意义。

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