帕金森氏病早期预警体系的建立

Parkinson's Disease (PD) is the second most common neurodegenerative disorder following Alzheimer's Disease (AD),and is characterized by a disturbance of the central dopaminergic system. Currently, diagnosis of PD mainly relies on the clinical features; however, differential diagnosis from other parkinsonian disorders, such as essential tremor (ET), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), can be rather challenging due to overlapping symptoms, particularly during the early disease stages. Therefore, it is very urgently to explore effective biomarkers to robustly diagnose PD, especially at the early stage. It has been shown that inflammatory responses have been initiated and play important roles in the pathogenesis and development of PD. This study aims to investigate specific and sensitive inflammatory biomarkers such as Nurr1/MMP9/3/NF-KB in the serum of patients as potential predictors of PD. We intend to assess PD patients in terms of nonmotor symptoms (NMS), cognitive deficits, disease severity, and motor status, according to the NMS scale (NMSS), Mini-Mental State Examination (MMSE), the modified Hoehn and Yahr staging scale (H&Y), and the Unified Parkinson's Disease Rating Scale (UPDRS), respectively. The presence of an association of biomarkers with motor and non-motor dysfunctions in all of the subjects will be determined, as measuring those biomarkers by real-time PCR, western blot, enzyme-linked immunosorbent assay, and flow cytometry. Imaging study including PET/SPECT will be supplied to detect dopamine transporter and receptors in PD patients; while any associations between imaging findings and motor/nonmotor dysfunctions in PD patients will be evaluated. MPTP induced PD mice model (in vivo PD model) and 6-OHDA induced PC12 (in vitro PD model) will be used to explore the impacts of inflammatory mediators such as Nurr1/MMP9/3/NF-KB in those in vivo and in vitro models, as assessing those mediators by immunohistochemistry, real-time PCR, western blot, enzyme-linked immunosorbent assay, and flow cytometry.In addition, siRNA technique will be applied to knock down the Nurr1 gene in vitro PD model and investigate Nurr1-mediated inflammatory mechanisms. Through this study, we would like to set up a complete predictive system including inflammatory mediators and imaging findings in diagnosing early PD, and assess the progression of PD.

帕金森氏病（PD）是一种严重的多巴胺神经元退化性疾病，尽管有非常清晰的诊断标准，但早期的诊断仍然较为困难，特别是在对多系统萎缩，进展性核上性麻痹的早期诊断容易混淆。为此PD早期生物学标记的制定和预警机制的设立，有着迫切的需要。研究显示炎性反应在PD的发病早、中期就已经被启动，同时早期PD病人的非运动症状明显受损。由此，筛选到高度特异性和敏感性的炎性预警生物标志，同时以阻止此炎症免疫的调节已成为在早期诊断及治疗PD中非常关键且有前途的目标。本研究将通过对周围血及脑脊液中特异性炎症因子的检测及采用PET,SPECT,MRS直接检测PD患者在早、中、晚期中的多巴胺载体、受体与波谱的改变情况，并评估此改变情况与PD患者的运动和非运动功能的相关性。通过此研究，我们希望找到特定的一个或几个受体、载体，对PD的病程发展和治疗愈后起到指标性作用，并且结合周围血与脑脊液的炎症因子的改变以建立一个早期预警机制

帕金森氏病(PD)与多系统萎缩(MSA)早期鉴别诊断中容易混淆，已引起学者的高度重视。炎性反应在PD的发病早、中期就已经被启动，PD早期生物学标志物的制定和预警机制的设立有着迫切的需要。本项目形成一套以炎症指标和影像学表现为主题的PD早期预警体系。本研究发现Nurr1通过PI3K-AKt-BDNF通路促进细胞存活，Nurr1亦能抑制MMP3等介导的炎性反应、进而产生神经保护作用，提示Nurr1/MMP3活性的改变在PD的发病机制中发挥重要作用，同时本研究发现美金刚通过上调Nurr1对神经元具有保护作用。在6-OHDA诱导的PD大鼠模型中，通过射线自显迹法发现NMDA受体在多个脑区下降。基于体液炎症指标，本研究发现血高Cystatin C及低UA水平是PD患者疾病严重程度的一个预测指标，同时我们在PD细胞模型和PD转基因小鼠中发现Cystatin C通过VEGF介导的PKC-α/ERK-Nurr1信号通路对神经元发挥保护作用。而在MSA患者中，血HCY与UA呈反向表达对MSA的鉴别及疾病严重程度的预测具有较好的价值。基于影像学预警体系，本研究通过PET/CT 18F-FDG显像发现VP和PD患者大脑葡萄糖代谢率下降，VP患者葡萄糖代谢率下降更显著，VP和PD患者大脑葡萄糖代谢率与患者的症状及疾病严重程度相关。本研究发现骨密度测量在PD中同样具有预警作用，我们的研究发现PD多部位骨密度显著低于正常对照者，并且中晚期PD患者的骨密度明显小于早期PD患者，同时PD患者骨密度与疾病严重程度呈负相关关系。本研究初步证实Nurr1/MMPs/NF-κB在PD的免疫炎症相关的发病机制中的作用，为进一步探索炎症反应在PD发病过程中的作用、以及以Nurr1/MMPs/NF-κB为靶点的抗炎治疗药物的开发提供了理论依据，具备良好的科学应用前景。基于本研究在PD外周血炎性介质和颅内神经递质受体、代谢等方面的发现，本项目能进一步加深我们对PD及相关神经退行性疾病的发病机制的认识，同时也具备良好的临床指导意义。