氧化应激生物标志物在帕金森病早期筛查中的研究进展

Research Progress of Oxidative Stress Biomarkers in the Early Screening of Parkinson’s Disease

摘要: 帕金森病(Parkinson’s disease, PD)是常见的神经退行性疾病之一，随着人口老龄化程度不断加重，其患病人数呈现出持续增长的趋势，已给患者家庭及社会医疗卫生体系带来较大的疾病和照护负担。目前，PD的诊断仍主要依赖运动迟缓、静止性震颤、肌强直及姿势步态异常等典型的临床表现，但当上述运动症状明显出现时，黑质多巴胺能神经元通常已经发生较大程度的不可逆性损伤，导致部分患者确诊时已错过较理想的早期干预时期。而影像学、脑脊液及其他生物标志物检测虽然能够为PD诊断提供一定依据，但部分检查存在价格较高、设备要求高、操作复杂或有创等不足，在社区卫生服务中心及基层医疗机构开展大规模早期筛查仍受到一定限制。需要明确的是，PD的临床诊断与人群筛查并非同一概念：诊断是在临床疑似患者中依据诊断标准确认疾病，而筛查是在尚未确诊、甚至尚未达到PD临床诊断阈值的人群中识别需要进一步评估的高风险个体；筛查阳性只能提示风险增加，不能等同于PD确诊。因此，寻找无创、经济、操作简便且具有较好重复性的生物标志物，是PD早期筛查及风险识别的重要研究方向。氧化应激(oxidative stress, OS)是PD发生发展的重要病理生理机制，可与线粒体功能障碍、多巴胺代谢异常、铁代谢紊乱、α-突触核蛋白异常聚集及神经炎症相互促进，形成持续性氧化损伤。RNA较易受到活性氧攻击，氧化后可形成8-氧-7,8-二氢鸟苷(8-oxo-7,8-dihydroguanosine, 8-oxoGsn)，其水平能够反映机体RNA氧化损伤程度。已有研究在PD患者黑质神经元、脑脊液及部分外周体液中发现RNA氧化损伤及8-oxoGsn水平异常，为其用于PD早期风险识别提供了一定生物学依据。但目前血液和尿液8-oxoGsn水平及二者之间关系的研究相对欠缺。由于8-oxoGsn可在血液和尿液中稳定检测，尤其尿液具有无创、便于重复采集等优势，因此其具有作为PD早期筛查候选生物标志物的潜力。但目前相关证据主要来自于已确诊PD患者，其在前驱期及高风险人群中的筛查效能仍需进一步验证。

Abstract: Parkinson’s disease (PD) is one of the common neurodegenerative disorders. With the continuous increase in the aging population, the number of patients with PD is showing a continuous growth trend, which has brought significant disease and care burdens to patients’ families and the social healthcare system. Currently, the diagnosis of PD mainly relies on typical clinical manifestations such as bradykinesia, resting tremor, muscle rigidity, and abnormal posture and gait. However, when the above movement symptoms are obvious, the dopaminergic neurons in the substantia nigra usually have undergone a significant irreversible damage, resulting in some patients missing the ideal early intervention period upon diagnosis. Although imaging, cerebrospinal fluid, and other biomarker tests can provide certain basis for PD diagnosis, some of these tests have disadvantages such as high cost, high equipment requirements, complex operation, or invasiveness. Large-scale early screening in community health centers and grassroots medical institutions is still limited due to these issues. It is important to note that the clinical diagnosis of PD and population screening are not the same concept: diagnosis is confirming the disease based on diagnostic criteria in clinically suspected patients, while screening is identifying high-risk individuals who need further assessment in populations that have not yet been diagnosed or even reached the clinical diagnostic threshold of PD; a positive screening result only indicates an increased risk, but cannot be equivalent to a confirmed diagnosis of PD. Therefore, finding non-invasive, economical, simple-to-operate, and highly reproducible biomarkers is an important research direction for early screening and risk identification of PD. Oxidative stress (OS) is an important pathological and physiological mechanism for the occurrence and development of PD, which can interact with mitochondrial dysfunction, abnormal dopamine metabolism, iron metabolism disorder, abnormal aggregation of α-synuclein, and neuroinflammation to form continuous oxidative damage. RNA is more susceptible to oxidative attack and can form 8-oxo-7,8-dihydroguanosine (8-oxoGsn) after oxidation, and its level can reflect the degree of RNA oxidative damage in the body. Studies have found that RNA oxidative damage and abnormal 8-oxoGsn levels have been detected in substantia nigra neurons of PD patients, cerebrospinal fluid, and some peripheral body fluids, providing certain biological basis for its use in early risk identification of PD. However, research on the levels of 8-oxoGsn in blood and urine and their relationships is relatively lacking. Since 8-oxoGsn can be stably detected in blood and urine, especially urine has the advantages of being non-invasive and easy to repeat collection, therefore it has the potential to be a candidate biomarker for early screening of PD. However, the screening efficacy of this biomarker in the prodromal stage and high-risk populations still needs further verification based on evidence from diagnosed PD patients.