Blood RNA biomarkers of Parkinson's disease and progressive supranuclear palsy

描述（由申请人提供）：帕金森病（PD）是全球第二常见的神经退行性疾病。PD以黑质致密部（SNpc）多巴胺能系统的进行性恶化为特征。大约95%的PD病例是特发性的，表明环境因素和遗传易感性在疾病发病中起作用。目前帕金森病的诊断是基于对运动症状的临床评估。不幸的是，PD患者的运动症状通常在病程的后期才表现出来，当患者被诊断出来时，大量的多巴胺能神经元已经死亡。此外，PD和非典型帕金森病（APD）之间有30%的误诊，特别是进行性核上性麻痹（PSP）。PD和PSP的高误诊率是由于两种疾病的临床症状和早期对左旋多巴治疗的初步反应有重叠。为了解决这些问题，我们之前在两项独立的临床研究中发现并复制了RNA生物标志物，可用于区分早期PD患者和健康对照（HC）的全血样本。具体而言，13个剪接变体可用于区分PD与HC和APD，灵敏度为90%，特异性为94%。随后，我们在两项临床试验中确定了APP、SOD2、HNF4A和PTBP1作为额外的假定生物标志物。然而，生物标志物的理想诊断PD生物特征尚未确定。8种原始剪接变体可用于区分PD和APD，包括PSP和多系统萎缩（MSA），诊断准确性相似。在另一项研究中，我们确定了PTPN1作为PSP的诊断性生物标志物。尽管如此，APD特征和PTPN1并没有在一组独立的样本中被复制。在拟议的研究中，我们将使用从帕金森病生物标志物计划（PDBP）获得的样本，在另一个独立的参与者队列中确定这些生物标志物的诊断效用。这项重复性研究有望确定诊断PD和PSP的生物特征，这将促进这些生物标记物的临床翻译。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide. PD is characterized by the progressive deterioration of the dopaminergic system in the substantia nigra pars compacta (SNpc). Approximately 95% of PD cases are idiopathic suggesting environmental factors and genetic susceptibility play a role in disease onset. Diagnosis of PD is currently based on clinical assessment of motor symptoms. Unfortunately, motor symptoms in PD patients are usually manifested later in the course of the disease, and by the time a patient is diagnosed, a substantial number of dopaminergic neurons are dead. Further, there is a 30% misdiagnosis between PD and atypical parkinsonian disorders (APD), in particular, with progressive supranuclear palsy (PSP). The high misdiagnosis rate observed between PD and PSP is due to the overlap in clinical symptoms and initial response to levodopa therapy in early stages of these diseases. To address these issues, we previously identified and replicated RNA biomarkers that can be used to distinguish early stage PD patients from healthy controls (HC) in whole blood samples obtained from two independent clinical studies. Specifically, 13 splice variants were useful to distinguish PD from HC and APD with 90% sensitivity and 94 % specificity. Subsequently, we identified APP, SOD2, HNF4A and PTBP1 as additional putative biomarkers in both clinical trials. The ideal diagnostic PD bio signature of the biomarkers has not yet been determined however. Eight of the original splice variants were useful to distinguish PD from APD, including PSP and multiple system atrophy (MSA) with similar diagnostic accuracy. In a separate study, we identified PTPN1 as a diagnostic biomarker for PSP. Nonetheless, the APD signature and PTPN1 have not been replicated in an independent set of samples. In the proposed studies, we will determine the diagnostic utility of these biomarkers in an additional independent cohort of participants using samples obtained from the Parkinson's disease Biomarker Program (PDBP). This replication study is expected to identify a diagnostic PD and PSP bio signatures, which should advance the translation of these biomarkers into the clinic.