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

描述(申请人提供)：帕金森氏病(PD)是全球第二大最常见的神经退行性疾病。帕金森病的特征是黑质致密部(SNPC)的多巴胺能系统进行性恶化。大约95%的PD病例是特发性的，这表明环境因素和遗传易感性在疾病的发生中发挥了作用。帕金森病的诊断目前是基于对运动症状的临床评估。不幸的是，帕金森病患者的运动症状通常出现在病程较晚的时候，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，帕金森病和非典型帕金森病之间有30%的误诊，特别是进行性核上性瘫痪(PSP)。PD和PSP之间的高误诊率是由于在这些疾病的早期阶段，临床症状和对左旋多巴治疗的初始反应重叠。为了解决这些问题，我们先前从两项独立的临床研究中获得了可用于区分早期PD患者和健康对照组(HC)的全血样本的RNA生物标志物。明确地说，13个剪接变异体有助于区分PD、HC和APD90%的敏感性和94%的特异性。随后，我们在两个临床试验中确定了APP、SOD2、HNF4a和PTBP1作为其他假定的生物标志物。然而，生物标志物的理想诊断PD生物特征尚未确定。8个原始剪接变异体有助于区分PD和APD，包括PSP和具有相似诊断准确性的多系统萎缩(MSA)。在另一项单独的研究中，我们确定PTPN1是PSP的诊断生物标记物。尽管如此，apd签名和PTPN1还没有在一组独立的样本中复制。在拟议的研究中，我们将使用从帕金森病生物标记物计划(PDBP)获得的样本，在另一组独立的参与者中确定这些生物标记物的诊断效用。这项复制研究有望确定诊断PD和PSP的生物标志，这将推动这些生物标志物进入临床。

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.