Early pathogenesis and diagnosis of Parkinsons Disease in peripheral tissues

帕金森病周围组织的早期发病机制和诊断

• 批准号: 10486334
• 负责人: Gregory David Scott
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486334
• 关键词: Age; Big Data; Biological Assay; Biological Markers; Biopsy; Cataloging; Cells; Characteristics; Clinical; Clinical Data; Data; Data Set; Databases; Dermatophytoses; Diagnosis; Disease; Disease Marker; Disease Progression; Enrollment; Freezing; Gene Frequency; Genetic; Genetic Risk; Genetic study; Genome; Genomics; Healthcare; Healthcare Systems; Histopathology; Immunofluorescence Immunologic; Individual; Knowledge; Link; Maps; Measures; Medical; Medical Records; Methods; Microscopy; Neurons; Parkinson Disease; Participant; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Prevalence; Resources; Seborrheic dermatitis; Services; Skin; Skin Tissue; Sleep; Sleep Disorders; Specimen; Subgroup; Susceptibility Gene; Symptoms; Testing; Time; Tissues; Veterans; Veterans Health Administration; alpha synuclein; biobank; clinical care; clinical subtypes; cohort; diagnostic value; differential expression; disease diagnosis; disorder subtype; experimental study; genetic variant; genome wide association study; indexing; innovation; insight; male; novel; programs; risk variant; segregation; skin disorder; synuclein; synucleinopathy

Background: Parkinson's Disease (PD) is an enormous burden on the Veterans Health Administration (VHA) and disease prevalence expected to double by 2030. Our understanding is very limited about the first two decades of PD progression before diagnosis, called the prodromal period, because this stage involves vague under-recognized symptoms such as non-motor disorders of the skin. Previous studies of skin tissue pathology are limited but have implicated pathologic features associated with prodromal-stage PD, particularly neuronal synuclein accumulation and aggregation. The knowledge gap about early PD and lack of tissue studies is a major obstacle toward understanding pathogenesis, identifying subtypes, and ultimately disease-modifying therapies. Significance: This proposal will map the early pathologic features of prodromal PD in peripheral skin tissues and link these pathologic features to clinical and genetic “big data” available at the VHA. Understanding the timing and diagnostic utility of early peripheral pathology in PD is of high importance for the VA healthcare system as the VA has an older average age, males are more likely to acquire the disease, PD is recognized as a service-connected disease, and veterans with PD are more likely to rely solely on the VA for their health care than veterans without PD. Innovation: This proposal is innovative by creating curating a novel dataset measuring twenty years of prodromal disorders in nationwide PD cases and 4:1 matched controls and cataloguing the presence of archival biopsies spanning 1-20 years before PD diagnosis. In addition, this study for the first time integrates histopathology, clinical data, and genetic data from the VA mega-biobank, called the Million Veterans Program (MVP). Finally, this study is novel in comparing two leading biomarker assays, immunofluorescence and real- time quaking induced conversion (RT-QuIC). Specific Aims: 1) Determine the presence of neuronal synuclein accumulation and seeded synuclein aggregation in skin preceding a diagnosis of PD and association with clinical disorders, 2) Determine the association of genetic variants with prodromal clinical disorders and a cluster of disorders that co-segregate with synuclein. Methods: All PD patients and 4:1 matched controls are identified in the VA medical database (n=1.5 million) and skin biopsies are identified before PD diagnosis or equivalent age controls. Tissue blocks will be collected initially from the Portland pathology service and if needed scaled to tissue collaborators at Phoenix and Palo Alto VAMC. Using immunofluorescent microscopy, we will measure neuronal α-synuclein and using RT-QuIC we will measure synuclein seeded aggregation. Genome association analysis will be performed between prodromal clinical disorders and variant allele frequencies from the MVP. Next Steps: By understanding the earliest features of PD, this project can lead to targeted study of the earliest causes of PD, relate complementary but oft unconnected data silos, and identify meaningful subtypes.

背景：帕金森病（PD）是退伍军人健康管理局（VHA）的一个巨大负担 到2030年，疾病患病率预计将翻一番。我们对前两者的了解非常有限 在诊断之前的几十年PD进展，称为前驱期，因为这个阶段涉及模糊的 未被充分认识的症状，如皮肤的非运动障碍。皮肤组织病理学的既往研究 局限性，但涉及与前驱期PD相关的病理特征，特别是神经元 突触核蛋白积累和聚集。关于早期PD的知识差距和缺乏组织研究是一个 了解发病机制，识别亚型，并最终改变疾病的主要障碍 治疗 意义：该建议将绘制周围皮肤组织中前驱PD的早期病理特征 并将这些病理特征与VHA提供的临床和遗传“大数据”联系起来。了解 PD早期外周病理学的时机和诊断效用对于VA医疗保健非常重要 由于VA的平均年龄较大，男性更容易患上这种疾病，PD被认为是一种 与服务相关的疾病，患有PD的退伍军人更有可能完全依赖VA为其提供医疗保健 没有PD的退伍军人。 创新：这项提案是创新的，它创建了一个新的数据集， 在全国范围内的PD病例和4：1匹配的对照中的前驱疾病， PD诊断前1-20年的活检。此外，本研究首次整合了 组织病理学、临床数据和遗传数据来自VA大型生物库，称为百万退伍军人计划 （MVP）。最后，这项研究是新的比较两个领先的生物标志物测定，免疫荧光和真实的- 时间震动诱导转换（RT-QuIC）。 具体目的：1）确定神经元突触核蛋白积聚和种子突触核蛋白的存在 在诊断PD之前皮肤中的聚集和与临床病症的关联，2）确定 遗传变异与前驱临床疾病和一组共分离的疾病的关联 与synuclein。 方法：在VA医学数据库中确定所有PD患者和4：1匹配的对照（n= 150万） 并且在PD诊断或相当的年龄对照之前鉴定皮肤活检。将采集组织块 最初来自波特兰病理学服务，如果需要，可扩展到凤凰城和帕洛的组织合作者 Alto VAMC。使用免疫荧光显微镜，我们将测量神经元α-突触核蛋白，并使用RT-QuIC 我们将测量突触核蛋白种子聚集。基因组关联分析将在 前驱临床疾病和MVP的变异等位基因频率。 下一步：通过了解PD的最早特征，该项目可以导致对最早的PD进行有针对性的研究。 PD的原因，相关的互补，但往往不连接的数据筒仓，并确定有意义的亚型。