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 诊断前数十年的 PD 进展，称为前驱期，因为此阶段涉及模糊 未被充分认识的症状，例如皮肤非运动障碍。皮肤组织病理学的既往研究 有限但涉及与前驱期 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 的知识差距和组织研究的缺乏是一个问题 了解发病机制、识别亚型以及最终缓解疾病的主要障碍 疗法。 意义：该提案将绘制外周皮肤组织中前驱 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 提供医疗保健 与没有 PD 的退伍军人相比。 创新：该提案具有创新性，它创建了一个测量二十年历史的新颖数据集 全国 PD 病例中的前驱性疾病和 4:1 匹配对照并对档案的存在进行编目 PD 诊断前 1-20 年的活检。此外，这项研究首次整合了 来自 VA 大型生物库（称为“百万退伍军人计划”）的组织病理学、临​​床数据和遗传数据 （最有价值球员）。最后，这项研究在比较两种领先的生物标志物检测（免疫荧光和真实检测）方面具有新颖性。 时间震动诱导转换（RT-QuIC）。 具体目标：1) 确定神经元突触核蛋白积累和种子突触核蛋白的存在 诊断 PD 之前皮肤中的聚集以及与临床疾病的关联，2) 确定 遗传变异与前驱临床疾病和一系列共分离疾病的关联 与突触核蛋白。 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） 在 PD 诊断或同等年龄控制之前进行皮肤活检。将收集组织块 最初来自波特兰病理学服务中心，如果需要的话可以扩展到菲尼克斯和帕洛的组织合作者 阿尔托 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。 后续步骤：通过了解 PD 的最早特征，该项目可以对最早的 PD 进行有针对性的研究 PD 的原因，关联互补但通常不相关的数据孤岛，并确定有意义的子类型。