Biomarkers of disease severity and progression in Parkinson's

背景：帕金森病（PD）是第二常见的神经退行性疾病， 在退伍军人中更为普遍，因为军队特定的暴露会增加PD风险。有很大 表型变异性：一些PD患者主要表现为震颤，并保持良好的生活质量， 而其他人表现出更恶性的表型，更快地进展为痴呆症。 和严重的运动障碍预测哪些患者将表现出缓慢或快速疾病进展的能力 对患者咨询和临床试验设计都是非常宝贵的。到目前为止，还没有生物标志物 预测PD进展。鉴于线粒体功能障碍是一种早期和持续的细胞 这种疾病的标志是随着疾病的进展而追踪，测量线粒体功能可以证明， 是一种这样的预测性生物标志物。两种很有前途的方法，磁共振光谱成像 （MRSI）和测量外周血单核细胞（PBMC）中的Nrf 2活性，可以关闭该功能。 知识差距。 意义：这项工作涉及两个高度优先领域。它通过其独特的 预测疾病进展的潜力，为改进临床试验设计奠定基础， 加快有前景的临床前工作的翻译。它还高度关注神经认知障碍 在VA人群中普遍存在。退伍军人管理局的平均年龄较大，男性更有可能获得 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仅仅依靠 比没有帕金森病的退伍军人更需要退伍军人管理局的医疗保健。 创新：该提案具有创新性，因为我们计划成为第一个将MRSI应用于 真实的测量帕金森病患者大脑中线粒体的功能。超越静态 测量含磷酸盐的化合物，我们也将是第一个应用磁化转移， 让我们进一步了解线粒体动力学，并提高我们评估的灵敏度。我们 这项工作还将评估基于成像的线粒体功能障碍测量是否能够预测 PD进展的后续临床变化。如果是这样的话，这将提供第一个生物标志物， 预测PD患者的进展。 具体目的：1）通过应用31 P-MRSI定量PD脑中的线粒体生物能量学。2)评价 与对照组相比，PD患者的PBMC Nrf 2 mRNA表达及其下游效应物。第三章 评估外周Nrf 2水平的纵向变化和脑生物能量学中基于31 P-MRSI的变化， 早期PD患者，以确定线粒体生物能量学差异是否可预测临床疾病 进展 方法：采用横断面研究，对早中期PD患者和健康对照者进行研究， MRSI和外周血分析。一年后，对照组和早期PD组将重复这些 测量. 下一步：通过测量体内线粒体功能，该提案将建立疾病的读数 接下来可用于测量靶向靶向试验中的靶向参与的活动 治疗学

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and it is even more prevalent in veterans, due to military-specific exposures that increase PD risk. There is great phenotypic variability: some PD patients present primarily with tremor and retain good quality of life for decades whereas others demonstrate a more malignant phenotype with more rapid progression to dementia and severe motor impairments. The ability to predict which patients will exhibit slow or fast disease progression would be invaluable for patient counseling and for clinical trial design. To date, no biomarkers have been identified which predict PD progression. Given that mitochondrial dysfunction is an early and consistent cellular hallmark of the disease that tracks with disease progression, measuring mitochondrial function could prove to be one such predictive biomarker. Two promising approaches, magnetic resonance spectroscopic imaging (MRSI) and measurement of Nrf2 activity in peripheral blood mononuclear cells (PBMCs), could close this knowledge gap. Significance: This work addresses two high-priority areas. It makes inroads into precision medicine through its potential for predicting disease progression and laying foundation for improving clinical trial design and expediting translation of promising preclinical work. It also focused on a neurocognitive disorder highly prevalent within the VA population. 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 because we plan to be the first to apply ultrahigh field MRSI to measure mitochondrial function in real time in the brains of patients with PD. Extending beyond static measurements of phosphate-containing compounds, we will also be the first to apply magnetization transfer, giving us further insight into mitochondrial dynamics and increasing the sensitivity of our assessments. Our work will also assess whether imaging-based measures of mitochondrial dysfunction will be able to predict subsequent clinical changes in PD progression. If so, this would provide the first biomarker that is able to predict progression in individuals with PD. Specific Aims: 1) Quantify mitochondrial bioenergetics in the PD brain by applying 31P-MRSI. 2) Evaluate PBMC Nrf2 mRNA expression and its downstream effectors in PD patients compared to controls. 3) Assess longitudinal changes in peripheral Nrf2 levels and 31P-MRSI-based changes in brain bioenergetics in early PD patients, to determine whether differences in mitochondrial bioenergetics predict clinical disease progression. Methods: A cross-sectional study of early and mid-stage patients with PD and healthy controls will undergo MRSI and peripheral blood analysis. One year later, the controls and early PD group will repeat these measurements. Next Steps: By measuring mitochondrial function in vivo, this proposal will establish readouts of disease activity which can next be used to measure target engagement in trials with mitochondria-directed therapeutics.