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，因为军队特有的暴露会增加帕金森病的风险。有很棒的 表型变异：一些PD患者主要以震颤为主，并保持良好的生活质量 几十年，而其他人表现出更恶性的表型，进展更快，成为痴呆症 以及严重的运动障碍。能够预测哪些患者将出现缓慢或快速的疾病进展 对于患者咨询和临床试验设计将是无价的。到目前为止，还没有生物标志物被 确定了预测帕金森病进展的方法。鉴于线粒体功能障碍是一种早期和持续的细胞 跟踪疾病进展的疾病的标志，测量线粒体功能可以证明 成为这样的预测性生物标记物之一。两种很有希望的方法，磁共振光谱成像 (MRSI)和外周血单核细胞(PBMC)中Nrf2活性的测定，可以结束这一过程 知识鸿沟。 意义：这项工作涉及两个高度优先的领域。它通过其业务进军精准医疗领域 预测疾病进展的潜力，并为改进临床试验设计和 加快有前景的临床前工作的翻译。它还高度关注一种神经认知障碍。 流行于退伍军人管理局人群中。退伍军人的平均年龄较大，男性更有可能患上 疾病，帕金森病被认为是一种与服务相关的疾病，患有帕金森病的退伍军人更有可能单独依赖 退伍军人的医疗保健费用比没有帕金森病的退伍军人要高。 创新：这项提议具有创新性，因为我们计划率先将超高场磁共振成像应用于 实时检测帕金森病患者脑内线粒体功能。超越静态扩展 对于含磷化合物的测量，我们也将是第一个应用磁化转移， 让我们更深入地了解线粒体动力学，并增加我们评估的敏感度。我们的 这项工作还将评估基于成像的线粒体功能障碍测量方法是否能够预测 帕金森病进展的后续临床变化。如果是这样的话，这将提供第一个能够 预测帕金森病患者的进展。 具体目的：1)应用31P-MRSI定量检测帕金森病大鼠脑内线粒体生物能量学。2)评估 PD患者PBMC Nrf2基因表达及其下游效应因子与对照组的比较。3) 评估外周NRF2水平的纵向变化和基于31P-MRSI的脑生物能量学变化 早期帕金森病患者，以确定线粒体生物能量学的差异是否预示临床疾病 进步。 方法：对早、中期帕金森病患者和健康对照进行横断面研究。 核磁共振成像和外周血分析。一年后，对照组和早期帕金森病组将重复这些步骤 测量。 下一步：通过测量体内线粒体的功能，这项提议将建立疾病读数 接下来可以用来在线粒体导向的试验中测量靶参与的活动 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.