Multimodal MRI markers of nigrostriatal pathology in Parkinson's disease

描述(申请人提供)：帕金森病(PD)的病理特征是基底节(BG)黑质(SN)的多巴胺神经元丢失和路易小体的存在。缺乏反映帕金森病相关细胞丢失和相关病理/生理过程的体内生物标志物(S)阻碍了发现研究，并限制了评估潜在的疾病修改治疗的能力。现有最好的技术，使用18FDOPA-PET和[123I]b-CIT SPECT的放射成像，可以评估纹状体多巴胺终末的活性或密度。然而，这些技术不能直接反映SN的病理过程，可能无法将帕金森病与其他帕金森综合征区分开来，而且可能会受到对症治疗的影响。此外，这两种技术都需要暴露在放射性物质中，而PET需要的设施并不广泛。磁共振成像(MRI)是一种非侵入性的、容易获得和广泛使用的方法，但其测量方法很难与特定的病理生理机制相关联。弥散张量(DTI)和R2*成像已被报道可以检测PD患者SN的变化，并有望成为MRI生物标记物。然而，对它们的临床意义和生物学/病理学基础缺乏了解。我们的初步数据支持这一假设，即分数各向异性(FA)和R2*测量反映了黑质纹状体病理的不同方面，可用作诊断PD和跟踪其进展的生物标志物。我们建议利用PI‘s R01(2009-2014)的纵向临床人群和现有基础设施来检验上述假设。此外，我们在开发疾病生物标志物方面拥有相当多的专业知识，特别是与铁(Fe)代谢相关的生物标志物。通过将体内高分辨率DTI和R2*MRI数据与体液中铁相关蛋白质谱的评估相结合，我们有望对预测PD进展有显著的洞察力。此外，我们在死后脑组织病理学和铁相关蛋白分析方面的优势将使体内临床和脑MRI测量与大脑中的生化变化相关联。这将提供对铁在帕金森病中作用的机制的理解，从而可能导致新的生物标记物或治疗靶点的发现。基于能量分析先导数据，将实现四个目标：1)确定DTI和R2*在PD检测和进展中的不同作用；2)证明黑质纹状体DTI和R2*区分PD和帕金森综合征；3)询问体液中与铁相关的蛋白质作为生物标记物；4)获得MRI生物标记物和尸检病理相关数据。这项研究的成功将为帕金森病及其进展的检测产生有效的标记物，这些标记物可以整合到临床试验中，并有望在可预见的未来对其产生影响。临床和MRI数据以及收集并存放到PDBP DMR的生物样本将为生物标记物社区的研究人员提供机会，以探索和了解黑质纹状体通路和非铁相关蛋白的变化及其与我们建议的标记物的关系。 公共卫生相关性：缺乏反映帕金森氏病(PD)相关细胞丢失和黑质纹状体结构相关病理/生理过程的体内生物标记物(S)，阻碍了发现研究，并限制了评估疾病修改治疗的能力。最近的研究激起了人们对使用弥散张量成像和R2*磁共振测量作为黑质纹状体通路帕金森病相关病理的生物标记物(S)的兴奋，但它们缺乏 了解它们的临床意义和生物学/病理学基础。与NINDS帕金森病生物标记物计划(PDBP)密切合作，拟议的工作将研究多模式MRI技术，结合基于液体的铁(Fe)蛋白图谱，作为PD相关黑质纹状体病理的活体标志物，可用作诊断PD、跟踪其进展以及了解PD病因学和病理生理学的生物标志物。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is marked pathologically by dopamine neuronal loss in the substantia nigra (SN) of the basal ganglia (BG) and the presence of Lewy bodies. The lack of in vivo biomarker(s) reflecting PD-related cell loss and associated pathoetiological/physiological processes has hindered discovery research and limited the ability to evaluate potentially disease-modifying therapies. The best available technology, radioimaging using 18FDOPA-PET and [123I]b-CIT SPECT, can assess the activity or density of striatal dopamine terminals. These techniques, however, do not reflect directly the pathological process in the SN, may not distinguish PD from other parkinsonian syndromes, and can be affected by symptomatic therapy. In addition, both techniques require exposure to radioactivity and PET requires facilities not widely available. Magnetic resonance imaging (MRI) is noninvasive, easily accessible, and widely available, yet its measures have been difficult to relate to a specific pathophysiological mechanism. Diffusion tensor (DTI) and R2* imaging have been reported to detect changes in the SN in PD, and offer the promise of being MRI biomarkers. There is, however, a lack of understanding of their clinical implications and biological/pathological underpinnings. Our pilot data support the hypothesis that fractional anisotropy (FA) and R2* measures reflect different aspects of nigrostriatal pathology that can be used as biomarkers for diagnosing PD and following its progression. We propose to leverage the longitudinal clinical population and existing infrastructure of the PI's R01 (2009-2014) to test the above hypothesis. In addition, we have considerable expertise in developing disease biomarkers, particularly related to iron (Fe) metabolism. By melding in vivo high-resolution DTI and R2* MRI data with assessment of Fe-related protein profiles in body fluids, we expect to gain marked insight into predicting PD progression. Moreover, our strengths in postmortem brain histopathology and analysis of Fe-related proteins will permit the correlation of the in vivo clinical and brain MRI measures with biochemical changes in the brain. This will provide a mechanistic understanding of the role of Fe in PD that may lead to the discovery of new biomarkers or therapeutic targets. Based on power analysis pilot data, four aims will be performed: 1) Establish the differential roles of DTI and R2* in PD detection and progression; 2) Demonstrate that nigrostriatal DTI and R2* differentiate PD from parkinsonian syndromes; 3) Interrogate Fe-related proteins in body fluids as biomarkers; 4) Obtain MRI biomarker and postmortem pathological correlation data. The success of the study shall yield valid markers for both detection of PD and its progression that can be integrated into and hopefully impact disease-modifying clinical trials within the foreseeable future. The clinical and MRI data and the biosamples collected and deposited to the DMR of the PDBP shall provide investigators in the biomarker community the opportunity to explore and understand changes outside of nigrostriatal pathways and non Fe-related proteins and their relationship with our proposed markers. PUBLIC HEALTH RELEVANCE: The lack of in vivo biomarker(s) reflecting Parkinson's disease (PD)-related cell loss and associated pathoetiological/physiological processes in nigrostriatal structures has hindered discovery research and limited the ability to evaluate disease-modifying therapies. Recent research has generated excitement for using DTI and R2* MRI measures as biomarker(s) for PD-related pathology in nigrostriatal pathways, but they fall short by the lack of understanding of their clinical implications and biological/pathological underpinnings. Working closely with the NINDS Parkinson's Disease Biomarkers Program (PDBP), the proposed work will investigate multimodal MRI techniques in combination with fluid-based iron (Fe) protein profiles to serve as in vivo markers for PD-related nigrostriatal pathology that can be used as biomarkers for diagnosing PD, following its progression, and gaining mechanistic understanding of PD pathoetiology and pathophysiology.