Multimodal MRI markers of nigrostriatal pathology in Parkinson's disease

帕金森病黑质纹状体病理的多模态 MRI 标记

• 批准号: 8554397
• 负责人: XUEMEI HUANG
• 金额: $ 64.63万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554397
• 关键词: Affect; Age; Amyloid; Amyloid beta-Protein; Anisotropy; Autopsy; Basal Ganglia; Biochemical; Biological; Biological Markers; Blood; Body Fluids; Brain; Cells; Clinical; Clinical Trials; Communities; Corpus striatum structure; Data; Data Correlations; Deposition; Detection; Diagnosis; Diagnostic tests; Diffusion; Discrimination; Disease; Disease Progression; Dopamine; Exposure to; Ferritin; Functional disorder; Future; Gender; Growth Factor; Handedness; Histopathology; Homeostasis; Image; Imaging Techniques; Individual; Inflammation; Iron; Lead; Lewy Bodies; Link; Liquid substance; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Multiple System Atrophy; Myelin; National Institute of Neurological Disorders and Stroke; Neuroglia; Neurons; Onset of illness; Parkinson Disease; Parkinsonian Disorders; Pathologic Processes; Pathology; Patients; Physiological Processes; Population; Positron-Emission Tomography; Progressive Supranuclear Palsy; Proteins; Radioactivity; Reporting; Research; Research Infrastructure; Research Personnel; Resolution; Role; Sensitivity and Specificity; Staging; Staining method; Stains; Structure; Substantia nigra structure; Techniques; Technology; Testing; Tissues; Tyrosine 3-Monooxygenase; Ubiquitin; Urine; Work; base; behavior measurement; clinical Diagnosis; density; disorder control; dopaminergic neuron; falls; hepcidin; in vivo; insight; neurobehavioral; neuron loss; nigrostriatal pathway; pars compacta; programs; protein profiling; single photon emission computed tomography; success; synuclein; tau Proteins; therapeutic target

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.

描述（由申请人提供）：帕金森氏病（PD）的病理特征是基底神经节（BG）黑质（SN）中多巴胺神经元的丧失以及路易体的存在。缺乏反映 PD 相关细胞损失和相关病理/生理过程的体内生物标志物阻碍了发现研究，并限制了评估潜在疾病缓解疗法的能力。目前最好的技术是使用 18FDOPA-PET 和 [123I]b-CIT SPECT 进行放射成像，可以评估纹状体多巴胺末端的活性或密度。然而，这些技术不能直接反映 SN 的病理过程，可能无法区分 PD 和其他帕金森综合征，并且可能受到对症治疗的影响。此外，这两种技术都需要接触放射性，而 PET 需要的设施并不广泛。磁共振成像 (MRI) 是无创的、易于获取且广泛使用，但其测量方法很难与特定的病理生理机制联系起来。据报道，弥散张量 (DTI) 和 R2* 成像可检测 PD 中 SN 的变化，并有望成为 MRI 生物标志物。然而，对其临床意义和生物学/病理学基础缺乏了解。我们的试验数据支持这样的假设：分数各向异性 (FA) 和 R2* 测量反映了黑质纹状体病理学的不同方面，可以用作诊断 PD 并跟踪其进展的生物标志物。我们建议利用 PI 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丰富的专业知识，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谱的评估相结合，我们期望获得预测 PD 进展的显着见解。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 测量与脑生化变化相关联。这将从机制上理解 Fe 在 PD 中的作用，从而可能导致新生物标志物或治疗靶点的发现。基于功率分析试验数据，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* 可区分 PD 和帕金森综合征； 3) 检测体液中与铁相关的蛋白质作为生物标志物； 4) 获得MRI生物标志物和死后病理相关数据。该研究的成功将为帕金森病及其进展的检测提供有效的标志物，这些标志物可以整合到并有望在可预见的未来影响疾病缓解临床试验。收集并存入 PDBP DMR 的临床和 MRI 数据以及生物样本将为生物标志物界的研究人员提供探索和了解黑质纹状体通路和非 Fe 相关蛋白之外的变化及其与我们提出的标志物的关系的机会。