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: 8473552
• 负责人: XUEMEI HUANG
• 金额: $ 64.95万
• 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/8473552
• 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. 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.

描述（由申请人提供）：帕金森氏病（PD）在病理上以多巴胺神经元损失在基底神经节（BG）和刘易身体的存在上标记。体内生物标志物缺乏反映与PD相关的细胞损失以及相关的病理学/生理过程的缺乏，这阻碍了发现研究，并限制了评估潜在疾病改良疗法的能力。最佳的技术，使用18FDOPA-PET和[123i] B-CIT SPECT进行放射影像可以评估纹状体多巴胺末端的活性或密度。但是，这些技术不能直接反映SN中的病理过程，可能不会将PD与其他帕金森氏综合症区分开，并且可能受到症状治疗的影响。此外，这两种技术都需要暴露于放射性，而宠物则需要不广泛使用的设施。磁共振成像（MRI）是无创的，易于访问且可广泛可用的，但其措施很难与特定的病理生理机制相关。据报道，扩散张量（DTI）和R2*成像可检测PD中SN的变化，并提供成为MRI生物标志物的承诺。但是，缺乏对它们的临床意义和生物/病理基础的了解。我们的试点数据支持了这样的假设：分数各向异性（FA）和R2*措施反映了骨纹状体病理学的不同方面，可以用作诊断PD和进展后的生物标志物。我们建议利用PI R01（2009-2014）的纵向临床人群和现有的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具有丰富的专业知识，特别是与铁（FE）代谢有关的专业知识。通过在体内融合体内高分辨率DTI和R2* MRI数据，并评估体液中的Fe相关蛋白质谱，我们希望能够获得明显的洞察力，以预测PD进展。此外，我们在死亡后脑组织病理学方面的优势和与FE相关蛋白的分析将允许体内临床和脑MRI测量与大脑生化变化的相关性。这将提供对FE在PD中的作用的机械理解，这可能导致发现新的生物标志物或治疗靶标。基于功率分析试验数据，将执行四个目标：1）在PD检测和进展中确定DTI和R2*的差异作用； 2）证明了黑质纹状体DTI和R2*将PD与帕金森氏综合症区分开； 3）将体液中与FE相关的蛋白质作为生物标志物进行询问； 4）获取MRI生物标志物和验尸病理相关数据。该研究的成功应产生有效的标志物，以便在可预见的将来将PD检测及其进展，并可以融入并有望影响疾病改良的临床试验。临床和MRI数据以及收集并沉积到PDBP DMR的生物样本应为生物标志物社区中的研究人员提供机会探索和理解nigrostriatal途径以外的变化以及非FE相关蛋白质及其与我们建议的标记的关系。 公共卫生相关性：缺乏反映帕金森氏病（PD）相关的细胞损失以及相关的病原体/生理过程的体内生物标志物，在黑质层状结构中妨碍了发现研究，并限制了评估疾病模化治疗疗法的能力。最近的研究引起了使用DTI和R2* MRI测量作为生物标志物（S）的兴奋，用于黑质途径中与PD相关的病理学，但由于缺乏缺乏 了解他们的临床意义和生物/病理基础。拟议的工作将与Ninds Parkinson Disease Biomarks计划（PDBP）紧密合作，将研究多模式MRI技术与基于流体的铁（FE）蛋白质概况相结合，以作为PD相关的Nigrostiriatal病理学的体内标记，可作为生物标志物，并遵循其进度的PD，及其诊断PD的机制，并在PD中进行诊断，并在PD中进行诊断，并在PD中进行诊断，并被纳入PD，并被纳入PD，并被用于诊断PD的病理学。病理生理学。