Using High Field MRI to Evaluate Metal Dyshomeostasis in Huntington???s Disease

使用高场 MRI 评估亨廷顿病中的金属动态平衡

• 批准号: 8584115
• 负责人: HERMINIA Diana ROSAS
• 金额: $ 26.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584115
• 关键词: Age; Algorithms; Alzheimer' s Disease; Autopsy; Binding; Bioavailable; Brain; Clioquinol; Cognitive; Copper; Corpus striatum structure; Data; Disease; Freezing; Functional disorder; Genes; High Pressure Liquid Chromatography; Homeostasis; Human; Huntington Disease; Image; Individual; Iron; Ligands; MRI Scans; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediating; Metals; Methods; Modification; Monitor; Neurodegenerative Disorders; Oxidation-Reduction; Parkinson Disease; Pathway interactions; Patients; Penetration; Play; Predisposition; Proteins; Regulator Genes; Resistance; Role; Scanning; Signal Transduction; Slice; Testing; Tissues; Zinc; analog; brain tissue; genetic regulatory protein; hepcidin; human Huntingtin protein; immunocytochemistry; improved; mouse model; novel; phase 2 study; pre-clinical; protein aggregation; protein misfolding; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Redox active metals have long been implicated in neurodegenerative disorders, especially those in which protein misfolding is a major feature, including Alzheimer's (AD), Parkinson's disease, and Huntington's disease (HD). Age or disease-mediated dyshomeostasis of copper, zinc and iron promote aberrant protein aggregation through direct binding to the protein concerned or by promoting aggregation indirectly by increasing the labile metal pool or enhancing the pro- oxidative capacity of the tissue micro-environment2, 3. Oxidative modifications of disease-related proteins by metals promote their oligomerization and resistance to degradation and clearance, resulting in their accumulation4, 5. Metals, especially iron, also accumulate in these disorders, as has been demonstrated in post-mortem studies and are themselves considered targets for disease- modifying therapies6. Compounds that target metal-protein interactions are being tested in AD and HD. PBT2, an orally bioavailable metal ligand with high brain penetration reduces the accumulation of toxic aggregates in Alzheimer's disease and improves several cognitive domains7, 8. PBT2 and its older analog, clioquinol are neuroprotective in mouse models of HD and reduce huntingtin aggregation in them, preclinical evidence that metals may be a valid therapeutic target in HD and it is now being assessed in a phase II study. At present, there is no direct way to monitor the effects in brain of therapies targeting metals. Because these diseases are slowly progressive and highly variable, imaging markers that could measure metal accumulation and have the potential to measure changes with progression or treatment would be invaluable. In the current proposal, we plan to evaluate novel acquisition and analytical algorithms to measure regional concentrations of iron using a 7 Tesla MRI scanner. The higher field strength will provide the much needed sensitivity to evaluate regional changes in the Field Map signal, which measures brain iron concentrations, and may provide important information about target engagement. Hypothesis: Field Map values obtained at 7T, corresponding to alterations in iron concentrations, will be present in the striatum and in select cortical regions n gene expanded pre-manifest individuals and in patients with early Huntington's disease that are also progressive. Specific Aim 1: To analyze Field Map measurements of healthy control subjects, premanifest and early HD at 7T. Hypothesis 2: Select regions of human post-mortem brain tissue will reflect changes in metals and metal regulating pathways. Specific Aim 2: Examine regional metal levels by ex vivo scanning at 7T and by ICP-MS and selected metal homeostasis regulators using immunocytochemistry, Western analysis, HPLC, and QPCR.

描述(申请人提供)：氧化还原活性金属长期以来一直与神经退行性疾病有关，特别是那些以蛋白质错误折叠为主要特征的疾病，包括阿尔茨海默氏症(AD)、帕金森病和亨廷顿病(HD)。年龄或疾病导致的铜、锌、铁代谢紊乱，通过直接与相关蛋白质结合，或通过增加活性金属库或增强组织微环境的促氧化能力间接促进蛋白质的聚集，2，3。金属对疾病相关蛋白质的氧化修饰促进了它们的寡聚化以及对降解和清除的抵抗，导致它们积累4，5。金属，特别是铁，也积累在这些紊乱中，正如尸检研究所证明的那样，它们本身也被认为是疾病修正治疗的目标6。针对金属-蛋白质相互作用的化合物正在AD和HD中进行测试。PBT2是一种具有高大脑渗透性的口服生物可用金属配体，它减少了阿尔茨海默病中有毒聚集体的积累，并改善了几个认知领域7、8。PBT2及其较老的类似物CLOQUOL在HD小鼠模型中具有神经保护作用，并减少它们中的亨廷顿蛋白聚集，临床前证据表明金属可能是HD的有效治疗靶点，目前正在进行II期研究评估。目前，还没有直接的方法来监测针对金属的治疗方法在大脑中的效果。由于这些疾病进展缓慢且变异性很大，可以测量金属积累并有可能测量进展或治疗变化的成像标记物将是无价的。在目前的提案中，我们计划评估新的采集和分析算法，以使用7特斯拉核磁共振扫描仪测量区域铁浓度。较高的场强将提供非常需要的灵敏度，以评估场图信号中的区域变化，该信号测量大脑中的铁浓度，并可能提供有关目标接触的重要信息。假设：在7T获得的对应于铁浓度变化的现场映射值将出现在纹状体和选定的皮质区域n基因扩大的预显性个体和早期亨廷顿病患者中，这些患者也是进行性的。具体目标1：分析7T时健康对照组、表现前期和早期HD受试者的视野图测量结果。假设2：人类死后脑组织的特定区域将反映金属和金属调节途径的变化。具体目标2：通过7T的体外扫描和电感耦合等离子体质谱检测局部金属水平，并使用免疫细胞化学、Western分析、高效液相色谱和定量聚合酶链式反应检测选定的金属动态平衡调节剂。