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: 8670040
• 负责人: HERMINIA Diana ROSAS
• 金额: $ 21.53万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670040
• 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（由申请人提供）：氧化还原活性金属长期以来与神经退行性疾病有关，特别是蛋白质错误折叠是主要特征的那些疾病，包括阿尔茨海默病（AD）、帕金森病和亨廷顿病（HD）。年龄或疾病介导的铜、锌和铁稳态异常通过直接结合相关蛋白质或通过增加不稳定金属库或增强组织微环境的促氧化能力间接促进聚集来促进异常蛋白质聚集2，3。金属对疾病相关蛋白质的氧化修饰促进其寡聚化和对降解和清除的抗性，导致其积累4，5。金属，特别是铁，也积累在这些疾病中，正如在死后研究中所证明的那样，并且它们本身被认为是疾病修饰疗法的靶点6。靶向金属-蛋白质相互作用的化合物正在AD和HD中进行测试。PBT 2是一种口服生物可利用的金属配体，具有高脑渗透性，可减少阿尔茨海默病中毒性聚集体的积累，并改善几个认知领域7，8。PBT 2及其较老的类似物氯碘羟喹在HD小鼠模型中具有神经保护作用，并减少其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II期研究中进行评估。目前，还没有直接的方法来监测针对金属的治疗对大脑的影响。由于这些疾病进展缓慢且高度可变，因此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非常宝贵的。在目前的提案中，我们计划评估新的采集和分析算法，使用7特斯拉MRI扫描仪测量铁的区域浓度。更高的场强将提供非常需要的灵敏度，以评估测量脑铁浓度的场图信号中的区域变化，并且可以提供关于目标接合的重要信息。假设：在7 T下获得的场图值（对应于铁浓度的改变）将存在于纹状体中和基因扩增的预显现个体和患有也是进行性的早期亨廷顿病的患者中的选定皮质区域中。具体目标1：分析健康对照受试者、预显和早期HD在7 T下的场标测测量值。假设2：人类死后脑组织的选定区域将反映金属和金属调节途径的变化。具体目标二：通过7 T离体扫描和ICP-MS检查局部金属水平，并使用免疫细胞化学、Western分析、HPLC和QPCR选择金属稳态调节剂。