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

描述（由申请人提供）：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，包括阿尔茨海默病（AD）、帕金森病和亨廷顿病（HD）。年龄或疾病介导的铜、锌和铁的失衡通过直接与相关蛋白质结合或通过增加不稳定金属池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的氧化修饰促进了它们的寡聚化和抵抗降解和清除，从而导致它们的积累4,5。金属，尤其是铁，也会在这些疾病中积累，这在死后的研究中得到了证实，而且它们本身也被认为是治疗疾病的靶点。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是一种口服生物可利用的金属配体，具有高脑穿透性，可减少阿尔茨海默病中毒性聚集体的积累，并改善几种认知领域7,8。PBT2及其早期类似物clioquinol在HD小鼠模型中具有神经保护作用，并可减少huntingtin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，因此能够测量金属积累并有可能测量进展或治疗变化的成像标记将是非常宝贵的。在目前的提案中，我们计划评估新的采集和分析算法，以使用7特斯拉MRI扫描仪测量铁的区域浓度。较高的磁场强度将提供急需的灵敏度，以评估磁场图信号的区域变化，测量脑铁浓度，并可能提供有关目标交战的重要信息。假设：在7T时获得的场图值，与铁浓度的改变相对应，将出现在纹状体和特定的皮质区域，在基因扩展的未表现个体和早期亨廷顿舞蹈病患者中，也是进行性的。目的1：分析7岁时健康对照、先兆和早期HD患者的Field Map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离体扫描和ICP-MS以及使用免疫细胞化学、Western分析、HPLC和QPCR选择的金属稳态调节剂检测区域金属水平。

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.