Analysis and imaging of metal-ion accumulation in neurodegenerative disease

在许多神经退行性疾病中，脑铁浓度异常高。例如，在帕金森病（PD）中，在包含负责运动控制的神经元的区域中，铁水平加倍，并且已知通常80%的运动控制神经元在临床症状发作之前已经死亡。铁积聚的磁共振成像（MRI）可能为早期诊断提供理想的方法，但在实践中，我们对铁的状态了解不够。这阻碍了理解潜在的疾病机制，解释MRI图像，并确定螯合治疗的效果，以消除多余的铁的进展。铁在神经退行性变中的作用还没有完全理解，部分原因是传统的研究技术不能提供足够的信息铁积累的类型。这是至关重要的，因为除非铁得到适当的管理并以相对惰性的形式储存，否则它会参与化学反应，为细胞创造有毒的环境。通过将新的同步加速器X射线方法的信息与MRI直接关联，我们的研究将在这些领域取得实质性进展。我们将研究两种相关且无法治愈的疾病中表现出最显著铁积累的基底神经节：PD和神经变性伴脑铁积累（NBIA），这是非常罕见的，但与PD有许多共同特征。利用我们的同步加速器X射线成像方法，可以直接观察尸检组织切片，并确定铁积累的形式，以及它们与其他金属积累和疾病病理学的关系。该信息将用于解释相同组织样本的MRI分析中观察到的特征，并转移到PD和NBIA患者和健康对照的MRI分析中，以了解体内存在的情况。我们将通过用磁力计定量尸检组织中的铁化合物来支持这项研究，然后提取铁化合物并用电子显微镜检查它们，以详细确认它们的性质。基尔大学将是这项研究的主办机构，在那里可以获得与这项建议直接相关的世界一流的专业知识，奖学金的海外部分将在佛罗里达大学举行。尸检组织的同步加速器X射线成像和分析将在芝加哥的高级光子源进行，佛罗里达大学可以定期使用为拟议研究类型专门建造的设施。我们还将在新的英国同步加速器DIAMOND开发同步加速器分析方法，确保未来在这个新的和不断扩大的领域中能够在英国实现世界级的研究。MRI工作将涉及尸检组织切片的成像，以及帕金森病患者，NBIA患者和健康年龄和性别匹配对照的临床研究。所有这些都将在佛罗里达大学麦克奈特脑研究所的优秀MRI设施中进行，对于样本表征，将通过佛罗里达大学直接访问塔拉哈西国家高磁场实验室的世界级设施。磁力测量和电子显微镜工作将在英国进行，与伦敦大学学院和剑桥大学的现有合作者合作。这些合作确保获得优秀的设施，以及提供频繁的机会，学术讨论与专家在各自的领域。我们将使用物理科学技术的独特组合，在帕金森病和NBIA的大脑的关键区域的铁积累。这些知识将用于确定铁蓄积的潜力，以使用MRI进行早期诊断，进一步了解PD发病机制，并支持开发安全的铁螯合疗法。

In many neurodegenerative diseases, brain iron concentrations are abnormally high. For example, in Parkinson's disease (PD), iron levels are doubled in the region containing the neurons responsible for motor control, and typically 80% of the motor control neurons are known to have died prior to the onset of clinical symptoms. Magnetic resonance imaging (MRI) of iron accumulations may provide an ideal method for early diagnosis, but in practice we do not know enough about the state of the iron. This hinders progress in understanding underlying disease mechanisms, in interpreting MRI images, and in determining the effects of chelation treatments to remove excess iron.The role of iron in neurodegeneration is not fully understood, partly because conventional research techniques do not provide enough information about the type of iron accumulations. This is critical, because unless iron is managed properly and stored in a relatively inert form, it can partake in chemical reactions that create a toxic environment for cells. Our proposed research will enable substantial progress in these areas, by directly correlating information from a new synchrotron x-ray approach with MRI.We will study the basal ganglia, which exhibits the most significant iron accumulation, in two relevant and incurable diseases: PD, and Neurodegeneration with Brain Iron Accumulation (NBIA), which is very rare, but shares many features with PD. With our synchrotron x-ray imaging approach, it is possible to look directly at autopsy tissue sections and determine the forms that the iron accumulations take, and their relationships with other metal accumulations and disease pathology. This information will be used to explain features seen in MRI analysis of the same tissue samples, and transferred to MRI analysis of PD and NBIA patients and healthy controls to understand what is present in vivo. We will support this research by quantifying iron compounds in autopsy tissue with magnetometry, and then extracting the iron compounds and examining them with electron microscopy to confirm their properties in detail. Keele University will be the host institution for this research, where there is access to world-class expertise directly relevant to this proposal, and the overseas portion of the Fellowship will be held at University of Florida. The synchrotron x-ray imaging and analysis of autopsy tissue will be performed at the Advanced Photon Source in Chicago, where University of Florida has regular access to facilities purpose-built for the type of research proposed. We will also develop the synchrotron analysis approach at the new UK synchrotron, DIAMOND, ensuring that world-class research in this new and expanding area can in the future be achieved in the UK. The MRI work will involve imaging of autopsy tissue sections, and a clinical study of Parkinson's disease patients, NBIA patients, and healthy age- and sex-matched controls. All this will be performed at the outstanding MRI facilities at the University of Florida McKnight Brain Institute, and for sample characterisation there will be direct access to world-class facilities at the National High Magnetic Field laboratory in Tallahassee, through University of Florida. The magnetometry and electron microscopy work will be performed in the UK, working with existing collaborators at University College London and at Cambridge University. These collaborations ensure access to excellent facilities, as well as providing frequent opportunities for academic discussion with experts in the respective fields.We will use a unique combination of physical sciences techniques to characterise iron accumulations in critical regions of the brain in PD and NBIA. This knowledge will be used to determine the potential of iron accumulations for early diagnosis using MRI, to further our understanding of PD pathogenesis, and to support the development of safe iron chelation therapies.