Analysis and imaging of metal-ion accumulation in neurodegenerative disease

神经退行性疾病中金属离子积累的分析和成像

• 批准号: EP/D066654/1
• 负责人: Joanna Collingwood
• 金额: $ 28.91万
• 依托单位: Keele University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FD066654%2F1
• 关键词: Analysis; imaging; metal; ion; accumulation

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.

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，铁水平增加了一倍，并且已知通常80%的运动控制神经元在临床症状出现之前已经死亡。核磁共振成像（MRI）的铁积累可能提供一个理想的方法，早期诊断，但在实践中，我们不知道足够的铁的状态。这阻碍了理解潜在疾病机制、解释MRI图像和确定螯合治疗去除过量铁的效果的进展。铁在神经退行性变中的作用还没有被完全理解，部分原因是传统的研究技术没有提供足够的关于铁积累类型的信息。这是至关重要的，因为除非铁被妥善管理并以相对惰性的形式储存，否则它会参与化学反应，为细胞创造有毒环境。我们提出的研究将通过将新的同步加速器x射线方法与MRI直接相关的信息，使这些领域取得实质性进展。我们将研究基底神经节，它在两种相关且无法治愈的疾病中表现出最显著的铁积累：PD和神经变性伴脑铁积累（NBIA），这是非常罕见的，但与PD有许多共同的特征。通过我们的同步加速器x射线成像方法，可以直接观察解剖组织切片，并确定铁积聚的形式，以及它们与其他金属积聚和疾病病理的关系。这些信息将用于解释在相同组织样本的MRI分析中看到的特征，并转移到PD和NBIA患者以及健康对照的MRI分析中，以了解体内存在的情况。我们将通过用磁强计定量解剖组织中的铁化合物，然后提取铁化合物并用电子显微镜对其进行检查以详细确认其性质来支持这项研究。基尔大学将是这项研究的主办机构，在那里可以获得与该提案直接相关的世界级专业知识，奖学金的海外部分将在佛罗里达大学举行。解剖组织的同步加速器x射线成像和分析将在芝加哥的先进光子源进行，佛罗里达大学在那里可以定期使用专门为这种研究类型建造的设施。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，确保在这个新的和不断扩大的领域的世界级研究能够在未来在英国实现。MRI工作将包括解剖组织切片的成像，以及帕金森病患者、NBIA患者和年龄和性别匹配的健康对照组的临床研究。所有这些都将在佛罗里达大学麦克奈特脑研究所优秀的核磁共振设备中进行，并且通过佛罗里达大学，可以直接使用塔拉哈西国家高磁场实验室的世界级设备进行样品表征。磁力计和电子显微镜的工作将在英国进行，与伦敦大学学院和剑桥大学的现有合作者合作。这些合作确保了学生能够使用优良的设施，并提供了与各自领域的专家进行学术讨论的频繁机会。我们将使用物理科学技术的独特组合来表征PD和NBIA中大脑关键区域的铁积累。这些知识将用于确定铁积累的潜力，用于MRI的早期诊断，进一步了解PD的发病机制，并支持开发安全的铁螯合疗法。

项目成果

Gene co-expression networks shed light into diseases of brain iron accumulation.

• DOI: 10.1016/j.nbd.2015.12.004
• 发表时间: 2016-03
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Bettencourt C;Forabosco P;Wiethoff S;Heidari M;Johnstone DM;Botía JA;Collingwood JF;Hardy J;UK Brain Expression Consortium (UKBEC);Milward EA;Ryten M;Houlden H
• 通讯作者: Houlden H

High-resolution MRI and iron-specific synchrotron X-ray analysis of the Parkinson's substantia nigra

帕金森病黑质的高分辨率 MRI 和铁特异性同步加速器 X 射线分析

• 发表时间: 2008
• 期刊: Movement Disorders
• 影响因子: 8.6
• 作者: Collingwood JF

High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron.

• DOI: 10.1016/j.neuroimage.2011.08.019
• 发表时间: 2012-01-16
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Antharam, Vijay;Collingwood, Joanna F.;Bullivant, John-Paul;Davidson, Mark R.;Chandra, Saurav;Mikhaylova, Albina;Finnegan, Mary E.;Batich, Christopher;Forder, John R.;Dobson, Jon
• 通讯作者: Dobson, Jon

Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material.

• DOI: 10.3233/jad-2008-14211
• 发表时间: 2008
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: J. Collingwood;R. Chong;T. Kasama;L. Cervera-Gontard;R. Dunin‐Borkowski;George Perry;M. Pósfai;S. Siedlak;E. Simpson;Mark A. Smith;J. Dobson

Biomedical Nanostructures

生物医学纳米结构

• DOI: 10.1002/9780470185834.ch18
• 发表时间: 2007
• 作者: Collingwood J