Translating brain magnetic resonance imaging signals to iron and myelin to appraise Alzheimer's disease

博士项目的目的：确定铁和髓磷脂对多模态定量磁共振成像（QMRI）信号的单独和联合贡献。随着年龄的增长，铁在大脑中积累，年龄的增长是阿尔茨海默病（AD）等神经退行性疾病的主要危险因素。． 事实上，铁平衡失调是AD的一个特征，铁螯合疗法正在进行一项针对AD的临床试验。定量磁共振成像（QMRI）方法对铁含量敏感（程度和特异性不同）。So实验室和其他人已经证明T2*值与T1和T2相比，与铁的相关性最好。不同寻常的是，So实验室将QMRI数据与同步辐射x射线荧光（SRXRF）获得的定量空间铁测量相关联，而不是依赖于定量体铁分析或非定量组织化学铁染色。髓磷脂也被认为可以显著调节QMRI信号，而髓磷脂本身的高铁含量使情况进一步复杂化。髓磷脂是由包裹在轴突周围的少突胶质细胞膜形成的，起着“电绝缘”的作用，以确保神经的快速传导。通常，髓磷脂是通过（免疫）组织化学染色和定性而不是定量来评估的。一般来说，QMRI与铁和/或髓磷脂之间的关系是通过对脑样本进行离体QMRI，然后对样本进行相关铁和/或髓磷脂组织学切片来评估的，如上所述。来自组织学处理的不同数据类型和工件之间的不同分辨率导致了不准确性/模糊性，特别是在共同注册数据集时。使用定制的高信噪比MRI线圈（以前由So实验室与PulseTeq Ltd开发），脑组织薄片将进行高分辨率QMRI，然后分别通过SRXRF/激光烧烧-电感耦合等离子体质谱（LA-ICP-MS）和解吸电喷雾电离质谱(DESI-MSI)/拉曼成像进行定量铁和髓磷脂制图。独特的是，多模态成像将以可比较的分辨率进行，模态之间的最小样本位移。薄脑样本的高分辨率QMRI具有挑战性，但使用定制的MRI线圈可以实现。通过这种方式，数据集之间的配准误差被最小化，并且可以确定单个QMRI，铁和髓鞘成像数据集之间准确的像素关系。值得注意的是，还可以获得脂质组成和髓鞘结构信息，以确定QMRI与特定脂质类型/髓鞘结构之间的关系。在这个项目中，我们的目标是将铁和髓磷脂敏感的QMRI信号与So和Bergholt实验室分别开发的最先进的定量理化铁和髓磷脂制图相关联。年龄匹配的对照和AD脑样本将从痴呆症脑库（So博士之前访问过）获得并分析，用于潜在的未来转化为监测人类铁螯合疗法。虽然阿尔茨海默病通常被认为是灰质疾病，但白质髓鞘也被证明是紊乱的。梳理髓磷脂和铁对多模态QMRI测量的贡献，有助于真正评估铁平衡失调和髓磷脂功能障碍在阿尔茨海默病中的作用，从而确定新的阿尔茨海默病治疗和监测方法。

Aim of the PhD Project:To determine the individual and combined contributions of iron and myelin to multi-modality quantitative magnetic resonance imaging (QMRI) signals.Project DescriptionIron accumulates in the brain with ageing, with advancing age being the major risk factor for neurodegenerative diseases such as Alzheimer's Disease (AD; ). Indeed, iron dyshomeostasis is a feature of AD [3] and iron chelation therapy is undergoing a clinical trial for AD.Quantitative magnetic resonance imaging MRI (QMRI) methods are sensitive to iron content (to differing extents and specificities). The So Lab and others have shown T2* values compared to T1 and T2, correlated best with iron. Unusually, the So Lab has correlated QMRI data with quantitative spatial iron measurements obtained by synchrotron radiation X-ray fluorescence (SRXRF), rather than rely on quantitative bulk iron analyses or non-quantitative histochemical iron staining.Myelin is also known to significantly modulate QMRI signals and the situation is further complicated by the high iron content of myelin itself. Myelin is formed from the wrapping of oligodendrocyte membranes around axons and functions as "electrical insulation" to ensure fast nerve conduction. Conventionally, myelin is assessed by (immuno)histochemical staining and qualitative, rather than quantitative.Generally, relationships between QMRI with iron and/or myelin are evaluated by ex vivo QMRI of brain samples and then sectioning of the sample for correlative iron and/or myelin histology as mentioned above. Disparate resolutions between such diverse data types and artefacts from histological processing contributes to inaccuracies/ambiguities, especially when co-registering datasets. Using bespoke high signal-to-noise MRI coils (previously developed by the So lab with PulseTeq Ltd), thin sections of brain tissues will undergo high resolution QMRI prior to quantitative iron and myelin mapping by SRXRF/laser-ablation-inductive coupled plasma-mass spectrometry (LA-ICP-MS) and desorption electrospray ionisation-mass spectroscopic (DESI-MSI)/Raman imaging, respectively. Uniquely, multi-modality imaging will be performed at comparable resolutions with minimal sample displacement between modalities. High resolution QMRI of thin brain samples is challenging but made possible using bespoke MRI coils. In this manner, registration errors between datasets are minimised and determination of accurate pixel-wise relationships between individual QMRI, iron and myelin imaging datasets are possible. Notably, lipid composition and myelin structural information can also be obtained to determine relationships between QMRI and specific lipid types/myelin structure.In this project, we aim to correlate iron- and myelin-sensitive QMRI signals with quantitative state-of-the-art physiochemical iron and myelin mapping developed by So and Bergholt Labs, respectively. Age-matched control and AD brain samples will be obtained from the Brain Bank for Dementia (which Dr So has previously accessed) and analysed, for potential future translation to monitoring iron chelation therapies in man. While AD is often considered a grey matter disease, white matter myelin has also been shown to be deranged. Teasing apart contributions of myelin and iron to multimodality QMRI measurements aids true assessment of the roles of iron dyshomeostasis and myelin dysfunction in AD for identification of novel AD therapeutics and monitoring.