MRI Signal Validation and Evaluation of Pathogenic Iron compounds as an Early Bio

描述(申请人提供)：我们的主要目标是评估与阿尔茨海默病(AD)相关的异常脑铁积聚作为磁共振成像(MRI)非侵入性早期诊断生物标记物的用途。铁是人类大脑许多过程中必不可少的元素，但众所周知，它也会随着年龄的增长而积累。在许多脑部疾病中脑细胞死亡的区域观察到显著的铁积累，并经常与疾病病理有关，例如在AD脑组织中看到的老年斑。我们从阿尔茨海默氏症的高分辨率x射线和电子显微镜研究中得知，脑组织中形成了不寻常形式的氧化铁颗粒(磁铁矿)，这些颗粒比我们通常存储大脑铁的颗粒具有更强的磁性。我们怀疑这些颗粒是在铁储存中断的情况下形成的，它们可能与自由基的过度产生和随后的细胞死亡有关。尽早诊断阿尔茨海默病是非常重要的，以便在脑细胞发生重大损失之前有治疗和减缓疾病进展的选择。MRI目前被用作AD的诊断工具，其中萎缩(脑细胞丢失)和老年斑都被成像，以帮助确认诊断。然而，当可检测到的萎缩程度和老年斑的形成发生时，临床症状通常已经出现。有大量证据表明铁积累可能先于临床症状的出现，我们建议使用改良的MRI扫描来确定这些铁积累是否可以作为AD的早期诊断标志。铁的区域集中会影响磁共振成像，因为铁是有磁性的，会扰乱聚集部位的局部磁场。这一特性已经被用来扫描患有肝铁超负荷疾病的患者。虽然阿尔茨海默病组织中的磁铁矿浓度很小，而且分布广泛，但我们将使用佛罗里达大学优秀的磁共振设备(包括17.6T Bruker Avance扫描仪)，研究20例阿尔茨海默病患者和20名年龄匹配的健康对照的尸检组织，以确定是否存在可检测到的差异。已有研究表明，阿尔茨海默氏症组织中的老年斑含有足够的铁，足以被核磁共振检测到。我们还将使用最近开发的高能微焦点X射线束技术扫描组织切片，该技术使我们能够确定、绘制和表征组织切片中微小的铁积累(即它们的化学和结构状态)，工作在国际同步加速器设施中，包括芝加哥的高级光子源和英国的钻石。我们将用磁学测量来支持这一发现，以量化组织中磁性铁颗粒的分布。同步加速器x射线技术和核磁共振技术的结合将为我们提供解释磁共振中铁诱导伪影的关键，使铁特异扫描技术的开发能够在未来用于AD及相关疾病的非侵入性临床早期检测和诊断。几乎所有正在评估的AD新疗法都依赖于早期干预才能有效，这给医生带来了两难境地，因为目前还没有可靠的AD早期诊断技术。在这里，我们建议开发一种非侵入性的、基于MRI的AD早期检测技术，基于我们在识别和量化与神经退行性疾病相关的铁化合物方面的工作结果。如果这项工作取得成功，将对阿尔茨海默病的诊断方式、治疗阿尔茨海默病的新药的评估以及高危个体可用的治疗选择产生深远影响。

DESCRIPTION (provided by applicant): Our primary objective is to evaluate the use of abnormal brain iron accumulations, associated with Alzheimer's disease (AD), as a non-invasive early diagnostic biomarker for Magnetic Resonance Imaging (MRI). Iron is an essential element for many processes in the human brain, but it is also known to accumulate with age. Significant accumulations of iron are observed in regions where brain cells die in many brain diseases, and are often linked to disease pathology such as the senile plaques that are seen in AD brain tissue. We know from high-resolution x-ray and electron microscopy studies of Alzheimer's that unusual forms of iron oxide particle (magnetite) form in the brain tissue, and that these particles have stronger magnetic properties than the particles in which we normally store brain iron. We suspect that these particles form under conditions where iron storage breaks down, and that they may be associated with the over-production of free radicals and subsequent cell death. It is very important that AD is diagnosed as early as possible, in order to have the option of treating and slowing disease progression before significant loss of brain cells occurs. MRI is currently being used as a diagnostic tool for AD, where both atrophy (the loss of brain cells), and senile plaques, are being imaged to assist confirmation of diagnosis. However, by the time detectable levels of atrophy and formation of senile plaques occur, clinical symptoms have usually developed. There is a substantial body of evidence to indicate that iron accumulation may precede the onset of clinical symptoms, and we propose to establish whether these iron accumulations can be used as an early diagnostic marker for AD using modified MRI scans. Regional concentrations of iron can affect MRI, as iron is magnetic and disrupts the local magnetic field at the site of the accumulation. This property is already being used to scan patients with liver iron overload disease. Although the concentrations of magnetite in Alzheimer's tissue are small, and widely dispersed, we will study autopsy tissue from twenty Alzheimer's cases and twenty healthy age-matched controls to establish whether there are detectable differences, using the outstanding MRI facilities (including the 17.6T Bruker Avance scanner) available at University of Florida. It has already been shown that senile plaques in Alzheimer's tissue contain enough iron to be detected by MRI. We will also scan the tissue sections using a recently developed high-energy microfocus x-ray beam technique that lets us determine map and characterize tiny iron accumulations in tissue sections (i.e. their chemical and structural state), working at international synchrotron facilities including the Advanced Photon Source in Chicago, and DIAMOND in the UK. We will support the findings with magnetometry measurements to quantify the distribution of magnetic iron particles in the tissue. The combination of synchrotron x-ray techniques and MRI will provide us with the key to interpret iron-induced artifacts in MRI, enabling the development of iron-specific scanning techniques that can in the future be used in non-invasive clinical early detection and diagnosis of AD and related disorders. Virtually all new treatments being evaluated for AD rely on early intervention in order to be effective, presenting doctors with a quandary as currently there are no reliable early diagnostic techniques for AD. Here we propose to develop a non-invasive, MRI-based technique for early detection of AD based on results of our work on identifying and quantifying iron compounds associated with neurodegenerative disorders. This work, if successful, will have a profound impact on the way that AD is diagnosed, the assessment of new drugs to treat AD, and the treatment options available to high-risk individuals.