MRI-based immune cell tracking in Alzheimer?s disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种导致痴呆并最终死亡的神经退行性疾病。淀粉样蛋白假说认为-淀粉样蛋白是从淀粉样前体蛋白中分离出来的，并聚集在一起形成低聚物。这些低聚物会形成紧致斑块，具有神经毒性。伴随这一过程的是小胶质细胞/单核细胞向斑块的浸润。目前尚不清楚这些细胞的作用是什么，但在动物模型中，有确凿的证据表明，在症状出现之前，斑块形成时，浸润率最高。因此，在人类中，这种渗透可能早在症状出现前几十年就开始了。因此，早期检测单核细胞浸润到淀粉样斑块可以提供大量的时间来减缓阿尔茨海默病的进展或完全停止它。在这里，我们建议研究基于核磁共振的细胞跟踪是否有助于检测外周单核细胞浸润到淀粉样斑块。由于单核细胞浸润发生在非常低的细胞数量，需要使用强大的磁颗粒。我们率先使用微米大小的氧化铁颗粒（MPIOs）进行细胞MRI。除了尺寸比纳米颗粒大之外，mpio与USPIO最显著的区别在于它们具有很强的磁性。由于这些颗粒的装载效率，细胞可以被标记为非常高的铁水平，从而可以在动物体内检测单个细胞。事实上，一些出版物已经使用MPIO来观察细胞数量非常低的免疫细胞浸润。在这项工作中，我们建议使用基于mri的细胞跟踪来研究外周单核细胞浸润到阿尔茨海默病模型小鼠的大脑（Aim 1）。这些MRI结果将通过免疫组织化学严格验证（目的2）。本项目具有明确的临床意义。首先，制定强有力的阿尔茨海默病早期检测方案至关重要。其次，需要对单核细胞浸润到淀粉样斑块的基本生物学有更深入的了解，特别是当它涉及到新的实验性抗炎治疗时。第三，如果MRI能检测到完整血脑屏障后浸润淀粉样斑块的外周单核细胞，那么MRI很有可能在其他神经退行性疾病或小肿瘤中诊断单核细胞浸润。所提出的工作中最具创新性的方面在于使用mpio作为磁细胞标签，使用复杂的图像处理算法来量化MRI结果，并在临床MRI能够实现的图像分辨率下进行这些实验。该项目的成功完成将为探索大规模动物试验提供动力，量化检测的敏感性和特异性。同时，通过将这项工作适应于我们正在开发的临床可行颗粒，也将证明探索临床效用是合理的。耶鲁大学的AD研究人员和专门的高场人体核磁共振成像的协调使其成为充分发展这一潜在的临床试验的理想场所。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease resulting in dementia and ultimately, death. The amyloid hypothesis states that amyloid beta is cleaved from amyloid precursor protein and clumps together into oligomers. These oligomers can then form tight plaques, which are neurotoxic. Co-incident with this process is the infiltration of microglia/monocytes into the plaque. It is currently unclear what the roles of these cells are, but in animal models, there is conclusive evidence that the rate of infiltration is highest when plaques are being formed, prior to symptoms. Thus in humans, this infiltration would begin as early as decades before the onset of symptoms. As such, early detection of monocyte infiltration into amyloid plaques could offer an enormous amount of time to either slow the progression of AD or halt it completely. Here we propose to investigate whether MRI-based cell tracking will be useful in detecting peripheral monocyte infiltration into amyloid plaques. As monocyte infiltration occurs in very low cell numbers, the use of a robust magnetic particle is required. We have pioneered the use of micron sized particles of iron oxide (MPIOs) for cellular MRI. Aside from simply being larger in size than nanoparticles, MPIOs differ most significantly from USPIO in that they are highly magnetic. Due to the loading efficiency of these particles, cells can be labeled with very high iron levels, allowing the detection of single cells in vivo in animals. Indeed, several publications have used MPIO to visualize immune cell infiltration at very low cell numbers. In this work we propose to use MRI-based cell tracking to investigate peripheral monocyte infiltration into the brains of Alzheimer's disease model mice (Aim 1). These MRI results will then be rigorously validated by immunohistochemistry (Aim 2). This project has clear clinical significance. First, it is crucial to develop robust early detection schemes for AD. Secondly, a greater understanding of the basic biology of monocyte infiltration into amyloid plaques is required, especially as it relates to new experimental anti-inflammatory treatments. Third, if MRI can detect peripheral monocytes infiltrating amyloid plaques behind the intact blood brain barrier, then there would be a high likelihood MRI could diagnostically monitor monocyte infiltration in other neurodegenerative diseases or in small tumors. The most innovative aspects of the proposed work lie in the use of MPIOs as the magnetic cell label, the sophisticated image processing algorithms for quantifying the MRI results, and performing these experiments at image resolutions for which clinical MRI is capable. Successful completion of this project will provide the motivation to explore a large scale animal trial, quantifying both sensitivity and specificity of detection. Concurrently, it would also justify exploration of clinical utility by adapting this work to clinically viable particles we are developing. The coordination of AD researchers and specialized high field human MRI at Yale makes this an ideal location for fully developing this potential bench to bedside endeavor. PUBLIC HEALTH RELEVANCE: Early detection of Alzheimer's disease (AD) could have far reaching implications on care and treatment of the disease. This project proposes new MRI-based cell tracking methods to detect immune cell infiltration towards amyloid plaques in a mouse model of AD. Successful completion of this project opens up the possibility to use these protocols on other neurodegenerative diseases.