MRI-based immune cell tracking in Alzheimer?s disease

基于 MRI 的阿尔茨海默病免疫细胞追踪

• 批准号: 8330777
• 负责人: Erik Shapiro
• 金额: $ 19.19万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330777
• 关键词: Algorithms; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Markers; Biology; Blood - brain barrier anatomy; Brain; Caring; Cell Count; Cells; Cessation of life; Cleaved cell; Clinical; Dementia; Detection; Diagnosis; Diagnostic; Disease; Early Diagnosis; Evolution; Eye; Future; Generations; Grant; Human; Image; Immune; Immunohistochemistry; Individual; Infiltration; Inflammation; Inflammatory; Injury; Iron; Label; Location; Magnetic Resonance Imaging; Magnetism; Methodology; Methods; Microglia; Monitor; Motivation; Mus; Neurodegenerative Disorders; Particle Size; Patients; Peripheral; Physics; Positron-Emission Tomography; Process; Protocols documentation; Publications; Qualifying; Reporting; Research; Research Personnel; Resolution; Risk; Role; Scheme; Senile Plaques; Sensitivity and Specificity; Spottings; Staging; Symptoms; System; Time; Tracer; Translating; Uncertainty; Work; base; bench to bedside; clinically significant; ferumoxtran; image processing; in vivo; innovation; iron oxide; magnetite ferrosoferric oxide; migration; monocyte; mouse model; nanoparticle; neurotoxic; particle; research study; tumor

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.

描述(申请人提供)：阿尔茨海默病(AD)是一种神经退行性疾病，导致痴呆症并最终导致死亡。淀粉样蛋白假说认为，淀粉样β蛋白是从淀粉样前体蛋白中分解出来的，并聚集在一起形成低聚物。然后，这些低聚物会形成致密的斑块，这是神经毒性的。与此过程同时发生的是小胶质细胞/单核细胞渗入斑块。目前尚不清楚这些细胞的作用是什么，但在动物模型中，有确凿证据表明，在症状之前形成斑块时，浸润率最高。因此，在人类中，这种渗透早在症状出现前几十年就开始了。因此，及早发现单核细胞渗入淀粉样斑块可以提供大量的时间来减缓AD的进展或完全阻止它。在这里，我们建议调查基于MRI的细胞跟踪是否有助于检测外周单核细胞对淀粉样斑块的渗透。由于单核细胞的渗透发生在非常低的细胞数量中，因此需要使用坚固的磁粉。我们率先将微米级的氧化铁颗粒(MPIO)用于细胞核磁共振。除了在尺寸上比纳米颗粒大之外，MPIO与USPIO最显著的区别在于它们具有高度的磁性。由于这些颗粒的负载效率，细胞可以被标记上非常高的铁水平，从而能够在动物体内检测到单个细胞。事实上，一些出版物已经使用MPIO来可视化免疫细胞在非常低的细胞数量下的渗透。在这项工作中，我们建议使用基于MRI的细胞跟踪来研究阿尔茨海默病模型小鼠外周血单核细胞对大脑的渗透(目标1)。然后，这些MRI结果将通过免疫组织化学进行严格验证(AIM 2)。该项目具有明确的临床意义。首先，制定强有力的AD早期检测方案至关重要。其次，需要对单核细胞渗入淀粉样斑块的基本生物学有更多的了解，特别是当它与新的实验性抗炎治疗有关时。第三，如果MRI可以检测到外周单核细胞在完整的血脑屏障后面渗入淀粉样斑块，那么MRI很有可能对其他神经退行性疾病或小肿瘤中的单核细胞渗透进行诊断监测。这项工作最具创新性的方面在于使用MPIO作为磁性细胞标记，使用复杂的图像处理算法来量化MRI结果，并在临床MRI能够达到的图像分辨率下进行这些实验。该项目的成功完成将提供探索大规模动物试验的动力，量化检测的敏感性和特异性。同时，通过使这项工作适应我们正在开发的临床上可行的颗粒，它也将证明对临床实用的探索是合理的。AD研究人员和耶鲁大学专门的高场人体磁共振成像的协调使这里成为充分开发这一潜在的长凳到床边努力的理想地点。