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.
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.
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