MRI Assessment--Transgenic Models of Alzheimer's Disease

虽然横断面和短期纵向研究都观察到了健康老年人认知功能下降导致痴呆，但我们仍然缺乏针对AD临床前阶段的敏感和特异的生物标志物。这种需要继续对变化的研究和管理产生负面影响，同时对年龄的影响相对不敏感。我们建议在患有广泛的β-淀粉样变性的转基因小鼠(PS/APP)中识别和评估这样一组潜在的标记。这些小鼠表现出广泛的淀粉样变性，从三个月大开始，并在它们的整个生命周期中继续积累。大脑中存在的淀粉样蛋白在晚年的水平远远超过在人类AD大脑中发现的水平，但细胞计数范例尚未看到过度的神经变性。在这项拟议的研究中，我们将系统地描述转基因小鼠大脑中表现出β-淀粉样蛋白沉积的区域的组织变化，并将它们与没有这种变化的区域进行比较。我们的目标是提供解剖学、生理学和神经病理学上有效的神经成像标记物来表征大脑受累的不同阶段。我们的研究计划将从利用核磁共振来表征β-淀粉样蛋白沉积的影响的研究开始。在纵向成像设计中，我们将使用MRI来表征进行性β淀粉样蛋白沉积对脑内水的生物物理环境的影响。此外，我们将把我们完善的灌注和扩散磁共振成像方案从大鼠扩展到小鼠，并进行两种类型的验证研究。首先，我们将使用[14C]2-脱氧葡萄糖(14C-2DG)表征PS/APP小鼠的局部葡萄糖利用，其次，通过从动物纵向队列中随时间采样，我们将利用无偏见的体视学来估计神经细胞数量、胶质增生的范围和淀粉样蛋白负荷作为转基因品系和动物年龄的函数。总体而言，预计这项工作将为我们提供更好的了解转基因模型和β-淀粉样蛋白负荷对脑结构和脑功能的影响。这一新的能力将使我们能够开发工具，非侵入性地评估新的动物模型以及治疗干预的有效性。这种类型的追求可能有助于将这些发现转化为改进的临床诊断和管理。

While both cross-sectional and short-term longitudinal studies have observed declines in cognitive functioning leading to dementia in healthy elderly individuals, we are still lacking sensitive and specific biological markers for the pre-clinical stages of AD. This need continues to negatively impact on research and the management of changes or a characterized and altered physiology while being relative insensitive to the effects of age. We propose to identify and evaluate such a set of potential markers in transgenic mice (PS/APP) that have extensive beta- amyloidosis. The mice show extensive amyloidosis, which begins at three months of age, and continues to build throughout their life span. The levels of amyloid present in the brain in later life far exceeds that found in human AD brain, but over neurodegeneration has not been seen by cell counting paradigms. In the proposed study, we will systematically characterize tissue changes in brain regions from transgenic mice that exhibit beta-amyloid deposition and compare them to regions that are free of such changes. Our objectives are to provide anatomically, physiologically, and neuropathologically valid neuroimaging markers to characterize the stages of brain involvement. Our research plan will begin with studies that utilize MRI to characterize the effects of beta-amyloid deposition. In a longitudinal imaging design, we will use MRI to characterize the effect of progressive beta-amyloid deposition on the biophysical environment of water in brain. Moreover, we will extend our well-established perfusion and diffusion MRI imaging protocols from the rat to the mouse along with two types of validation studies. First, we will characterize regional glucose utilization in the PS/APP mouse using [14C] 2-deoxyglucose (14C-2DG), and second, by sampling over time from the longitudinal cohort of animals, we will utilize unbiased stereology to estimate neuronal numbers, the extend of gliosis, and amyloid burden as a function of transgenic strain and age of the animal. Overall, it is expected that this work will provide us with a better understanding of the effects of the transgenic model and beta-amyloid burden on brain structure and brain function. This new capability will enable us to develop the tools to non-invasively assess new animal models as well as the efficacy of therapeutic interventions. This type of pursuit could potentially aid the translation of these findings into improved clinical diagnosis and management.