MRI Assessment--Transgenic Models of Alzheimer's Disease

虽然横断面和短期纵向研究都观察到健康老年人认知功能下降导致痴呆，但我们仍然缺乏AD临床前阶段的敏感和特异性生物标志物。这种需要继续对研究和管理变化或表征和改变的生理学产生负面影响，同时对年龄的影响相对不敏感。我们建议在具有广泛β-淀粉样变性的转基因小鼠（PS/APP）中鉴定和评估这样一组潜在的标记物。这些小鼠表现出广泛的淀粉样变性，从三个月大开始，并在其整个生命周期中继续建立。在以后的生活中，大脑中存在的淀粉样蛋白水平远远超过人类AD大脑中发现的水平，但通过细胞计数范例尚未观察到过度神经变性。在拟议的研究中，我们将系统地表征表现出β-淀粉样蛋白沉积的转基因小鼠大脑区域的组织变化，并将其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影像学标记，以表征大脑参与的阶段。我们的研究计划将开始利用MRI来表征β淀粉样蛋白沉积的影响。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中水的生物物理环境的影响。此外，我们将扩展我们完善的灌注和扩散MRI成像协议从大鼠到小鼠沿着两种类型的验证研究。首先，我们将使用[14 C] 2-脱氧葡萄糖（14 C-2DG）表征PS/APP小鼠的局部葡萄糖利用率，其次，通过从纵向动物队列中随时间采样，我们将利用无偏体视学来估计神经元数量、神经胶质增生程度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，预计这项工作将使我们更好地了解转基因模型和β-淀粉样蛋白负荷对脑结构和脑功能的影响。这种新的能力将使我们能够开发工具来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.