MRI and mouse models of Alzheimer's disease and aging

描述（由申请人提供）：一系列研究表明，阿尔茨海默病（AD）始于海马结构选定亚区的突触功能受损。以解剖学精度检测突触功能障碍已经成为一个重要的目标，既可以提高我们的诊断能力，也可以用于药物开发。突触功能障碍通常会影响基础脑代谢。在可以用磁共振成像（MRI）评估的脑代谢的血流动力学相关性中，脑血容量（CBV）是最容易可视化单个海马子区域的一个。 该提案的第一个目标是确定CBV的高分辨率测量是否确实反映了潜在的生理和代谢，以及它是否可以检测AD相关和年龄相关的神经元功能障碍。第二个目标是确认AD相关和年龄相关的海马功能障碍靶向不同的海马亚区。第三个目标是证明CBV测量可以可靠地检测药物干预的效果，从而测试这种方法是否可以用于药物开发。 神经元功能障碍的独立验证需要侵入性技术-例如离体切片电生理学和体外组织化学-因此这些目标只能在实验动物中实现。在这里，我们专注于小鼠，因为它们是唯一既能提供AD模型又能提供正常衰老模型的物种。此外，由于它们的寿命相对较短，我们可以纵向跟踪小鼠，从而绘制功能障碍的时间和空间模式。考虑到这些优势，我们已经建立了一个专门针对小鼠MRI的MRI实验室，并优化了CBV方法，用于海马的次区域分析。

DESCRIPTION (provided by applicant): A range of studies suggests that Alzheimer's disease (AD) begins by impairing synaptic function in select subregions of the hippocampal formation. Detecting synaptic dysfunction with anatomical precision has emerged as an important goal, both to improve our diagnostic abilities and for the purposes of drug development. Synaptic dysfunction typically affects basal brain metabolism. Among the hemodynamic correlates of brain metabolism that can be assessed with magnetic resonance imaging (MRI), cerebral blood volume (CBV) is the one that can most readily visualize individual hippocampal subregions. The first goal of this proposal is to determine whether high-resolution measures of CBV do in fact reflect underlying physiology and metabolism, and whether it can detect AD-related and age-related neuronal dysfunction. The second goal is to confirm that AD-related and age-related hippocampal dysfunction target separate hippocampal subregions. The third goal is to demonstrate that CBV measures can reliably detect the effect of a pharmacological intervention, thereby testing whether this approach can be used for drug development. Independent validation of neuronal dysfunction requires invasive techniques--such as ex vivo slice electrophysiology and in vitro histochemistry-- and therefore these goals can only be achieved in experimental animals. Here we focus on mice because they are the only species that provide both a model of AD and a model of normal aging. Furthermore, because of their relatively short life span, we can follow mice longitudinally, thereby mapping the temporal as well as spatial pattern of dysfunction. With these advantages in mind, we have constructed an MRI laboratory tailored exclusively to mouse MRI, and have optimized CBV approaches for subregional analysis of the hippocampus.