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）始于海马形成的特定亚区突触功能受损。解剖学上精确地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。突触功能障碍通常影响基础脑代谢。在磁共振成像（MRI）可以评估的脑代谢的血流动力学相关因素中，脑血容量（CBV）是最容易看到单个海马亚区的一种。

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.