Characterization and validation of cerebrovascular reactivity (CVR) as a biomarker of vascular dementia in mouse models

项目概要/摘要 小血管相关的血管性认知障碍和痴呆（VCID）是第二大原因， 痴呆症在美国然而，与其他类型的痴呆症（例如淀粉样蛋白和tau成像）相比， 阿尔茨海默病），VCID的有效成像生物标志物有限。最近对人类的研究表明 大脑的血管舒张能力，被称为脑血管反应性（CVR），是最重要的 VCID的敏感指标。虽然人体研究在证明CVR在临床中的效用方面很重要， 动物模型对于验证和表征这种新的生物标志物是非常宝贵的。与适当 动物模型，可以阐明CVR和经典的测量之间的机械联系， 小血管疾病的神经病理学标志，如血管密度、血管平滑肌细胞和 内皮细胞此外，动物模型可以被设计成具有相对纯的机制， 避免混淆病理，这通常发生在人类痴呆症患者中。因此本 探索性/开发性（R21）研究将通过表征和验证来解决上述科学差距 CVR作为小鼠模型VCID的生物标志物。应该注意的是，定量CVR技术还没有 由于血液动力学参数的测量和 在小动物中的血管活性刺激的定量。因此，本申请将首先进行系统的 在小鼠中开发CVR MRI技术，随后在两种小鼠模型中应用该技术 小血管疾病（SVD）这两个模型是互补的，一个是经典的遗传模型， 常染色体显性遗传性脑动脉病伴皮质下白质脑病（CADASIL）和 另一种是基于环境的高同型半胱氨酸血症（HHcy）小鼠模型。这项研究有两个 具体目标。目的1：建立小鼠CVR MRI技术。我们将测量血液动力学反应， 血管活性激发，其强度将产生CVR指数。对于血管活性药物的选择， 挑战，我们将使用乙酰唑胺注射液作为血管扩张剂，其血浆浓度 将被量化并用作输入函数。对于成像读数，全局和局部CVR方法 将使用先进的生理MRI技术开发。乙酰唑胺效应的剂量依赖性 也将被研究。目的2是在SVD小鼠模型的纵向研究中表征CVR损伤。 我们将比较CVR与几种组织学指标，包括胶原染色的总血管密度 IV，用Acta 2染色的血管平滑肌细胞密度，和用Acta 2染色的血管内皮蛋白。 CD31。区域CVR研究将集中在皮质下核团，这是人类最敏感的区域 SVD.我们还将研究CVR的纵向时间过程，并将其与行为评分、脑功能评分和脑功能评分进行比较。 体积和WM高信号。

Project summary/Abstract Small-vessel-related vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia in the United States. However, compared to other dementia types (e.g. amyloid and tau imaging in Alzheimer's disease), validated imaging biomarkers for VCID are limited. Recent studies in humans suggested that the brain's vasodilatory capacity, referred to as cerebrovascular reactivity (CVR), is one of the most sensitive indicators of VCID. While human studies are important in demonstrating the utility of CVR in clinical settings, animal models are invaluable for validating and characterizing this new biomarker. With appropriate animal models, one can elucidate the mechanistic link between CVR and classical measures of neuropathologic hallmarks of small vessel disease such as vessel density, vascular smooth muscle cells, and endothelial cells. Additionally, animal models can be designed to have relatively pure mechanism and therefore avoid confounding pathologies, which often occur in human patients of dementia. Therefore, the present exploratory/developmental (R21) study will address the above scientific gap by characterizing and validating CVR as a biomarker of VCID with mouse models. It should be noted that quantitative CVR techniques have not been available in mouse, because of the difficulties in both the measurement of hemodynamic parameters and quantification of vasoactive stimuli in small animals. Therefore, this application will first conduct systematic development of CVR MRI technique in mice, followed by an application of the technique in two mouse models of small vessel disease (SVD). The two models are complementary in that one is a classic genetic model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and the other is an environmentally based model of hyper-homocysteinemia (HHcy) mice. This study has two specific aims. Aim 1 is to develop a CVR MRI technique in mice. We will measure hemodynamic responses to vasoactive challenge, the magnitude of which will yield an index of CVR. For the choice of vasoactive challenge, we will use injection of acetazolamide as a vasodilative agent, the plasma concentration of which will be quantified and used as an input function. For imaging readouts, both global and regional CVR methods will be developed using advanced physiological MRI techniques. Dose-dependence of acetazolamide effects will also be studied. Aim 2 is to characterize CVR impairment in a longitudinal study of SVD mouse models. We will compare CVR with several histological measures, including total vessel density stained with collagen IV, vascular smooth muscle cell density stained with Acta 2, and vascular endothelial proteins stained with CD31. Regional CVR studies will focus on subcortical nuclei which are the most susceptible regions in human SVD. We will also study the longitudinal time course of CVR and compare it to that of behavioral scores, brain volume, and WM hyperintensities.