Pathophysiological mechanisms of hypoperfusion in mouse models of Alzheimer?s disease and small vessel disease

项目概要/摘要 低灌注被广泛报道为阿尔茨海默病相关痴呆的重要症状 （ADRD）.脑血流量（CBF）损失的严重程度与认知缺陷的严重程度相关。然而，在这方面， 低灌注仅仅是ADRD中微血管功能障碍的迹象之一，事实上， 敏感的或具体的。例如，在最近NIH资助的MarkVCID联盟研究中， 脑血流量是血管对认知障碍和痴呆（VCID）最敏感的生物标志物， 未被选为候选生物标志物试剂盒（尽管已提出），而血管舒张功能指数， 称为脑血管反应性（CVR）。在AD中，尽管广泛报道了观察结果， 在后扣带皮层和颞顶区域存在灌注不足，一些人认为这是 通过代谢-血管偶联归因于代谢异常的间接效应。因此 为了系统地了解ADRD中低灌注的机制，人们需要超越灌注， 检查大脑中一系列相关的血管和代谢参数。 因此，本申请的中心目标是进行多参数研究，以充分表征 低灌注与相关血管和代谢基础之间的关系，分别在AD和 小血管病（SVD）小鼠，因为它们代表痴呆的两个主要原因， 与灌注不足有关在小鼠模型中进行的拟议研究将与我们正在进行的人类研究平行 参与者，使这项工作具有很强的翻译相关性。使用新的MRI技术，我们将 测量CBF、脑血管反应性、氧摄取分数、脑氧代谢率， BBB通透性，并将其与行为（例如新物体识别）和组织学进行比较 (e.g.平滑肌细胞密度、紧密连接蛋白密度）结果（目的1）。这些参数将 被集成到一个机械模型，这是完全可测试的基础上提出的实验措施。 PI，一个早期的调查员，是独一无二的定位来开展这项工作，因为他开创了 在过去的几年里，在老鼠身上使用了几种这样的MRI技术。这些技术的非侵入性 (e.g.不需要颅骨变薄或造影剂）也使它们非常适合于纵向研究 (Aim 2），这将允许表征低灌注（和相关的 血管/代谢参数）和行为结果。两种新的Tau 4 R ΔK-AP小鼠模型（复制 AD的tau蛋白病和淀粉样变性）和CADASIL（SVD的复制血管病理学）将基于 我们合作者的最新发现团结在一起，我们处于一个独特的位置， 有助于理解ADRD中的低灌注。

Project summary/Abstract Hypoperfusion is broadly reported as an important symptom of Alzheimer’s disease related dementia (ADRD). Severity of cerebral blood flow (CBF) loss correlates with severity of cognitive deficit. However, hypoperfusion is only one of the signs of microvascular dysfunction in ADRD and, in fact, may not be the most sensitive or specific one. For example, in the recent NIH-funded MarkVCID Consortium study to identify the most sensitive biomarkers of vascular contributions to cognitive impairment and dementia (VCID), CBF was not selected as a candidate biomarker kit (despite proposed), whereas an index of vasodilatory function, referred to as cerebrovascular reactivity (CVR), was selected. In AD, despite the widely reported observations that there is hypoperfusion in posterior cingulate cortex and temporoparietal regions, some proposed this to be an indirect effect attributed to metabolic abnormalities via metabolism-vascular coupling. Therefore, to systematically understand the mechanism of hypoperfusion in ADRD, one needs to look beyond perfusion to examine a suite of related vascular and metabolic parameters in the brain. Therefore, the central goal of this application is to conduct a multi-parametric study to fully characterize the relationship between hypoperfusion and related vascular and metabolic underpinnings, separately in AD and small vessel disease (SVD) mice, as they represent two leading causes of dementia and most prominently linked to hypoperfusion. The proposed study in mouse models will parallel our ongoing efforts in human participants, making this work having a strong translational relevance. Using novel MRI techniques, we will measure CBF, cerebrovascular reactivity, oxygen extraction fraction, cerebral metabolic rate of oxygen, and BBB permeability concomitantly, and compare them to behavior (e.g. novel object recognition) and histology (e.g. smooth muscle cell density, tight-junction protein density) results (Aim 1). These multiple parameters will be integrated into a mechanistic model, which is fully testable based on the experimental measures proposed. The PI, an early stage investigator, is uniquely positioned to carry out this work because he has pioneered several of these MRI techniques in mice over the past few years. The non-invasive nature of these techniques (e.g. does not require skull thinning or contrast agents) also make them ideally suited for longitudinal studies (Aim 2), which will allow the characterization of the temporal relationship between hypoperfusion (and related vascular/metabolic parameters) and behavior outcomes. Two novel mouse models of Tau4RΔK-AP (replicating tauopathy and amyloidosis of AD) and CADASIL (replicating vascular pathology of SVD) will be utilized, based on the recent discovery of our collaborators. Taking together, we are in a unique position to make meaning contributions to the understanding of hypoperfusion in ADRD.