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

项目摘要/摘要 低灌注率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(CBF)丧失的严重程度与认知障碍的严重程度相关。然而， 低灌注量只是ADRD微血管功能障碍的迹象之一，事实上，可能不是最严重的 敏感的或特定的。例如，在最近由NIH资助的MarkVCID财团研究中，确定了 最敏感的血管对认知损害和痴呆(VCID)的生物标志物，CBF是 未被选为候选生物标志物试剂盒(尽管建议)，而血管扩张功能的指数， 称为脑血管反应性(CVR)。在公元后，尽管有广泛报道的观察 在后扣带回皮质和顶叶区域存在低灌流，有人认为这是 通过代谢-血管耦合引起的代谢异常的间接影响。因此，要 系统地了解ADRD的低灌流机制，需要超越灌流的范围 检查大脑中一系列相关的血管和代谢参数。 因此，此应用程序的中心目标是进行多参数研究，以充分描述 阿尔茨海默病和阿尔茨海默病患者低血流灌注与相关血管和代谢基础的关系 小血管疾病(SVD)小鼠，因为它们代表了导致痴呆的两个主要原因，最突出的是 与低灌注率有关。在老鼠模型上的拟议研究将与我们在人类上正在进行的努力相一致 参与者，使这部作品具有很强的翻译相关性。使用新的核磁共振技术，我们将 测定脑血流量、脑血管反应性、氧摄取分数、脑氧代谢率及 血脑屏障通透性，并将其与行为(例如，新对象识别)和组织学进行比较 (例如，平滑肌细胞密度、紧密连接蛋白密度)结果(目标1)。这些多个参数将 被集成到一个机械模型中，该模型基于所提出的实验措施是完全可检验的。 PI是一名早期调查员，他具有开展这项工作的独特地位，因为他开创了 在过去的几年里，有几项这样的核磁共振技术在老鼠身上进行了试验。这些技术的非侵入性 (例如，不需要头骨稀释剂或造影剂)也使其非常适合于纵向研究 (目标2)，这将能够描述低灌注率(和相关的 血管/代谢参数)和行为结果。两种新的Tau4RΔK-AP(复制)小鼠模型 阿尔茨海默病和淀粉样变性)和CADASIL(复制SVD的血管病理)将被利用，基于 最近发现了我们的合作者。综上所述，我们处于一个独特的位置，可以创造意义 有助于对ADRD低灌注症的认识。

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.