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

脑血管反应性 (CVR) 作为小鼠模型血管性痴呆生物标志物的表征和验证

• 批准号: 10302475
• 负责人: Zhiliang Wei
• 金额: $ 46.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-01-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302475
• 关键词: Acetazolamide; Address; Age; Alzheimer' s Disease; Amyloid; Animal Model; Animals; Area; Arterial Disorder; Arteries; Autopsy; Behavioral; Biological Markers; Blood Vessels; Brain; Caliber; Cell Density; Cell Nucleus; Cerebrum; Clinical; Collagen Type IV; Correlation Studies; Data; Dementia; Dependence; Development; Diagnosis; Diet; Dose; Endothelial Cells; Endothelium; Functional Imaging; Genetic; Genetic Models; Goals; Gold; Histologic; Human; Hyperhomocysteinemia; Image; Imaging Techniques; Impairment; Individual; Injections; Lesion; Lewy Body Disease; Link; Logistics; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Methods; Microvascular Dysfunction; Modeling; Multicenter Trials; Mus; National Institute of Neurological Disorders and Stroke; Neurobiology; Nitric Oxide; PECAM1 gene; Parkinson Disease; Pathology; Patients; Phase; Physiological; Plasma; Proteins; Quantitative Evaluations; Relaxation; Research Personnel; Resistance; Rest; Rodent Model; Scanning; Selection for Treatments; Smooth Muscle Myocytes; Spin Labels; Stains; Stimulus; Structure; Subcortical Infarctions; Subcortical Leukoencephalopathy; Techniques; Testing; Time; United States; Validation; Vascular Cognitive Impairment; Vascular Dementia; Vascular Endothelium; Vascular Smooth Muscle; arteriole; base; blood oxygen level dependent; brain volume; candidate marker; cardiovascular risk factor; cerebrovascular; cognitive function; density; design; early detection biomarkers; experience; hemodynamics; imaging biomarker; indexing; mild cognitive impairment; mouse model; neuropathology; processing speed; response; tau Proteins; vascular cognitive impairment and dementia

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.

项目摘要/摘要 与小血管相关的血管认知障碍和痴呆（VCID）是第二个主要原因 美国的痴呆症。但是，与其他痴呆症类型相比（例如，淀粉样蛋白和tau成像 阿尔茨海默氏病），经过验证的VCID成像生物标志物受到限制。最近在人类的研究表明 大脑的血管舒张能力，称为脑血管反应性（CVR），是最多的。 VCID的敏感指标。尽管人类研究对于证明CVR在临床中的实用性很重要 设置，动物模型对于验证和表征这种新的生物标志物是无价的。适当 动物模型，可以阐明CVR与经典测量之间的机械联系 小血管疾病的神经病理学标志，例如血管密度，血管平滑肌细胞和 内皮细胞。此外，可以设计动物模型具有相对纯净的机制，因此 避免在痴呆症患者中经常发生的混杂病变。因此，现在 探索/发展（​​R21）研究将通过表征和验证来解决上述科学差距 CVR用小鼠模型为VCID的生物标志物。应该注意的是，定量CVR技术尚未 由于血液动力学参数的测量和 在小动物中定量血管活性刺激。因此，该应用将首先进行系统 在小鼠中开发CVR MRI技术，然后在两种鼠标模型中应用该技术 小血管疾病（SVD）。这两个模型是互补的，因为一个是一个经典的遗传模型 脑常染色体显性动脉炎，具有下皮质梗塞和白细胞症（卡达西尔）和 另一种是基于环境的高型结晶血症（HHCY）小鼠的模型。这项研究有两个 具体目标。 AIM 1是在小鼠中开发CVR MRI技术。我们将衡量对 血管活性挑战，其大小将产生CVR的指数。用于选择血管活性 挑战，我们将使用注射乙唑酰胺作为血管舒张剂，血浆浓度 将被量化并用作输入函数。用于成像读数，包括全球和区域CVR方法 将使用先进的生理MRI技术开发。乙酰唑胺作用的剂量依赖性 也将研究。目的2是在SVD小鼠模型的纵向研究中表征CVR损伤。 我们将将CVR与多种组织学测量进行比较，包括用胶原蛋白染色的总血管密度 iv，用ACTA 2染色的血管平滑肌细胞密度，以及用染色的血管内皮蛋白 CD31。区域CVR研究将集中于皮层核，这是人类最易感区域 SVD。我们还将研究CVR的纵向时间过程，并将其与行为得分，大脑进行比较 体积和WM超强度。