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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是第二大原因美国的痴呆症。然而，与其他痴呆类型（例如淀粉样蛋白和 tau 蛋白成像）相比阿尔茨海默病），经验证的 VCID 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，称为脑血管反应性（CVR），是最重要的血管舒张能力之一。 VCID敏感指标。虽然人体研究对于证明 CVR 在临床中的实用性很重要在环境条件下，动物模型对于验证和表征这种新的生物标志物非常有价值。与适当的通过动物模型，我们可以阐明 CVR 与经典测量方法之间的机制联系小血管疾病的神经病理学特征，例如血管密度、血管平滑肌细胞和内皮细胞。此外，动物模型可以设计成具有相对纯粹的机制，因此避免混淆病理，这种情况经常发生在人类痴呆症患者身上。因此，目前探索性/发展性（R21）研究将通过表征和验证来解决上述科学差距 CVR 作为小鼠模型中 VCID 的生物标志物。应该指出的是，定量 CVR 技术尚未由于血流动力学参数的测量和小动物血管活性刺激的量化。因此，本应用首先会进行系统的在小鼠中开发 CVR MRI 技术，随后将该技术应用于两种小鼠模型小血管病（SVD）。这两个模型是互补的，其中一个是经典的遗传模型伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病 (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。本研究有两个具体目标。目标 1 是开发小鼠 CVR MRI 技术。我们将测量血流动力学反应血管活性挑战，其程度将产生 CVR 指数。对于血管活性药物的选择挑战中，我们将注射乙酰唑胺作为血管扩张剂，其血浆浓度将被量化并用作输入函数。对于成像读数，全局和区域 CVR 方法将使用先进的生理 MRI 技术进行开发。乙酰唑胺作用的剂量依赖性也将被研究。目标 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 与多种组织学指标，包括胶原蛋白染色的总血管密度 IV、Acta 2 染色的血管平滑肌细胞密度，以及 Acta 2 染色的血管内皮蛋白 CD31。区域 CVR 研究将重点关注皮质下核，这是人类最易受影响的区域 SVD。我们还将研究 CVR 的纵向时间进程，并将其与行为评分、大脑容量和 WM 高信号。