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

阿尔茨海默病和小血管疾病小鼠模型低灌注的病理生理机制

• 批准号: 10657993
• 负责人: Zhiliang Wei
• 金额: $ 55.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657993
• 关键词: Age; Air; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloidosis; Anatomy; Animal Disease Models; Arterial Disorder; Behavior; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood specimen; Brain; Cell Density; Cerebrovascular Circulation; Cerebrum; Clinical Trials; Cognitive; Cognitive deficits; Contrast Media; Coupling; Cross-Sectional Studies; Data; Dementia; Disease model; Enzyme-Linked Immunosorbent Assay; Euthanasia; Funding; Genetic; Goals; Histologic; Histology; Human; Hypercapnia; Image; Imaging Techniques; Immunohistochemistry; Impaired cognition; Interleukin-6; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Memory; Metabolic; Metabolism; Methods; Microvascular Dysfunction; Modeling; Mus; Nature; Neurofibrillary Tangles; Oxygen; Participant; Pathology; Pattern; Perfusion; Physiological; Physiology; Positioning Attribute; Proteins; Reporting; Reproducibility of Results; Research; Research Design; Research Personnel; Senile Plaques; Severities; Smooth Muscle Myocytes; Subcortical Infarctions; Subcortical Leukoencephalopathy; Symptoms; TNF gene; Tauopathies; Techniques; Testing; Therapeutic; Thinness; Tight Junctions; Time; United States National Institutes of Health; Vascular Smooth Muscle; Wild Type Mouse; Work; autosome; behavior test; behavioral outcome; blood-brain barrier permeabilization; brain metabolism; candidate marker; cerebrovascular; cingulate cortex; cognitive function; cohort; cranium; density; fluorodeoxyglucose positron emission tomography; glucose metabolism; hypoperfusion; imaging study; in vivo; indexing; inflammatory marker; metabolic rate; mouse model; novel; object recognition; optical imaging; processing speed; vascular cognitive impairment and dementia

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.

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（CBF）的严重程度与认知缺陷的严重程度相关。 低灌注只是 ADRD 微血管功能障碍的症状之一，事实上，可能不是最重要的症状 例如，最近由 NIH 资助的 MarkVCID 联盟研究确定了 CBF 是血管对认知障碍和痴呆 (VCID) 最敏感的生物标志物 未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， 尽管观察结果被广泛报道，但在 AD 中仍选择了称为脑血管反应性 (CVR) 的药物。 后扣带皮层和颞顶叶区域存在灌注不足，一些人提出这是 通过代谢-血管耦合对代谢异常产生间接影响。 显然要了解 ADRD 中低灌注的机制，我们需要超越灌注来了解 ADRD 的低灌注机制。 检查大脑中一系列相关的血管和代谢参数。 因此，该应用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，因为它们代表了痴呆症的两个主要原因，而且最显着的是 与灌注不足有关的小鼠模型研究将与我们正在进行的人类研究相平行。 参与者，使这项工作具有很强的转化相关性，我们将使用新颖的 MRI 技术。 测量 CBF、脑血管反应性、氧提取分数、脑氧代谢率，以及 BBB 渗透性同时发生，并将其与行为（例如新物体识别）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）。 集成到机械模型中，该模型可以根据所提出的实验措施进行完全测试。 PI 是一名早期研究者，在开展这项工作方面处于独特的地位，因为他开创了 过去几年中，一些 MRI 技术在小鼠身上进行了研究。 （例如不需要颅骨变薄或造影剂）也使它们非常适合纵向研究 （目标 2），这将允许描述灌注不足（以及相关的 血管/代谢参数）和行为结果的两种新型 Tau4RΔK-AP 小鼠模型（复制） 将利用 tau 蛋白病和 AD 淀粉样变性）和 CADASIL（复制 SVD 血管病理学），基于 根据我们合作者最近的发现，我们处于一个独特的位置来创造意义。 对理解 ADRD 低灌注的贡献。