Quantitative cerebral blood vessel imaging biomarkers for AD and VCID

项目摘要/摘要 阿尔茨海默病(AD)和血管认知障碍和痴呆(VCID)是导致 老年人的认知能力下降和痴呆，两者都与脑血管疾病(CVD)有关。 尸检结果显示，AD和VCID的潜在血管病理类型不同。在AD中，Aβ 通常聚集在软脑膜和皮质小动脉(称为脑淀粉样血管病(CAA))， 而在VCID中，动脉粥样硬化或动脉硬化(ASCVD)影响大进食和小穿孔 动脉(例如豆纹动脉(LSA))。然而，更复杂的是，AD/VCID混合在一起 病理是很常见的，特别是随着年龄的增长。到目前为止，中国的血管病理学研究 AD/VCID主要限于间接测量脑实质中的血管脑损伤(例如，白色 物质高信号、脑梗塞和微出血)，对其严重程度和类型缺乏特异性 潜在的血管病理。动脉僵硬和动脉搏动是血管的重要指标 功能障碍。动脉僵硬增加或动脉搏动性增强可导致过度 脉动能量进入下游微血管系统，并导致内皮功能障碍和血管 发炎。目前，这些评估大多在中央或主要大脑动脉进行。 脑血管形态也反映了脑血管的健康状况，但脑血管分支的个体差异 脑血管使得在受试者之间提供可靠的定量形态指标变得困难。 因此，直接评估脑血管的健康和功能状态(例如，动脉僵硬， 脉动和形态)可以在不同水平的脑血管树上提供更全面的 了解AD/VCID的血管病理，有助于鉴别CAA/ASCVD。这样做的目的是 应用是开发一类脑血管血流动力学和形态指标，并对 AD和VCID患者脑血管功能障碍的特征。AIM1将开发和验证量化 血流动力学和形态血管指标(Vm)使用先进的MRI技术和新的图像- 在不同层次的脑血管树上处理算法流水线。AIM2将衍生出这些血管 在100名老年受试者样本中，载脂蛋白E基因和心血管危险因素指标丰富。在AIM ，我们将把VM与脑血流量、血管性脑损伤和认知障碍联系起来。在目标2b中，我们 将软脑膜动脉或豆纹动脉的Vm与摄取淀粉样蛋白PET配体和 心血管风险概况，以确定特定部位VM的改变是否有助于区分CAA和 ASCVD。拟议研究的成功完成将提供一类可靠的脑血管 鉴定和鉴别AD/VCID血管病理的生物标志物。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) and Vascular Cognitive Impairment and Dementia (VCID) are two leading causes of cognitive decline and dementia in the elderly and are both associated with cerebrovascular disease (CVD). Postmortem findings show that the underlying type of vascular pathology differs in AD and VCID. In AD, Aβ often accumulates in leptomeningeal and cortical arterioles (known as cerebral amyloid angiopathy (CAA)), while in VCID, atherosclerosis or arteriolosclerosis (ASCVD) affects large feeding and small perforating arteries (e.g., lenticulostriate arteries (LSA)), respectively. However, to complicate matters, mixed AD/VCID pathologies are common, especially with increasing age. To date, the investigations of vascular pathology in AD/VCID are mainly limited to indirect measures of vascular brain injury in brain parenchyma (e.g., white matter hyperintensity, infarcts, and microbleeds), which lack specificity vis a vis the severity and type of underlying vascular pathology. Arterial stiffness and arterial pulsatility are important indicators of blood vessel dysfunction. Increased arterial stiffness or elevated arterial pulsatility can result in transmission of excessive pulsatile energy into downstream microvasculature, and lead to endothelial dysfunction and vascular inflammation. Currently, these assessments are mostly carried out on central or major cerebral arteries. Cerebral vascular morphology also reflects the health of brain vessels, but individual variation in branching of cerebral vessels has made it difficult to provide reliable quantitative morphological metrics across subjects. Therefore, directly assessing the health and functional status of cerebral blood vessels (e.g., arterial stiffness, pulsatility, and morphology) at various levels of the cerebral vascular tree could provide a more comprehensive understanding of the vascular pathology in AD/VCID and help differentiate CAA/ASCVD. The goal of this application is to develop a class of cerebral blood vessel hemodynamic and morphological metrics and to characterize cerebral blood vessel dysfunction in AD and VCID. Aim1 will develop and validate quantitative hemodynamic and morphological vascular metrics (VM) using advanced MRI technologies and novel image- processing algorithm pipelines at different levels of cerebrovascular tree. Aim2 will derive these vascular metrics in a sample of 100 elderly subjects enriched for apoE genotype and cardiovascular risk factors. In Aim 2a, we will correlate VM with cerebral blood flow, vascular brain injury, and cognitive impairment. In Aim 2b, we will correlate VM in leptomeningeal arteries or lenticulostriate arteries with uptake of amyloid PET ligands and cardiovascular risk profile to determine whether alterations in site-specific VM can help differentiate CAA vs. ASCVD. Successful completion of the proposed research would deliver a class of reliable cerebral vascular biomarkers to characterize and differentiate vascular pathology in AD/VCID.