Quantitative cerebral blood vessel imaging biomarkers for AD and VCID

项目概要/摘要 阿尔茨海默病（AD）和血管性认知障碍和痴呆（VCID）是阿尔茨海默病的两个主要原因。 认知能力下降和老年痴呆，两者都与脑血管疾病（CVD）有关。 尸检结果表明，潜在的血管病理类型不同，在AD和VCID。在AD中，A β 通常积聚在软脑膜和皮质小动脉中（称为脑淀粉样血管病（CAA））， 而在VCID中，动脉粥样硬化或小动脉硬化（ASCVD）影响大供血和小穿通 动脉（例如，纹状体动脉（LSA））。然而，为了使问题复杂化，混合AD/VCID 病理是常见的，特别是随着年龄的增长。迄今为止，血管病理学的研究， AD/VCID主要限于脑实质中血管性脑损伤的间接测量（例如，White 高信号物质、梗死和微出血），其缺乏对严重程度和类型的特异性。 潜在的血管病理学动脉僵硬度和动脉搏动性是血管的重要指标 功能障碍动脉僵硬度增加或动脉搏动性升高可导致过度的 脉动能量进入下游微血管，并导致内皮功能障碍和血管 炎症目前，这些评估主要在中央或主要脑动脉上进行。 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 脑血管使得难以提供跨受试者的可靠的定量形态学度量。 因此，直接评估脑血管的健康和功能状态（例如，动脉硬化， 搏动性和形态学）可以提供更全面的 了解AD/VCID中的血管病理学，并帮助鉴别CAA/ASCVD。这个目标 应用的目的是开发一类脑血管血液动力学和形态学度量， 描述AD和VCID中脑血管功能障碍的特征。AIM1将开发和验证定量 血液动力学和形态学血管度量（VM）， 处理脑血管树不同层次的算法流水线。Aim2将导出这些血管 在100例富含apoE基因型和心血管危险因素的老年受试者样本中，在aim中 2a，我们将VM与脑血流量、血管性脑损伤和认知障碍相关联。在目标2b中，我们 将使软脑膜动脉或纹状体动脉中的VM与淀粉样PET配体的摄取相关， 心血管风险特征，以确定特定部位VM的改变是否有助于区分CAA与 ASCVD。成功完成拟议的研究将提供一类可靠的脑血管 用于表征和区分AD/VCID中的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.