Imaging Microvascular Hemodynamics In Older Adults With Varying Genetic Risk For Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）目前影响着560万65岁及以上的美国人，预计 到2050年增加到1380万。β-淀粉样蛋白斑块和神经纤维缠结是AD的特征 病理学，但白色病变（WML）指示脑小血管疾病也已被证明， 是AD患者认知能力下降的独立因素。具有载脂蛋白ε4等位基因 E基因（APOE）被认为是晚发性AD最强的危险因素。此外，APOE-ε4还 是脑血管疾病的主要危险因素，已知APOE-ε4携带者表现出更大的 与非携带者相比，WML的负担和进展更快。然而，生理机制 通过APOE-ε4导致组织缺氧，这些损伤的形成仍然不完全 明白本研究的总体目标是阐明APOE-1和APOE-2之间微血管生理学的差异。 ε4携带者和非携带者，这可能表明APOE-ε4的病理作用的潜在机制， 血管功能这种血流动力学损害可能是由与异常的血流动力学相关的机制引起的。 组织灌注然而，先前的研究已经检查了APOE-ε4对脑灌注的影响， 报道了关于APOE-ε4携带者与非携带者的灌注是否减少或升高的相互矛盾的结果， 表明血流量的差异本身可能不能完全解释血液动力学损害的程度。 血流动力学损害也可能是由于从脉管系统到组织的氧气交换效率低下所致 由于在毛细管水平上的流动扰动，这在以前已经被证明与不均匀性有关 毛细流动模式。最近，我们的特点是静脉高信号（VHS）的脑血 使用动脉自旋标记磁共振成像（MRI）作为标记物采集的血流（CBF）加权图像 毛细水平流动扰动和氧气交换效率低下。在这项工作中，我们建议应用 非侵入性MRI方法和这种新的结构，以阐明组织水平血流动力学之间的关联， 老年APOE-ε4携带者和非携带者的生理学和WML负荷。具体而言，我们将（i）研究 微血管血流紊乱对氧交换效率的影响，（ii）研究 根据APOE基因型，微血管功能障碍和CBF，和（iii）确定相关性的差异 APOE-ε4携带者和非携带者之间的微血管生理学和WML负荷之间的关系。成功 这项工作的完成将确定在多大程度上观察到的较高负担的WML在老年人 与APOE-ε4相关的机制涉及氧交换效率低下，这是由 VHS对比受损的CBF。这些发现可能对不同治疗药物的滴定有影响。 预防有与无APOE-ε4老年人血管相关认知功能下降的方法

PROJECT SUMMARY Alzheimer’s disease (AD) currently affects 5.6 million Americans aged 65 years and older, with a projected increase to 13.8 million by 2050. Beta-amyloid plaques and neurofibrillary tangles are characteristic of AD pathology, but white matter lesions (WMLs) indicative of cerebral small vessel disease have also been shown to be an independent contributor to cognitive decline in AD patients. Possession of an ε4 allele of the apolipoprotein E gene (APOE) is considered the strongest risk factor for developing late-onset AD. In addition, APOE-ε4 also represents a major risk factor for cerebrovascular disease, and APOE-ε4 carriers are known to exhibit a greater burden and faster progression of WMLs compared with non-carriers. However, the physiological mechanisms through which APOE-ε4 leads to tissue hypoxia and the formation of these lesions remain incompletely understood. The overall goal of this study is to elucidate differences in microvascular physiology between APOE- ε4 carriers and non-carriers that may indicate potential mechanisms for the pathological effects of APOE-ε4 on vascular function. Such hemodynamic impairment could be caused by mechanisms associated with abnormal tissue perfusion. However, prior studies that have examined effects of APOE-ε4 on cerebral perfusion have reported conflicting results on whether perfusion is reduced or elevated APOE-ε4 carriers versus non-carriers, indicating that differences in blood flow alone may not fully explain the extent of hemodynamic compromise. Hemodynamic impairment may also result from inefficiencies in oxygen exchange from vasculature into tissue due to flow disturbances at the capillary level, which have previously been shown to be related to heterogeneities in capillary flow patterns. Recently, we have characterized venous hyperintense signal (VHS) on cerebral blood flow (CBF)-weighted images acquired using arterial spin labeling magnetic resonance imaging (MRI) as a marker of capillary-level flow disturbances and oxygen exchange inefficiency. In this work, we propose to apply noninvasive MRI methods and this novel construct to elucidate associations between tissue-level hemodynamic physiology and WML burden in older APOE-ε4 carriers and non-carriers. Specifically, we will (i) study the effect of microvascular flow disturbances on oxygen exchange efficiency, (ii) investigate the association between microvascular dysfunction and CBF according to APOE genotype, and (iii) identify differences in associations between microvascular physiology and WML burden between APOE-ε4 carriers and non-carriers. Successful completion of this work will determine the degree to which the observed higher burden of WMLs in older adults with APOE-ε4 is associated with mechanisms involving oxygen exchange inefficiency, which are indicated by VHS, versus impaired CBF. These findings could have implications for the titration of different therapeutic approaches for preventing vascular-related cognitive decline in older adults with versus without APOE-ε4.