Gas-free cerebrovascular reactivity (CVR) MRI in vascular cognitive impairment

项目总结/摘要 血管性认知障碍（VCI）是继阿尔茨海默病之后的第二大痴呆病因 （AD）。然而，虽然AD生物标志物相对较好地开发，但脑中VCI病理学的生物标志物 更加有限。脑血管反应性（CVR），反映脑血管扩张能力的指标 是一个很有前途的大脑血管功能的标志。我们的首要假设是，CVR是 一种用于诊断VCI的合理生物标志物，目前没有其他生物标志物可用于VCI。 尽管有一些承诺，但CVR在临床实践中并不常见，主要是由于后勤方面的原因。 在成像期间应用血管“挑战”的困难。目前的CVR测量需要血管 成像期间激发，包括注射药理学试剂（例如乙酰唑胺）或 吸入二氧化碳气体。然而，这些策略在患者负担和成本方面并不理想， 由于手术的复杂性、特殊设备的要求以及生理学上可能的副作用， 操纵以诱导血管激发。因此，开发不需要人工神经网络的CVR技术， 明确的血管激发将扩大CVR在诊断VCI和血管性痴呆中的临床应用。 该项目的中心目标是开发一种无气体CVR MRI技术， 对CO2吸入CVR的敏感性仍然保持受试者的高舒适度。这项新技术是 主要基于静息状态扫描并利用受试者呼吸模式中的自发波动， 而且还引入了他们呼吸节律的间歇性调节， CO2（EtCO2）。该项目分为三个逻辑步骤。首先，我们将开发无气体CVR技术 在健康受试者中，用于BOLD和CBF读数及其整合（目标1）。第二，由于此前 关于气基CVR的研究工作表明，CVR数据中的很大一部分（约2/3）变化可以归因于 对于生理噪声，我们将确定无气体CVR正常变化的生理机制， 然后对它们进行说明/控制，以减少变化（目标2）。我们将重点关注两个最重要的 影响血管张力的重要因素，在日常生活中，二氧化碳和咖啡因水平，但也将考虑其他 生理因素。最后，我们将无气体CVR技术应用于轻度认知障碍患者， 有无血管危险因素的损伤，并将其诊断灵敏度与已建立的 以CSF Aβ42的痴呆生物标志物为基准，以检查无气体CVR作为痴呆生物标志物的效用。 血管性认知障碍和痴呆的潜在生物标志物（目标3）。 影响：一旦这些特定目标实现，临床实用的CVR方法将成为 开发的生物标志物的开发将具有重要的应用（与其他生物标志物一起）。 生物标志物）用于血管性认知障碍和痴呆的诊断和治疗监测。

Project Summary/Abstract Vascular cognitive impairment (VCI) is the second leading cause of dementia after Alzheimer’s disease (AD). However, while AD biomarkers are relatively well developed, biomarkers for VCI pathology in the brain are more limited. Cerebrovascular reactivity (CVR), an index of cerebral vessel’s capacity to dilate in response to stimulation, is a promising marker of the brain’s vascular function. Our overarching hypothesis is that CVR is a plausible biomarker for the diagnosis of VCI, for which no other biomarkers are currently available. Despite some promises, CVR is not commonly measured in clinical practice, primarily due to logistical difficulties in applying a vascular “challenge” during imaging. Current CVR measurement requires a vascular challenge during imaging, involving either the injection of pharmacological agent (e.g. acetazolamide) or inhalation of CO2 gas. However, these strategies are not ideal in terms of both patient burden and costs, due to the complexity of the procedure, requirement of special equipment, and possible side-effect of physiological maneuver to induce vascular challenge. Therefore, development of a CVR technique that does not need an explicit vascular challenge will broaden the clinical utility of CVR in the diagnosis of VCI and vascular dementia. The central goal of this project is to develop a gas-free CVR MRI technique that can provide comparable sensitivity to CO2-inhalation CVR yet maintains a high comfort level to the subjects. This new technique is largely based on resting-state scan and exploits spontaneous fluctuations in the subject’s breathing pattern, but also introduces intermittent modulations of their breathing rhythm to enhance fluctuations in their end-tidal CO2 (EtCO2). This project is divided into three logical steps. First, we will develop the gas-free CVR technique in healthy subjects, for BOLD and CBF readouts as well as their integration (in Aim 1). Second, since previous work on gas-based CVR has suggested that a large portion (~2/3) of variations in CVR data can be attributed to physiological noise, we will identify physiological mechanism(s) of normal variations in gas-free CVR and then account/control for them in order to reduce variations (in Aim 2). We will focus on two of the most important factors that affect vascular tone in daily life, CO2 and caffeine levels, but will also consider other physiological factors. Finally, we will apply the gas-free CVR technique in patients with mild cognitive impairment with and without vascular risk factors, and compare its diagnostic sensitivity to an established dementia biomarker of CSF Aβ42 as a benchmark, in order to examine the utility of gas-free CVR as a potential biomarker in vascular cognitive impairment and dementia (in Aim 3). Impact: Once these specific aims are accomplished, clinically practical methods of CVR will have been developed that will have important applications for the development of biomarkers (in conjunction with other biomarkers) for the diagnosis and treatment monitoring of vascular cognitive impairment and dementia.