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

项目概要/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。在当前的临床环境中，CVR测量 需要在成像期间进行血管挑战，包括注射药理学试剂（例如， 乙酰唑胺）或吸入CO2气体。然而，这些策略在两个患者方面都不理想。 负担和成本，由于程序的复杂性，特殊设备的要求，以及可能的 诱导血管挑战生理操作的副作用。因此，开发CVR 不需要明确血管挑战的技术将扩大CVR在 诊断为VCI和血管性痴呆。 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，分别用于BOLD和CBF MRI采集（目标1）。第二，由于以前的工作， 基于气体的CVR表明，在受试者内和受试者之间CVR存在相当大的差异 我们将确定无气体CVR正常变化的生理机制，然后 对它们进行核算/控制，以减少差异（目标2）。最后，我们将应用无气体CVR 在有和没有血管危险因素的轻度认知障碍患者中， 无气体CVR作为诊断血管性认知障碍的潜在生物标志物的效用， 痴呆症（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 这将对理解血管疾病的神经生物学和 开发用于诊断和治疗的生物标志物（与其他生物标志物结合） 监测血管性认知障碍和痴呆。

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. In current clinical settings, 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, separately for BOLD and CBF MRI acquisitions (in Aim 1). Second, since previous work on gas-based CVR has suggested that there exist fairly large variations in CVR in both within and across subjects settings, 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). Finally, we will apply the gas-free CVR technique in patients with mild cognitive impairment with and without vascular risk factors, in order to examine the utility of gas-free CVR as a potential biomarker in the diagnosis of 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 understanding the neurobiology of vascular disease and for the development of biomarkers (in conjunction with other biomarkers) for the diagnosis and treatment monitoring of vascular cognitive impairment and dementia.