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

项目摘要/摘要 血管认知障碍(VCI)是继阿尔茨海默病之后导致痴呆的第二大原因 (Ad)。然而，虽然AD生物标记物相对发达，但大脑中VCI病理的生物标记物 是更有限的。脑血管反应性(CVR)，脑血管扩张能力的指标 对刺激来说，是一个很有希望的大脑血管功能的标志。我们的主要假设是CVR是 一个看似合理的VCI诊断生物标记物，目前还没有其他生物标记物可用。 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 在成像过程中应用血管“挑战”的困难。目前的CVR测量需要血管 成像过程中的挑战，包括注射药剂(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都不理想 针对手术过程的复杂性，对特殊设备的要求，以及生理治疗可能产生的副作用 动作以诱导血管挑战。因此，CVR技术的开发不需要 明确的血管挑战将扩大CVR在诊断VCI和血管性痴呆方面的临床应用。 该项目的中心目标是开发一种无气体的CVR MRI技术，该技术可以提供类似的 对吸入二氧化碳的CVR的敏感性仍然保持了对受试者的高舒适性。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的自发波动， 而且还对它们的呼吸节律进行了间歇性的调制，以增强其潮气末的波动 二氧化碳(ETCO2)。该项目分为三个合乎逻辑的步骤。首先，我们将开发无气体CVR技术 对于健康受试者，用于BOLD和CBF读数以及它们的整合(在目标1中)。第二，自上一次 对基于气体的CVR的研究表明，CVR数据的很大一部分(~2/3)变化可以归因于 对于生理噪声，我们将识别无气体CVR正常变化的生理机制(S)和 然后对它们进行核算/控制，以减少差异(目标2)。我们将重点关注两个最重要的 影响日常生活中血管张力、二氧化碳和咖啡因水平的重要因素，但也会考虑其他 生理因素。最后，我们将在轻度认知障碍患者中应用无气体CVR技术。 有和没有血管危险因素的损害，并将其诊断敏感性与已建立的 以脑脊液Aβ42作为痴呆生物标记物，以考察无气体CVR作为 血管性认知障碍和痴呆的潜在生物标记物(目标3)。 影响：一旦这些特定的目标实现，CVR的临床实用方法将被 开发的将对开发生物标记物具有重要应用的(与其他 生物标志物)，用于诊断和治疗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. 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.