Determining cerebral small vessel function and flow in small vessel disease

小血管疾病(SVD)是中风的主要原因，并导致全球25%的痴呆症(Wardlaw等人，2018年)。虽然SVD是一种流行的疾病，特别是在老龄化人口中，但其潜在的病理生理学机制尚不清楚。血管损伤在患者中很常见：较高的SVD负担与较低的脑血管反应性(CVR)值有关，CVR值衡量的是血管对增加的需求做出反应的能力、更僵硬的血管(Ship等人，2020年)和更高的血脑屏障(BBB)功能障碍(Wardlaw等人，2018年)。然而，对CVR延迟如何在患者和其他血管功能障碍患者之间变化的了解是极其有限的。我们可以在高二氧化碳气体挑战期间使用血氧水平依赖(BOLD)磁共振成像(BOLD)扫描来测量CVR的幅度和延迟。然而，虽然CVR延迟在患者和组织类型之间有所不同(Sleight等人)。2023)，很少有研究说明CVR延迟，而且新的延迟/转运时间测量方法还没有在患者中进行评估(Fitzgerald等人。2023年)。先前的研究表明，CVR衰竭在SVD中经历了不同的阶段，从患者的轻度损害到局部组织灌注点的严重损害。准确测量CVR延迟将提供更完整的血管健康状况图，以更好地描述患者群体，以及疾病如何随着严重程度的增加而不同，并随着时间的推移而演变。了解CVR延迟指标的变化将有助于根据脑血管功能障碍的损害对患者进行分层，并评估与疾病严重程度、预后和即将到来的治疗的相关性(Wardlaw等人，2018年)。在这个项目中，我们将开发和评估新的延迟指标，以评估它们在SVD患者中的临床相关性、根据疾病严重程度分层的能力以及与其他血管功能障碍的相关性。我们将利用来自高表型患者的几个大型现有数据集，包括具有长期结果和1年和3年随访数据的轻度卒中研究3(n=230)，以及多中心横断面调查-SVDS研究(n=77)。本项目的主要目标是：1.评估不同SVD严重程度、预后和血管危险因素的患者的CVR延迟指标的变化。基于MRI和脉搏波速度研究CVR延迟、血脑屏障功能障碍和血管僵硬之间的相关性。评估在基线和3年随访期间疾病进展较快的患者的CVR延迟指标有何不同。实施和评估不同CVR延迟测量的重复性参考1.Wardlaw JM，Smith C，Dichgans M.小血管疾病：机制和临床意义。《柳叶刀神经》2019；18(7)：684-96.2.石勇，Thripleton MJ，Blair GW，等.小血管疾病与脑血管搏动性改变有关，但与静息脑血流无关。《大脑血流动力学杂志》2020；40(1)：85-99.3。使用3T BOLD MRI和固定吸入CO(2)气体挑战测量脑血管反应性：处理策略的重复性和影响。Forward Physiol 2023；14：1070233.4。Fitzgerald B，姚俊芬，Hocke LM，Frederick BD，van Niftrik CHB，童勇。使用地毯图分析高碳酸血症挑战磁共振成像期间血液在大脑中的传输时间。《生理前线》2023年；14：1134804。

Small vessel disease (SVD) is a leading cause of stroke and is responsible for 25% of dementias worldwide (Wardlaw et al., 2018). Though a prevalent disease, particularly in ageing populations, the underlying pathophysiology of SVD is poorly understood. Vascular impairment is common in patients: a higher SVD burden is linked to a lower cerebrovascular reactivity (CVR) magnitude, which measures the capacity of blood vessels to respond to increased demand, stiffer blood vessels (Shi et al., 2020) and higher blood-brain barrier (BBB) dysfunction (Wardlaw et al., 2018). However, understanding of how CVR delay varies between patients and with other vascular dysfunctions is extremely limited.We can measure CVR magnitude and delay using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) scans during hypercapnic gas challenge. However, while CVR delay varies between patients and tissue types (Sleight et al. 2023), few studies account for CVR delay and novel delay/transit time measures have not been assessed in patients (Fitzgerald et al. 2023). Previous studies have shown that CVR failure moves through different stages in SVD, ranging from mild impairment through to critical impairment in patients at the point of local tissue perfusion failure. Accurate measurement of CVR delay will give a more complete picture of vascular health to better characterise patient populations and how disease differs with increasing severity and evolves over time. Understanding how CVR delay metrics vary will aid patient stratification by impairment in cerebrovascular dysfunction, and assessing associations with disease severity, prognosis and therapies on the imminent horizon (Wardlaw et al., 2018).In this project we will develop and evaluate novel delay metrics to assess their clinical relevance in SVD patients, ability to stratify by disease severity and associations with other vascular dysfunctions. We will draw on several large, existing datasets from highly phenotyped patients including the Mild Stroke Study 3 (n=230), with long term outcomes and follow-up data at 1- and 3-years, and the multicentre cross-sectional Investigate-SVDs (n=77) study. The key aims of this project are:1. Assess how CVR delay metrics vary in patients with differing SVD severity, prognosis and vascular risk factors2. Investigate associations between measures of CVR delay, BBB dysfunction and vascular stiffness based on MRI-based and pulse wave velocity3. Evaluate how CVR delay metrics differ in patients with greater disease progression between baseline and year 3 follow-up4. Implement and evaluate repeatability of different CVR delay measuresReferences1.Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019; 18(7): 684-96.2.Shi Y, Thrippleton MJ, Blair GW, et al. Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow. J Cereb Blood Flow Metab 2020; 40(1): 85-99.3.Sleight E, Stringer MS, Mitchell I, et al. Cerebrovascular reactivity measurements using 3T BOLD MRI and a fixed inhaled CO(2) gas challenge: Repeatability and impact of processing strategy. Front Physiol 2023; 14: 1070233.4.Fitzgerald B, Yao JF, Hocke LM, Frederick BD, van Niftrik CHB, Tong Y. Using carpet plots to analyze blood transit times in the brain during hypercapnic challenge magnetic resonance imaging. Front Physiol 2023; 14: 1134804.