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，是全球25%的痴呆症的罪魁祸首（Wardlaw等人，2018）。尽管SVD是一种流行疾病，特别是在老龄化人群中，但其潜在的病理生理机制尚不清楚。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）大小有关，CVR大小衡量血管应对需求增加、血管硬化的能力（Shi等人，2020）和较高的血脑屏障（BBB）功能障碍（Wardlaw等人，2018）。然而，对CVR延迟在患者和其他血管功能障碍患者之间的差异的理解是非常有限的。我们可以使用血氧水平依赖（BOLD）磁共振成像（MRI）扫描在高碳酸气体挑战期间测量CVR的大小和延迟。然而，尽管CVR延迟因患者和组织类型而异（Sleight et al. 2023），但很少有研究解释CVR延迟，并且尚未对患者进行新的延迟/传递时间测量（Fitzgerald et al. 2023）。既往研究表明，在SVD中，CVR衰竭经历了不同的阶段，从轻度损害到局部组织灌注衰竭时的严重损害。CVR延迟的准确测量将提供更完整的血管健康图像，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和随时间的发展而变化。了解CVR延迟指标的变化将有助于通过脑血管功能障碍损伤对患者进行分层，并评估与疾病严重程度、预后和即将到来的治疗方法的关联（Wardlaw et al., 2018）。在这个项目中，我们将开发和评估新的延迟指标，以评估其在SVD患者中的临床相关性，根据疾病严重程度和与其他血管功能障碍的关联进行分层的能力。我们将利用来自高表型患者的几个大型现有数据集，包括轻度卒中研究3 (n=230)，具有长期结果和1年和3年随访数据，以及多中心横断面调查- svds （n=77）研究。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患者CVR延迟指标的差异2。研究基于mri和脉搏波速度的CVR延迟、血脑屏障功能障碍和血管硬度测量之间的关系3。评估基线和第3年随访期间疾病进展较大的患者CVR延迟指标的差异。实施和评估不同CVR延迟测量的可重复性参考文献1。张建平，张建平，张建平，等。小血管疾病的临床研究进展。柳叶刀神经杂志2019；18(7): 684 - 96.2。Shi Y, Thrippleton MJ, Blair GW，等。小血管疾病与脑血管搏动改变有关，但与静息脑血流量无关。[J]脑血流动力学杂志；40(1): 85 - 99.3。李建军，李建军，李建军，等。脑血管反应性测量使用3T BOLD MRI和固定吸入CO(2)气体挑战：处理策略的可重复性和影响。《前沿物理》2023；14: 1070233.4。Fitzgerald B, Yao JF, Hocke LM, Frederick BD, van Niftrik CHB, Tong Y.利用地毯图分析高碳挑战磁共振成像期间大脑血液传输时间。《前沿物理》2023；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.