Determining cerebral small vessel function and flow in small vessel disease

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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.