Oxygen extraction fraction in small vessel disease: relationship to disease burden and progression

Chronic hypoperfusion has been considered a major mechanism of cerebral small vessel disease. Nonetheless, brain tissue may increase oxygen extraction fraction to mitigate hypoxia and delay parenchymal damage. This study aims to investigate oxygen extraction fraction in cerebral small vessel disease and understand its relationship to disease burden and progression. We retrospectively included 195 patients with cerebral small vessel disease and 178 normal controls. Cerebral blood flow was measured by arterial spin labelling. Oxygen extraction fraction was estimated by quantitative susceptibility mapping plus quantitative blood oxygen-level dependence imaging. We compared baseline cerebral blood flow and oxygen extraction fraction in the whole white matter, normal-appearing white matter and white matter hyperintensities between the patient and control groups. Then, we studied whether cerebral blood flow and oxygen extraction fraction differed among patients with varying disease burdens. Longitudinally, we used linear mixed models to evaluate whether cerebral blood flow and oxygen extraction fraction could together predict the progression of white matter hyperintensities or free water (mean follow-up time = 2.6 years) in a subset of 47 patients. Compared to the control group, the patient group exhibited reduced cerebral blood flow in the whole white matter, normal-appearing white matter and white matter hyperintensities. Additionally, the oxygen extraction fraction increased in normal-appearing white matter but decreased in white matter hyperintensities. Notably, the white matter oxygen extraction fraction was elevated in patients with mild-to-moderate disease burden but decreased in those with the most severe disease burden. Longitudinal analyses revealed that adding oxygen extraction fraction measurements to cerebral blood flow measurements can improve the prediction of disease progression. Higher baseline values of cerebral blood flow and oxygen extraction fraction in the white matter were both linked to a slower increase in free water. In summary, oxygen extraction fraction exhibited an ‘increase-then-decrease’ pattern in patients with cerebral small vessel disease. Together, oxygen extraction fraction and cerebral blood flow can predict disease progression. Non-invasive MRI assessment of oxygen extraction fraction may provide valuable tools for future research on cerebral small vessel disease.