Elevated brain oxygen extraction fraction measured by MRI susceptibility relates to perfusion status in acute ischemic stroke

Abstract

Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3 ± 3.4%) versus the contralateral hemisphere (25.5 ± 3.1%) of patients with large diffusion-perfusion lesion mismatch (P = 0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI (P = 0.004), suggesting compensation for reduced flow. Patients with perfusion-diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2 ± 0.1 at baseline that normalized (decreased) to 1.0 ± 0.1 at follow-up three days later (P = 0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time. Clinical trial registration: Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; clinicaltrials.org :NCT02077582.

Keywords: Acute ischemic stroke; MRI; oxygen extraction fraction; penumbra; quantitative susceptibility mapping.

Figures

Figure 1.

Susceptibility-weighted magnitude, reconstructed quantitative susceptibility map (QSM), and reformatted, post-contrast T1-weighted MRI in an 86-year-old female patient with right middle cerebral artery (MCA) occlusion. Bright signal on the QSM map corresponded to venous vasculature observed on the post-contrast T1 MRI. Cortical vessels (green arrows) were identified for OEF quantification from magnetic susceptibility values.

Figure 2.

Boxplots of absolute oxygen extraction fraction OEF (%) values in the infarcted and contralateral hemispheres of stroke patient groups with different perfusion status. Hypo-perfusion was defined with a threshold of greater than 6 s on mean transit times (MTT) maps from dynamic susceptibility contrast MRI. Patients with large perfusion–diffusion mismatch volume showed pathological OEF elevation compared to the contralateral hemisphere (corrected P = 0.025), but this was not observed in patients with perfusion–diffusion match or no hypo-perfusion.

Figure 3.

(a) Longitudinal oxygen extraction fraction (OEF) imaging in a 66-year-old female patient with right M1 occlusion. The baseline quantitative susceptibility map (QSM) shows ∼20% OEF increase within the mismatch area between perfusion (red outline) and diffusion (blue) lesions, relative to the contralateral hemisphere. This OEF pathophysiology was also observed in the same vein on the follow-up QSM scan, consistent with lack of recanalization and persistent occlusion at discharge in this patient. (b) Ratio of OEF in ischemic to contralateral hemisphere in nine stroke patients who received baseline and follow-up MRI a median of three days after the initial scan. The OEF ratio decreased (normalized) over time (P = 0.03), and dotted lines indicate patients who received thrombolysis.

Figure 4.

Scatter plot between oxygen extraction fraction (OEF) from quantitative susceptibility mapping with relative cerebral blood flow (CBF) from dynamic susceptibility contrast on the baseline MRI. Each data point represents one vein and its corresponding perfusion region of interest from stroke patients classified with large perfusion–diffusion mismatch. In these patients, the linear mixed model revealed a significant inverse relationship between absolute OEF and relative CBF (P = 0.002), as well as between relative OEF and relative CBF (P = 0.010).

Figure 5.

Relative OEF and CBF profiles in the ischemic hemisphere, plotted against distance from the diffusion lesion in four stroke patients at baseline. OEF measurements were normalized to the mean OEF in the contralateral hemisphere of the same individual. Polynomial fit of the physiological profiles and standard deviation (dotted lines) are overlaid onto observed data points. (a, b) In patients with large perfusion–diffusion mismatch volume, OEF was elevated adjacent to the diffusion lesion, corresponding to reduced relative perfusion. This pathophysiology was not observed distal to the lesion. There was a significant relationship between OEF and distance in patients with large mismatch (P < 0.0001). Patient B did not receive follow-up MRI, so percent growth in the diffusion lesion is not displayed. (c, d) On the other hand, in patients with perfusion–diffusion match, the OEF profiles were relatively uniform across distance from the diffusion lesion, with values less than or equal to 1. These patients tended to have minimal growth of the diffusion lesion (−68%, 25% growth respectively) on the follow-up scan.