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Cerebral oxygen extraction fraction (OEF): comparison of challenge-free gradient echo QSM+qBOLD (QQ) with 15O PET in healthy adults1Weill Cornell Medicine, New York, NY, United States, 2Washington University School of Medicine, Saint Louis, MO, United States, 3Banner Alzheimers Institute, Phoenix, AZ, United States
Synopsis
Cerebral oxygen extraction fraction (OEF) maps are critical to investigate salvageable tissue in ischemic stroke. We compare OEF maps obtained using quantitative susceptibility mapping plus quantitative blood oxygen level-dependent modeling (QSM+qBOLD=QQ) with the reference standard OEF maps obtained using 15O PET in 10 healthy adults. The whole brain and regional average OEF values were found to be substantially equivalent between the two methods, e.g. 32.8 ± 6.7 % on PET and 34.2 ± 2.6 % on QQ (p=0.002, TOST) for whole brain average. QQ estimates OEF maps from a single routine MRI sequence without burdensome gas inhalation or respiratory-control procedures.
Introduction
Quantitative mapping of oxygen extraction fraction (OEF) is essential for investigating investigating salvageable tissue and irreversibly damaged core in stroke1-4 and neurologic diseases5,6. Positron emission tomography (PET) with 15O tracers is the current reference standard2, 7-16, but it has not been used in clinical practice because of the need to produce the 15O tracers with 122-second half-lives by a cyclotron within the PET facility8, the cumbersome tracer administration, the complex data processing, and the significant cost.In contrast, MRI is widely available and, recently, a promising comprehensive method using both phase and magnitude signal (QSM+qBOLD, or QQ)17, 18 was introduced to map OEF from multi-echo gradient (mGRE) data alone without burdensome vascular challenges. The purpose of this study is to validate QQ-OEF against the reference standard 15O PET-OEF in healthy adults, which is among the first efforts in MRI based OEF mapping validation.
Method
Data acquisitionQQ was compared with PET in 10 healthy subjects on a PET/MR system (Siemens Biograph 3T mMR). PET data was acquired with sequential administrations of C[15O], O[15O], H2[15O], C[15O], O[15O], and H2[15O]. During PET, MRI was acquired simultaneously. Time-of-flight MR angiography (TOF-MRA) was acquired for image-derived arterial input function (IDAIF): TR=22ms, TE=3.94ms, flip angle = 18º, and voxel size=0.57×0.57×0.70 mm3. During O[15O] PET data acquisition, a mGRE was acquired using TR= 33 ms, TE1/ΔTE/TE10 = 4.7/2.5/28.4 ms, flip angle 15º, bandwidth=465 Hz/pixel, voxel size =0.94×0.94×3 mm3. The mGRE acquisition was repeated to investigate repeatability.
Data processing
QQ-OEF: The QQ model estimates OEF based on the venous deoxyheme-dependent signal in mGRE signal phase using QSM and signal magnitude using qBOLD17, 18. The QSM modeling considers that voxel-wise susceptibility (estimated by MEDI toolbox19-24) is the sum of three susceptibility components: non-blood tissue ($$$\chi_{nb}$$$), plasma, and the hemoglobin (a function of venous oxygenation, $$$Y$$$, and volume, $$$v$$$)25-27. The qBOLD models the mGRE magnitude signal decay by the field contribution within a voxel by the susceptibility difference between blood and surrounding tissue (a function of $$$v$$$, $$$Y$$$, and $$$\chi_{nb}$$$)28, 29. As the QSM and qBOLD commonly have $$$v$$$, $$$Y$$$, and $$$\chi_{nb}$$$, OEF (=$$$1-Y/Y_{a}$$$ where $$$Y_{a}$$$: arteriole oxygenation) can be estimated by the combined model of QSM+qBOLD (QQ). For robust OEF reconstruction against noise, cluster analysis of time evolution (CAT) was used18.
15O PET-OEF: PET-OEF was estimated using two compartmental tracer kinetic modeling8 and IDAIF based on the PET/MR hybrid scanner approach30. Using the tracer kinetic modeling with time-activity curves (TACs), CBF and CBV were estimated from the 15O-water scans9, 31 and 15O-carbon monoxide scans32, respectively. OEF was finally estimated from the 15O-oxygen scans in conjunction with calculated CBF and CBV images33. The linearized version of the original CBF and OEF model was used to avoid performing model fitting with noisy TACs30.
ROI analysis
Comparisons between QQ-OEF and PET-OEF were performed using Bland-Altman (BA) plots, box plots, and Two One-Sided Tests (TOST) for substantial equivalence in the whole brain and regional ROIs: cortical gray matter (CGM), frontal, temporal, parietal, and occipital lobe of CGM, white matter (WM), and deep gray matter (DGM) regions (Thalamus, Caudate, Putamen, and Pallidum). For TOST, the limit of the equivalence interval (Δ) w as set to the maximum scan-rescan difference within each method.
Results
Example OEF maps are shown in Fig. 1. Whole brain OEF was 32.8 ± 6.7 % on PET and 34.2 ± 2.6 % on QQ (p=0.002, TOST), and the corresponding Bland-Altman plot is shown in Figure 2C. ROI based OEF values for PET and QQ were: 34.4 ± 7.0% vs. 32.5 ± 2.4% (p=0.003, TOST) for CGM, 32.2 ± 6.8 vs. 35.7 ± 3.0% (p=0.01, TOST) for WM, and 32.0 ± 5.9 vs. 35.1 ± 2.7% (p=0.001, TOST) for Thalamus. The corresponding box plots are shown in Figure 3, and Bland-Altman plots in Figure 4. Compared to PET-OEF, QQ-OEF showed smaller inter-subject variation, e.g. average coefficient of variation (COV) in whole brain=7.6% for QQ vs 20.5% for PET (Figs. 2, 3, and 4).Discussion
Both PET and QQ showed fairly uniform OEF maps over the brain (Fig. 1), which is in line with previous PET and MRI studies8, 10, 28, 35, 36. Global and CGM OEF values estimated with the two methods were substantially equivalent and agree with prior OEF values obtained from PET, e.g. 35 ± 7 % to 40 ± 9 %10, 16, 36, 3, from calibrated BOLD, e.g. 35 ± 4 % to 44 ± 14 %38-45, and from QSM, e.g. 29 ± 3 % to 50 ± 5 %15, 17, 18, 25, 26, 38, 46, 47. The PET inter-subject COV (20.5%) is consistent with previous PET studies10, 16, 17, which might arise from physiologic reason or various complexities in PET data acquisition and processing, such as the dependency of PET-OEF estimation on CBF and CBV from two independent PET scans with different tracers8, 11 and the sensitivity of IDAIF to PET-MRI registration uncertainty17.Conclusion
In healthy adults, the QQ model generates whole brain and regional OEF estimates that agree with the current gold standard 15O PET OEF estimation. The noninvasive, challenge-free, gradient echo MRI based QQ OEF mapping is ready for further evaluation in patients with regional OEF abnormalities.Acknowledgements
No acknowledgement found.References
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