Whole-brain Oxygen Extraction Fraction Research Articles

Test-retest analysis of cerebral oxygen extraction estimates in healthy volunteers: comparison of methods based on quantitative susceptibility mapping and dynamic susceptibility contrast magnetic resonance imaging

BackgroundEstimation of the oxygen extraction fraction (OEF) by quantitative susceptibility mapping (QSM) magnetic resonance imaging (MRI) is promising but requires systematic evaluation. Extraction of OEF-related information from the tissue residue function in dynamic susceptibility contrast MRI (DSC-MRI) has also been proposed. In this study, whole-brain OEF repeatability was investigated, as well as the relationships between QSM-based OEF and DSC-MRI-based parameters, i.e., mean transit time (MTT) and an oxygen extraction index, referred to as apparent OEF (AOEF). MethodTest-retest data were obtained from 20 healthy volunteers at 3 T. QSM maps were reconstructed from 3D gradient-echo MRI phase data, using morphology-enabled dipole inversion. DSC-MRI was accomplished using gradient-echo MRI at a temporal resolution of 1.24 s. ResultsThe whole-brain QSM-based OEF was (40.4±4.8) % and, in combination with a previously published cerebral blood flow (CBF) estimate, this corresponds to a cerebral metabolic rate of oxygen level of CMRO2 = 3.36 ml O2/min/100 g. The intra-class correlation coefficient [ICC(2,1)] for OEF test-retest data was 0.73. The MTT-versus-OEF and AOEF-versus-OEF relationships showed correlation coefficients of 0.61 (p = 0.004) and 0.52 (p = 0.019), respectively. DiscussionQSM-based OEF showed a convincing absolute level and good test-retest results in terms of the ICC. Moderate to good correlations between QSM-based OEF and DSC-MRI-based parameters were observed. The present results constitute an indicator of the level of robustness that can be achieved without applying extraordinary resources in terms of MRI equipment, imaging protocol, QSM reconstruction, and OEF analysis.

Reduced magnetic resonance angiography signal intensity in the middle cerebral artery ipsilateral to severe carotid stenosis may be a practical index of high oxygen extraction fraction

ObjectivesAngiographic “slow flow” in the middle cerebral artery (MCA), caused by carotid stenosis, may be associated with high oxygen extraction fraction (OEF). If the MCA slow flow is associated with a reduced relative signal intensity (rSI) of the MCA on MR angiography, the reduced rSI may be associated with a high OEF. We investigated whether the MCA slow flow ipsilateral to carotid stenosis was associated with a high OEF and aimed to create a practical index to estimate the high OEF.MethodsWe included patients who underwent digital subtraction angiography (DSA) and MRA between 2015 and 2019 to evaluate carotid stenosis. MCA slow flow by image count using DSA, MCA rSI, minimal luminal diameter (MLD) of the carotid artery, carotid artery stenosis rate (CASr), and whole-brain OEF (wb-OEF) was evaluated. When MCA slow flow was associated with a high wb-OEF, the determinants of MCA slow flow were identified, and their association with high wb-OEF was evaluated.ResultsOne hundred and twenty-seven patients met our inclusion criteria. Angiographic MCA slow flow was associated with high wb-OEF. We identified MCA rSI and MLD as determinants of angiographic MCA slow flow. The upper limits of MCA rSI and MLD for angiographic MCA slow flow were 0.89 and 1.06 mm, respectively. The wb-OEF was higher in patients with an MCA rSI ≤ 0.89 and ipsilateral MLD ≤ 1.06 mm than patients without this combination.ConclusionsThe combination of reduced MCA rSI and ipsilateral narrow MLD is a straightforward index of high wb-OEF.Key Points• The whole-brain OEF in patients with angiographic slow flow in the MCA ipsilateral to high-grade carotid stenosis was higher than in patients without it.• Independent determinants of MCA slow flow were MCA relative signal intensity (rSI) on MRA or minimal luminal diameter (MLD) of the carotid stenosis.• The wb-OEF was higher in patients with an MCA rSI ≤ 0.89 and ipsilateral MLD ≤ 1.06 mm than patients without this combination.

Quantification of Whole-Brain Oxygenation Extraction Fraction Among People with Sickle Cell Anemia without Stroke History

IntroductionAn increased oxygen extraction fraction (OEF) is an indicator of decreased cerebrovascular reserve and may help predict the risk of cerebral infarction in people with sickle cell anemia (SCA). MRI T2 oximetry can conveniently convert measured venous blood T2 values to venous oxygenation fraction (Yv) using predetermined hematocrit (Hct)-dependent calibration curves. Previously, calibration models established for healthy adults and neonates were applied to people with SCA. However, a recent study on SCA blood showed T2 dependence on Y, but not on Hct (Bush et al. ISMRM, 2017, #1898). This might be due to the variations in disease history and treatment status of the SCA cohort in that study. Here, we established a calibration curve specific to people with SCA without a history of stroke or recent transfusion. Whole-brain OEFs for individuals with SCA were derived using this calibration model.MethodsExperiments were performed on a 3T Philips Achieva scanner. Thirteen healthy volunteers (35 ± 8 yrs; 7M / 6F; Hct: 0.42+/-0.03) and ten people with SCA (25 ± 7 yrs; 4M / 6F; HbS: 82%+/-7%; HbF: 9%+/-4%; Hct: 0.24+/-0.05) with no history of stroke, recent transfusion, or renal impairment were enrolled after informed consent.Venous blood T2 values were measured in the internal jugular vein (IJV) using a 48 sec protocol (Qin et al. MRM, 2011, 65:471). In vitro T2 measurements were conducted on the same day on venous blood drawn from the healthy volunteers and patients with SCA under physiological conditions (T=37ºC) following established protocols. Nitrogen and air gas were used to prepare different oxygenation levels (ranging from ~50% to 100%) for each blood sample. CPMG experiments in vitro were performed within 1 min to prevent sedimentation of erythrocytes. Blood oxygenation was measured immediately after every measurement using a blood analyzer. Blood T2 values measured in vitro from both normal and SCA samples were separately fitted relative to Y and Hct using an empirical model proposed by Lu et al. (MRM, 2012, 67:42) (Fig. 1a). Then venous blood T2 values in healthy volunteers and people with SCA were converted to Yv using these calibration curves from normal and SCA blood and their individual Hct. The whole-brain OEF was calculated as 1-Yv.ResultsGood fitting was obtained for the results of the in vitro experiments. The relationship between blood T2, Y and Hct for both the normal and SCA blood samples are illustrated with surface plots in Figs. 1b,c. The red dots indicate the experimental data points and the mesh shows the model-fitted surface.In a Bland-Altman plots comparison of the predicted and measured Y for SCA blood samples, our calibration model for SCA blood corresponded well (Figs. 2a,b), while the SCA calibration model based on mixed SCA blood (Bush et al. ISMRM, 2017, #1898) (Figs. 2c,d) had a slight underestimation (~5%), and both the normal blood calibration models developed in this work and by Bush et al. (Bush et al. MRM, 2017, Epub ahead) underestimated Y by 10%-20% (Figs. 2e-h).Using our SCA in vitro blood model, the averaged whole-brain OEFs of participants with SCA were measured as 0.39+/-0.08 (Table 1), similar to the result (0.41+/-0.06) based on Bush-Wood SCA model, but 25% lower than the values of 0.52 estimated using a calibration models based on normal human blood. Participants with SCA showed similar whole-brain OEF (0.39+/-0.08 vs 0.40+/-0.04) with greater variation among participants (P<0.004, Table 1).Discussion and ConclusionWe developed an empirical blood T2-Y calibration model for SCA blood. For people with SCA, underestimations of Yv or overestimations of OEF were observed when using developed calibration models based on normal blood. This may be caused by the sickle erythrocytes' irregular shape and degree of hemoglobin S polymerization, which require specific calibrations. The average whole-brain OEF values estimated using our SCA blood calibration model did not differ significantly from healthy volunteers, which is consistent with an earlier PET study (Stroke 1986, 17:692), but contradictory to an earlier T2 oximetry study (Brain, 2016, 139:738) using a calibration model derived from normal blood. [Display omitted] DisclosuresStrouse:Sickle Cell Adult Provider Network: Membership on an entity's Board of Directors or advisory committees; HRSA-Sickle Cell Treatment Demonstration Program: Research Funding.

Abstract P509: Signal Intensity in the Middle Cerebral Artery as a Practical and Feasible Index of Hemodynamic Insufficiency Due to Carotid Artery Stenosis

Introduction: Intracranial hemorrhage occasionally occurs after carotid revascularization in presents with hemodynamic insufficiency. Positron emission tomography is unavailable in most facilities, and a feasible index is required to identify high-risk patients. Reduced signal intensity (SI) of the middle cerebral artery (MCA) on magnetic resonance angiography (MRA) is associated with postoperative hyperperfusion. Hypothesis: Reduced signal intensity (SI) of the MCA on MRA is associated with decreased regional cerebral blood flow (rCBF) on single-photon emission CT (SPECT) and increased blood-sampling whole-brain oxygen extraction fraction (wb-OEF). Methods: We included patients who: 1) were admitted from 2015 to 2019 for carotid artery stenting (CAS), 2) MRA, and SPECT before CAS, and 3) examined the wb-OEF immediately before CAS. We measured bilateral MCA SI on MRA and defined the MCA relative SI as (SI in the affected MCA)/ (SI in the contralateral MCA). We defined the rCBF% as rCBF in the affected MCA territory against the ipsilateral cerebellum. Before CAS, we sampled blood, measured the arterial oxygen and the venous oxygen content in the dominant-sided jugular vein, and calculated the wb-OEF. We evaluated the correlation between the MCA relative SI, the MCA slow flow, the rCBF%, and the wb-OEF. We estimated the upper limits of the MCA relative SI for the rCBF% &lt; 80% or wb-OEF ≥ 0.40 using the area under the curve (AUC) values derived from the receiver operating characteristic (ROC) curves. Results: During the study period, 150 patients met our inclusion criteria. The MCA relative SI was positively correlated with rCBF% and negatively with the wb-OEF. The ROC curve for the rCBF% &lt; 80% showed that the upper limit of the relative SI was 0.77 (the sensitivity of 53.9%, the specificity of 83.9%, AUC of 0.723). The ROC curve for the wb-OEF ≥ 0.40 showed that the upper limit of the relative SI was 0.95 (the sensitivity of 67.7%, the specificity of 55.2%, AUC of 0.625). Conclusion: Reduced MCA SI on MRA ≤ 0.77 is a practical and feasible index of hemodynamic insufficiency, indicating the decreased rCBF and increased wb-OEF.

Validation of T2 -based oxygen extraction fraction measurement with 15 O positron emission tomography.

To evaluate the accuracy of T2 -based whole-brain oxygen extraction fraction (OEF) estimation by comparing it with gold standard 15 O-PET measurements. Sixteen healthy adult subjects underwent MRI and 15 O-PET OEF measurements on the same day. On MRI, whole-brain OEF was quantified by T2 -relaxation-under-spin-tagging (TRUST) MRI, based on subject-specific hematocrit. The TRUST OEF was compared to the whole-brain averaged OEF produced by 15 O-PET. Agreement between TRUST and 15 O-PET whole-brain OEF measurements was examined in terms of intraclass correlation coefficient (ICC) and in absolute OEF values. In a subset of 10 subjects, test-retest reproducibility of whole-brain OEF was also evaluated and compared between the two modalities. Across the 16 subjects, the mean whole-brain OEF of TRUST and 15 O-PET were 36.44±4.07% and 36.45±3.65%, respectively, showing no difference between the two modalities (P=.99). TRUST whole-brain OEF strongly correlated with that of 15 O-PET (N=16, ICC=0.90, P=4×10-7 ). The coefficient-of-variation of TRUST and 15 O-PET whole-brain OEF measurements were 1.79±0.67% and 2.06±1.55%, respectively, showing no difference between the two modalities (N=10, P=.64). Further analyses on the effect of hematocrit revealed that correlation between PET OEF and TRUST OEF with assumed hematocrit remained significant (ICC=0.8, P<2×10-5 ). Whole-brain OEF measured by TRUST was in excellent agreement with gold standard 15 O-PET, with highly comparable accuracy and reproducibility. These findings suggest that TRUST MRI can provide accurate quantification of whole-brain OEF noninvasively.

Quantification of whole-brain oxygenation extraction fraction and cerebral metabolic rate of oxygen consumption in adults with sickle cell anemia using individual T2 -based oxygenation calibrations.

To evaluate different T2 -oxygenation calibrations for estimating venous oxygenation in people with sickle cell anemia (SCA). Blood T2 values were measured at 3 T in the internal jugular veins of 12 healthy volunteers and 11 SCA participants with no history of stroke, recent transfusion, or renal impairment. T2 -oxygenation relationships of both sickled and normal blood samples were calibrated individually and compared with values generated from published models. After converting venous T2 values to venous oxygenation, whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen were calculated. Sickle blood samples' oxygenation values calculated from our individual calibrations agreed well with measurements using a blood analyzer, whereas previous T2 calibrations based on normal blood samples showed 13%-19% underestimation. Meanwhile, oxygenation values calculated from previous grouped T2 calibration for sickle blood agreed well with experimental measurement on averaged values, but showed up to 20% variation for several individual samples. Using individual T2 calibrations, the whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen of SCA participants were 0.38 ± 0.08 and 172 ± 42 µmol/min/100 g, respectively, which were comparable to those values measured on healthy volunteers. Our results confirm that sickle blood T2 values not only depend on the hematocrit and oxygenation values, but also on other hematological factors. The individual T2 calibrations minimized the effect of heterogeneity of sickle blood between different SCA populations and improved the accuracy of T2 -based oximetry. The measured oxygen extraction fraction and cerebral metabolic rate of oxygen of this group of SCA participants were found to not differ significantly from those of healthy individuals.

Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia

AbstractChronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

Preliminary evidence for cerebral capillary shunting in adults with sickle cell anemia

Elevated flow velocities in adults with sickle cell anemia (SCA) may cause rapid erythrocyte transit through capillaries. This phenomenon could present as dural venous sinus hyperintensity on arterial spin labeling (ASL)-MRI and could be indicative of capillary shunting. Here, the prevalence of ASL venous hyperintensities and association with relevant physiology in adults with SCA was investigated. SCA (n = 46) and age-matched control (n = 16) volunteers were recruited for 3.0 T MRI. Pseudo-continuous ASL-MRI was acquired for cerebral blood flow (CBF) calculation and venous hyperintensity determination; venous signal intensity and a categorical venous score (three raters; 0 = no hyperintensity, 1 = focal hyperintensity, and 2 = diffuse hyperintensity) were recorded. Flow velocity in cervical internal carotid artery segments was determined from phase contrast data (venc = 40 cm/s) and whole-brain oxygen extraction fraction (OEF) was determined from T2-relaxation-under-spin-tagging MRI. Cerebral metabolic rate of oxygen was calculated as the product of OEF, CBF, and blood oxygen content. ASL venous hyperintensities were significantly (p < 0.001) more prevalent in SCA (65%) relative to control (6%) participants and were associated with elevated flow velocities (p = 0.03). CBF (p < 0.001), but not OEF, increased with increasing hyperintensity score. Prospective trials that evaluate this construct as a possible marker of impaired oxygen delivery and stroke risk may be warranted.

Abstract TMP93: Elevated Oxygen Extraction Fraction Measured With Noninvasive MRI may be Discriminatory for Stroke Risk in Adults With Sickle Cell Anemia

Introduction: No screening procedures exist for evaluating stroke risk in adults with sickle cell anemia (SCA). Reduced oxygen carrying capacity is present in SCA, which may initially be compensated for by an increase in cerebral blood flow (CBF) and then by increased oxygen extraction fraction (OEF). Hypothesis: OEF and CBF can be measured noninvasively and reproducibly with MRI using clinically-available equipment in adults with SCA; elevated OEF provides added discriminatory capacity for clinical impairment relative to vasculopathy extent and CBF alone. Methods: Structural, CBF-weighted, and MRA imaging, together with a noninvasive OEF-weighted T 2 -relaxation-under-spin-tagging (TRUST)-MRI method was applied in SCA adults (n=26) and race and age-matched controls (n=11). A Kruskal-Wallis test was applied to evaluate mean differences between SCA and control parameters. Linear regression assessed how elevated OEF correlated with increasing clinical impairment defined by presence of infarct, vasculopathy, or use of regular blood transfusions for SCA. Results: OEF had high reproducibility within the same scan session, n=37 (ICC = 0.989). Whole-brain OEF and CBF were increased in SCA adults (OEF=0.46±0.08; CBF=52.4±8.3 ml/100g/min) versus controls (OEF=0.35±0.06; CBF=43.6±5.1 ml/100g/min). Hematocrit and OEF were inversely correlated (R 2 =0.72; p&lt;0.01). Linear regression revealed a stronger relationship of OEF than CBF with clinical impairment. In SCA adults without impairment (n=12) CBF and OEF have an inverse relationship (R 2 =0.41; p=0.01, Fig. 1A) but with clinical impairment (infarct, vasculopathy or severe pain requiring regular transfusions, n=14) CBF and OEF become uncoupled (R 2 =0.08; p=0.16; Fig. 1B) as CBF may not be able to increase further and may plateau or decline. Conclusion: TRUST-MRI OEF is a rapid, reproducible measure. OEF shows promise as screening tool for hemodynamic impairment and stroke risk in adults with SCA.

Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia.

Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia.

Depression of whole-brain oxygen extraction fraction is associated with poor outcome in pediatric traumatic brain injury

Introduction:Traumatic brain injury (TBI) is a leading cause of death and disability in children. Metabolic failure is an integral component of the pathological aftermath of TBI. The oxygen extraction fraction (OEF) is a valuable parameter for characterization and description of metabolic abnormalities; however, OEF measurement has required either invasive procedures or the use of ionizing radiation, which significantly limits its use in pediatric research.Results:Patients with TBI had depressed OEF levels that correlated with the severity of injury. In addition, the OEF measured within 2 weeks of injury was predictive of patient outcome at 3 mo after injury. In pediatric TBI patients, low OEF—a marker of metabolic dysfunction—correlates with the severity of injury and outcome.Discussion:Our findings support previous literature on the role of metabolic dysfunction after TBI.Methods:Using a recently developed magnetic resonance (MR) technique for the measurement of oxygen saturation, we determined the whole-brain OEF in both pediatric TBI patients and in healthy controls. Injury and outcome were classified using pediatric versions of the Glasgow Coma Scale (GCS) and Glasgow Outcome Scale–Extended (GOS-E), respectively.

Determination of whole‐brain oxygen extraction fractions by fast measurement of blood T2 in the jugular vein

The oxygen extraction fraction of the brain reports on the balance between oxygen delivery and consumption and can be used to assess deviations in physiological homeostasis. This is relevant clinically as well as for calibrating blood oxygen level-dependent functional MRI responses. Oxygen extraction fraction is reflected in the arteriovenous difference in oxygen saturation fraction (Y(v) - Y(a) ), which can be determined from venous T(2) values when arterial oxygenation is known. A pulse sequence is presented that allows rapid measurement (<1 min) of blood T(2) s in the internal jugular vein. The technique combines slice-saturation and blood inflow to attain high signal-to-noise ratio in blood and minimal contamination from tissue. The sequence is sensitized to T(2) using a nonselective Carr-Purcell-Meiboom-Gill T(2) preparation directly after slice saturation. Fast scanning (pulse repetition time of about 2 sec) is possible by using a nonselective saturation directly after acquisition to rapidly achieve steady-state longitudinal magnetization. The venous T(2) (for 10 msec Carr-Purcell-Meiboom-Gill interecho time) for normal volunteers was 62.4 ± 6.1 msec (n = 20). A calibration curve relating T(2) to blood oxygenation was established using a blood perfusion phantom. Using this calibration, a whole-brain oxygen extraction fraction of 0.37 ± 0.04 was determined (n = 20), in excellent agreement with literature values.