Changes In Oxygen Extraction Fraction Research Articles

Streamlined quantitative BOLD for detecting visual stimulus-induced changes in oxygen extraction fraction in healthy participants: toward clinical application in human glioma

ObjectiveMonitoring brain oxygenation is critical in brain tumors, as low oxygenation influences tumor growth, pathological angiogenesis, and treatment resistance. This study examined the ability of the streamlined quantitative (sq)BOLD MRI technique to detect oxygenation changes in healthy individuals, as well as its potential application in a clinical setting.MethodsWe used the asymmetric spin echo (ASE) technique with FLAIR preparation, along with model-based Bayesian inference to quantify the reversible transverse relaxation rate (R2') and oxygen extraction fraction (OEF) across the brain at baseline and during visual stimulation in eight healthy participants at 3T; and two patients with glioma at rest only.ResultsComparing sqBOLD-derived parameters between baseline and visual stimulation revealed a decrease in OEF from 0.56 ± 0.09 at baseline to 0.54 ± 0.07 at the activated state (p = 0.04, paired t test) within a functional localizer-defined volume of interest, and a decline in R2' from 6.5 ± 1.3s−1 at baseline to 6.2 ± 1.4s−1 at the activated state (p = 0.006, paired t test) in the visual cortex.ConclusionThe sqBOLD technique is sensitive enough to detect and quantify changes in oxygenation in the healthy brain and shows potential for integration into clinical settings to provide valuable information on oxygenation in glioma.

Quantitative Evaluation of Oxygen Extraction Fraction Changes in the Monkey Brain during Acute Stroke by Using Quantitative Susceptibility Mapping.

The oxygen extraction fraction (OEF) indicates the brain's oxygen consumption and can be estimated by using the quantitative susceptibility mapping (QSM) MRI technique. Recent studies have suggested that OEF alteration following stroke is associated with the viability of at-risk tissue. In the present study, the temporal evolution of OEF in the monkey brain during acute stroke was investigated using QSM. Ischemic stroke was induced in adult rhesus monkeys (n = 8) with permanent middle cerebral artery occlusion (pMCAO) by using an interventional approach. Diffusion-, T2-, and T2*-weighted images were conducted on day 0, day 2, and day 4 post-stroke using a clinical 3T scanner. Progressive changes in magnetic susceptibility and OEF, along with their correlations with the transverse relaxation rates and diffusion indices, were examined. The magnetic susceptibility and OEF in injured gray matter of the brain significantly increased during the hyperacute phase, and then decreased significantly on day 2 and day 4. Moreover, the temporal changes of OEF in gray matter were moderately correlated with mean diffusivity (MD) (r = 0.52; p = 0.046) from day 0 to day 4. Magnetic susceptibility in white matter progressively increased (from negative values to near zero) during acute stroke, and significant increases were seen on day 2 (p = 0.08) and day 4 (p = 0.003) when white matter was significantly degenerated. However, significant reduction of OEF in white matter was not seen until day 4 post-stroke. The preliminary results demonstrate that QSM-derived OEF is a robust approach to examine the progressive changes of gray matter in the ischemic brain from the hyperacute phase to the subacute phase of stroke. The changes of OEF in gray matter were more prominent than those in white matter following stroke insult. The findings suggest that QSM-derived OEF may provide complementary information for understanding the neuropathology of the brain tissue following stroke and predicting stroke outcomes.

Associations between neurological examination at term-equivalent age and cerebral hemodynamics and oxygen metabolism in infants born preterm.

Infants born at 29-36 weeks gestational age (GA) are at risk of experiencing neurodevelopmental challenges. We hypothesize that cerebral hemodynamics and oxygen metabolism measured by bedside optical brain monitoring are potential biomarkers of brain development and are associated with neurological examination at term-equivalent age (TEA). Preterm infants (N = 133) born 29-36 weeks GA and admitted in the neonatal intensive care unit were enrolled in this prospective cohort study. Combined frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) were used from birth to TEA to measure cerebral hemoglobin oxygen saturation and an index of microvascular cerebral blood flow (CBF i ) along with peripheral arterial oxygen saturation (SpO2). In combination with hemoglobin concentration in the blood, these parameters were used to derive cerebral oxygen extraction fraction (OEF) and an index of cerebral oxygen metabolism (CMRO2i ). The Amiel-Tison and Gosselin Neurological Assessment was performed at TEA. Linear regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and GA at birth. Logistic regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and neurological examination at TEA. Steeper increases in CBF i (p < 0.0001) and CMRO2i (p = 0.0003) were associated with higher GA at birth. Changes in OEF, CBF i , and CMRO2i from birth to TEA were not associated with neurological examination at TEA. In this population, cerebral FDNIRS-DCS parameters were not associated with neurological examination at TEA. Larger increases in CBF i and CMRO2i from birth to TEA were associated with higher GA. Non-invasive bedside FDNIRS-DCS monitoring provides cerebral hemodynamic and metabolic parameters that may complement neurological examination to assess brain development in preterm infants.

MRI assessment of cerebral oxygen extraction fraction in the medial temporal lobe

The medial temporal lobe (MTL) is a key area implicated in many brain diseases, such as Alzheimer's disease. As a functional biomarker, the oxygen extraction fraction (OEF) of MTL may be more sensitive than structural atrophy of MTL, especially at the early stages of diseases. However, there is a lack of non-invasive techniques to measure MTL-OEF in humans. The goal of this work is to develop an MRI technique to assess MTL-OEF in a clinically practical time without using contrast agents. The proposed method measures venous oxygenation (Yv) in the basal veins of Rosenthal (BVs), which are the major draining veins of the MTL. MTL-OEF can then be estimated as the arterio-venous difference in oxygenation. We developed an MRI sequence, dubbed arterial-suppressed accelerated T2-relaxation-under-phase-contrast (AS-aTRUPC), to quantify the blood T2 of the BVs, which was then converted to Yv through a well-established calibration model. MTL-OEF was calculated as (Ya−Yv)/Ya × 100%, where Ya was the arterial oxygenation. The feasibility of AS-aTRUPC to quantify MTL-OEF was evaluated in 16 healthy adults. The sensitivity of AS-aTRUPC in detecting OEF changes was assessed by a caffeine ingestion (200 mg) challenge. For comparison, T2-relaxation-under-spin-tagging (TRUST) MRI, which is a widely used global OEF technique, was also acquired. The dependence of MTL-OEF on age was examined by including another seven healthy elderly subjects. The results showed that in healthy adults, MTL-OEF of the left and right hemispheres were correlated (P=0.005). MTL-OEF was measured to be 23.9±3.6% (mean±standard deviation) and was significantly lower (P<0.0001) than the OEF of 33.3±2.9% measured in superior sagittal sinus (SSS). After caffeine ingestion, there was an absolute percentage increase of 9.1±4.0% in MTL-OEF. Additionally, OEF in SSS measured with AS-aTRUPC showed a strong correlation with TRUST OEF (intra-class correlation coefficient=0.94 with 95% confidence interval [0.91, 0.96]), with no significant bias (P=0.12). MTL-OEF was found to increase with age (MTL-OEF=20.997+0.100 × age; P=0.02). In conclusion, AS-aTRUPC MRI provides non-invasive assessments of MTL-OEF and may facilitate future clinical applications of MTL-OEF as a disease biomarker.

Cerebral Metabolic Stress Improves after Voxelotor Treatment in Pediatric Sickle Cell Disease

Introduction In sickle cell disease (SCD), hemoglobin S rapidly forms intracellular polymers in the deoxygenated state, resulting in red blood cell sickling, hemolysis, and vaso-occlusion. These changes alter cerebral perfusion and dramatically increase risk for neurocognitive deficits and stroke (Bush et al., 2014; Wang et al., 2021). Voxelotor (Oxbryta®) is an inhibitor of HbS polymerization that has been shown to significantly improve anemia and reduce hemolysis in sickle cell disease. However, it is unknown whether these changes are accompanied by improvements in perfusion and reductions in cerebral metabolic stress. Here we employ two novel optical techniques known as frequency-domain near-infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to non-invasively monitor regional changes in oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) as markers of cerebral metabolic stress in a pilot cohort of children with SCD beginning voxelotor. Our primary objective was to test the hypothesis that voxelotor decreases CBF, OEF, and CMRO2 from pre-treatment levels. We also explored the relationship between CBF, OEF, and CMRO2 and hemoglobin. Methods Children ages 4 to 17 years old with SCD (HbSS or HbS-thalassemia) were enrolled at Children's Healthcare of Atlanta. Participants who met study criteria started open label voxelotor at recommended dose. Participants were monitored prior to treatment initiation, as well as at weeks 4, 8, and 12 weeks. At each study visit, laboratory measurements of anemia (CBC, Retic) and FDNIRS/DCS measurements of regional cerebral blood flow, oxygen extraction fraction, and oxygen metabolism were made (Lee et al., 2022). Transcranial Doppler ultrasound (TCD, middle cerebral artery, internal carotid artery, and carotid bifurcations) along with markers of hemolysis (LDH, T.Bili) were performed at weeks 0 and 12. Paired Wilcoxon signed-rank tests were used to test whether all measures were significantly different from pre-treatment levels. Linear mixed-effects regression models with random-intercept at the patient level were used to examine the association of the relative change in each outcome measure (OEF, CBF, and CMRO2) from pre-treatment levels and delta changes in laboratory data. These models were two-level and accounted for repeated measures nested within each patient. Results Ten of the 12 recruited patients met study criteria. All patients were HbSS on stable dose of hydroxyurea (Table 1). Following initiation of voxelotor, the median (interquartile range, IQR) blood hemoglobin levels increased by 1.2 (0.4, 1.5) g/dL at week 4 (p=0.023); these increases persisted at weeks 8 and 12. Bilirubin was significantly decreased at week 12 (p=0.008), and LDH increased, although the trend was not statistically significant (p=0.24). While TCD velocities were unchanged at week 12, significant decreases in OEF, CBF, and CMRO2 were observed by week 4 (all p < 0.05) that persisted at weeks 8 and 12 (Table 2). Across all time points, relative changes in OEF, CBF, and CMRO2 from pre-treatment levels were inversely associated with changes in hemoglobin (p = 0.0015, 0.071, and 0.020, respectively). Discussion Non-invasive FDNIRS/DCS was used to successfully measure changes in regional cerebral blood flow and oxygen utilization in response to treatment with voxelotor. Results suggest that voxelotor treatment in children with SCD reduces cerebral metabolic stress by improving oxygen delivery to the tissue. Work is ongoing to validate these measurements with MRI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development of a novel 10-echo multi-contrast sequence based on EPIK to deliver simultaneous quantification of T2 and T2* with application to oxygen extraction fraction.

The simultaneous quantification of T2 and T2 * maps based on fast sequences for combined GE and SE acquisition has rekindled research and clinical interest by offering a wide range of attractive applications, e.g., dynamic tracking of oxygen extraction fraction (OEF). However, previously published methods based on EPI-readouts have been hindered by resolution and the number of acquired echoes. This work presents a novel 10-echo GE-SE EPIK (EPI with keyhole) sequence for the rapid quantification of T2 '. T2 /T2 * maps from the GE-SE EPIK sequence were validated using three phantoms and 15 volunteers at 3T. The incorporation of a sliding window approach, combined with the full sampling of the k-space center inherent to EPIK, enables a high effective temporal resolution. That is, for an eight-slice breath-hold experiment, a temporal sampling rate of eight reconstructed slices per 1.1s. In comparison with repeated single-echo SE, multi-echo GE, and spectroscopy methods, the GE-SE EPIK sequence shows good agreement in quantifying T2 /T2 * values, while the gray matter/white matter separation yielded the expected contrast differentiation. The OEF was calculated with a view to an initial application with clinical relevance, producing results comparable to those in the literature and with good sensitivity in breath-hold experiments. GE-SE EPIK provides increased resolution and more echoes, including two SEs, than comparable sequences. Moreover, GE-SE EPIK achieves this within an acquisition time of 57 s for 20 slices (matrix size=128×128; FOV=24 cm) and with a reasonably short TE for the final echo (114 ms). The sequence can dynamically track OEF changes in a breath-hold experiment.

Abstract TP479: Early Effect of Human Immunodeficiency Virus on Cerebral Blood Flow and Autoregulation

Introduction: Human immunodeficiency virus (HIV)-infected individuals are at high risk for ischemic stroke. We measured cerebral blood flow (CBF), oxygen extraction fraction (OEF), and autoregulation in HIV infected subjects and controls. Methods: In treatment-naive HIV infected subjects and age-, gender-, and race-matched controls, OEF was measured by using MRI T2*-weighted echo-planar imaging sequences and CBF was measured by MRI pulsed arterial spin labeling (PASL) approach. Static cerebral autoregulation was determined by measuring changes in CBF and OEF, in response to ≈10% reductions in MAP induced by using IV Nicardipine infusion. All images were acquired using a Siemens 3T MR scanner (Treo, Siemens Medical Systems Inc). Cerebral autoregulation was measured globally and regionally in gray matter (GM), white matter (WM) and subcortical GM. Autoregulatory Index (AI) was computed using the equation AI = %CBF change/% MAP change supplemented by CBF associated OEF changes. Nominal p-values are uncorrected for multiple comparisons. Results: Forty-one treatment naive HIV-infected subjects and 47 age-, gender-, race-matched controls participated. HIV-infected subjects had higher CBF in cortical GM compared to the controls (76.8± 12 mL/100 g/min versus 71.6 ± 11 mL/100 g/min; p= 0.04), but not in white matter (30.9± 8 mL/100 g/min versus 30.0 ± 8 mL/100 g/min; p = 0.60) or subcortical GM (62.8± 13 mL/100 g/min versus 61.3 ± 13 mL/100 g/min; p = 0.57). Whole brain (WB), GM, WM, and subcortical GM, OEF were similar between the groups (p &gt; .05). The median AI were similar between cases and controls in WB (0.40 vs 0.18, p=0.86), GM (0.10 vs. 0.16, p=0.87), WM (0.80 vs. 0.87, p=0.31), and subcortical GM (1.65 vs. 1.77, p=0.26). A 12-month follow-up (N=30) in HIV-subjects on antiretroviral therapy did not produce a significant change in CBF or OEF in the WB, GM, WM, or subcortical GM (Paired sample t test p&gt;0.05). Similarly, no changes were noted on the AI (Wilcoxon Match Rank test p&gt;0.05). Conclusions: AI was similar between HIV cases and control and remained so after 12-months of antiretroviral therapy. We found no evidence of a defect in autoregulation to explain the high-risk of ischemic stroke documented in other studies.

Brain Oxygen Extraction by Using MRI in Older Individuals: Relationship to Apolipoprotein E Genotype and Amyloid Burden.

Background Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset Alzheimer disease. However, the mechanisms by which APOE4 affects the brain, underpinning this risk, have not been fully elucidated. Purpose To investigate the influence of APOE4 on global cerebral oxygen extraction fraction (OEF) and possible mediation through amyloid burden by using MRI-based brain oxygen extraction technique. Materials and Methods Participants were enrolled from a longitudinal prospective study, the Biomarkers for Older Controls at Risk for Dementia study (data collected from January 2015 to December 2017), of whom 35% (50 of 143 participants) were APOE4 carriers. OEF was measured by using a T2-relaxation-under-spin-tagging MRI technique with a 3.0-T MRI system. PET acquired with carbon 11-labeled Pittsburgh compound B tracer was available in 119 participants to measure amyloid burden. Cognitive performance was assessed by using domain-specific composite scores including executive function, episodic memory, visual-spatial processing, and language. Linear regression analysis was performed to investigate the relationship between APOE4, OEF, and amyloid burden. The association between OEF and cognitive function was studied for the entire study cohort and separately for the APOE4 carriers and noncarriers. Results A total of 143 cognitively healthy individuals (mean age 6 standard deviation, 69.1 years 6 8.2; 57 men and 86 women) were studied. APOE4 genetic status was associated with lower OEF (noncarriers, 41.1% 6 5.8; one E4 allele, 40.1% 6 4.9; two E4 alleles, 36.7% 6 4.5; P = .03). Furthermore, among APOE4 carriers, lower OEF correlated with lower executive function scores (b = 0.079 z score for each percent change in OEF; P = .03). Amyloid burden and OEF were independently associated with APOE4 but were not associated with one another, suggesting that the effect of APOE4 on OEF is not mediated by amyloid. Conclusion MRI-based brain oxygen extraction shows that cognitively healthy carriers of the apolipoprotein E4 gene manifest diminished brain oxygen extraction capacity independent of amyloid burden. ©RSNA, 2019 Online supplemental material is available for this article.

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

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

Differential cerebral hemometabolic responses to blood transfusions in adults and children with sickle cell anemia.

Blood transfusions are administered to children and adults with sickle cell anemia (SCA) for secondary stroke prevention, or as treatment for recurrent pain crises or acute anemia, but transfusion effects on cerebral hemodynamics and metabolism are not well-characterized. To compare blood transfusion-induced changes in hemometabolic parameters, including oxygen extraction fraction (OEF) and cerebral blood flow (CBF), within and between adults and children with SCA. Prospective, longitudinal study. Adults with SCA (n = 16) receiving simple (n = 7) or exchange (n = 9) transfusions and children with SCA (n = 11) receiving exchange transfusions were scanned once when hematocrit was near nadir and again within 7 days of transfusion. Adult controls without SCA or sickle trait (n = 7) were scanned twice on separate days. 3.0T T1 -weighted, T2 -weighted, and T2 -relaxation-under-spin-tagging (TRUST) imaging, and phase contrast angiography. Global OEF was computed as the relative difference between venous oxygenation (from TRUST) and arterial oxygenation (from pulse oximetry). Global CBF was computed as total blood flow to the brain normalized by intracranial tissue volume. Hemometabolic variables were compared using two-sided Wilcoxon signed-rank tests; associations were analyzed using two-sided Spearman's correlation testing. In adults with SCA, posttransfusion OEF = 0.38 ± 0.05 was lower (P = 0.001) than pretransfusion OEF = 0.45 ± 0.09. A change in OEF was correlated with increases in hematocrit (P = 0.02; rho = -0.62) and with pretransfusion hematocrit (P = 0.02; rho = 0.65). OEF changes after transfusion were greater (P = 0.002) in adults receiving simple versus exchange transfusions. Posttransfusion CBF = 77.7 ± 26.4 ml/100g/min was not different (P = 0.27) from pretransfusion CBF = 82.3 ± 30.2 ml/100g/min. In children with SCA, both posttransfusion OEF = 0.28 ± 0.04 and CBF = 76.4 ± 26.4 were lower than pretransfusion OEF = 0.36 ± 0.06 (P = 0.004) and CBF = 96.4 ± 16.5 (P = 0.004). Cerebral OEF reduces following transfusions in adults and children with SCA. CBF reduces following transfusions more often in children compared to adults, indicating that vascular reserve capacity may remain near exhaustion posttransfusion in many adults. 2 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;49:466-477.

Abstract TP211: Gray and White Matter Hemodynamics and Metabolism Measured Using Magnetic Resonance Imaging

Background: Reliable methods used to measure cerebral hemodynamics, metabolism and autoregulation are time-consuming and invasive. Objectives: We sought to measure cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO 2 ), in the whole brain, gray and white matter and detect physiological changes in humans under normal and ≈10% reductions in mean arterial pressure (MAP). Methods: CBF was measured using pseudo continuous arterial spin labeling (pCASL). OEF was measured using a MRI asymmetric spin echo-planar imaging (EPI). The arterial content of oxygen (CaO 2 ) was computed. CMRO 2 was calculated using the equation CMRO 2 =CaO 2 xCBFxOEF. Cerebral autoregulation was determined by measuring changes in CBF, OEF and CMRO 2 in response to ≈10% reductions in MAP in stroke-free controls induced by IV Nicardipine infusion. Autoregulation was measured in the whole brain, gray matter and white matter. Autoregulatory Index (AI) was computed using the equation AI = %CBF change/% MAP change supplemented by CBF associated OEF changes. Results: A total of 30 subjects were consented (Mean age 31, 93% male, 40% white, 43% black and 17% others). At baseline, CBF was measured in the whole brain (52.5±9.5 ml/100g/min), gray matter (72.0±13.0 ml/100g/min) and white matter (30.2±8.4 ml/100g/min). OEF was measured in the whole brain (0.32±0.02), gray matter (0.33±0.02) and white matter (0.30±0.01). CMRO 2 was measured in the whole brain (3.2±0.8 ml/100g/min), gray matter (4.6±1.1 ml/100g/min) and white matter (1.8±0.5 ml/100g/min). A target of 10% MAP lowering was successfully achieved in 18 subjects, resulting in a change of mean CBF in the whole brain (52 vs. 50, p=0.1), gray matter (72 vs. 69, p=0.2) and white matter (30 vs. 28, p=0.08). This translated to a AI of 0.3 ± 0.9 in the whole brain, 0.2±1.0 in the gray matter and 0.5±1.7 in the white matter. These CBF changes corroborated with no significant changes in OEF and CMRO 2 . Conclusions: MR measurement of CBF, OEF and CMRO 2 , in the whole brain, gray and white matter was comparable to measures obtained by invasive methods. Differences in these measures, as well as AI in the gray and white matter, may help understand cerebrovascular diseases that affect white matter such as lacunar strokes.

Functional oxygen extraction fraction (OEF) imaging with turbo gradient spin echo QUIXOTIC (Turbo QUIXOTIC).

QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption (QUIXOTIC) is a recent technique that measures voxel-wise oxygen extraction fraction (OEF) but suffers from long scan times, limiting its application. We implemented multiecho QUIXOTIC dubbed turbo QUIXOTIC (tQUIXOTIC) that reduces scan time eightfold and then applied it in functional MRI. tQUIXOTIC utilizes a novel turbo gradient spin echo readout enabling measurement of venular blood transverse relaxation rate in a single tag-control acquisition. Using tQUIXOTIC, we estimated cortical gray matter (GM) OEF, created voxel-by-voxel GM OEF maps, and quantified changes in visual cortex OEF during a blocked design flashing checkerboard visual stimulus. Contamination from cerebrospinal fluid partial volume averaging was estimated and corrected. The average cortical GM OEF was estimated as 0.38 ± 0.06 (n = 8) using a 3.4-min acquisition. The average OEF in the visual cortex was estimated as 0.43 ± 0.04 at baseline and 0.35 ± 0.05 during activation, with an average %ΔOEF of -20%. These values are consistent with those of past studies. tQUIXOTIC successfully estimated cortical GM OEF in clinical scan times and detected changes in OEF during blocked design visual stimulation. tQUIXOTIC will be useful to monitor regional OEF clinically and in blocked design or event-related functional MRI experiments. Magn Reson Med 79:2713-2723, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Noninvasive Assessment of Oxygen Extraction Fraction in Chronic Ischemia Using Quantitative Susceptibility Mapping at 7 Tesla

The oxygen extraction fraction (OEF) is an effective metric to evaluate metabolic reserve in chronic ischemia. However, OEF is considered to be accurately measured only when using positron emission tomography (PET). Thus, we investigated whether OEF maps generated by magnetic resonance quantitative susceptibility mapping (QSM) at 7 Tesla enabled detection of OEF changes when compared with those obtained with PET. Forty-one patients with chronic stenosis/occlusion of the unilateral internal carotid artery or middle cerebral artery were examined using 7 Tesla-MRI and PET scanners. QSM images were obtained from 3-dimensional T2*-weighted images, using a multiple dipole-inversion algorithm. OEF maps were generated based on susceptibility differences between venous structures and brain tissues on QSM images. OEF ratios of the ipsilateral middle cerebral artery territory against the contralateral side were calculated on the QSM-OEF and PET-OEF images, using an anatomic template. The OEF ratio in the middle cerebral artery territory showed significant correlations between QSM-OEF and PET-OEF maps (r=0.69; P<0.001), especially in patients with a substantial increase in the PET-OEF ratio of 1.09 (r=0.79; P=0.004), although showing significant systematic biases for the agreements. An increased QSM-OEF ratio of >1.09, as determined by receiver operating characteristic analysis, showed a sensitivity and specificity of 0.82 and 0.86, respectively, for the substantial increase in the PET-OEF ratio. Absolute QSM-OEF values were significantly correlated with PET-OEF values in the patients with increased PET-OEF. OEF ratios on QSM-OEF images at 7 Tesla showed a good correlation with those on PET-OEF images in patients with unilateral steno-occlusive internal carotid artery/middle cerebral artery lesions, suggesting that noninvasive OEF measurement by MRI can be a substitute for PET.

Severity-specific alterations in CBF, OEF and CMRO2 in cirrhotic patients with hepatic encephalopathy.

To assess how the severity of hepatic encephalopathy (HE) affects perfusion and metabolic changes in cirrhotic patients and the association between severity and liver disease and anemia. The study groups comprised 31 healthy subjects and 33 cirrhotic patients who underwent MR examinations, and blood and neuropsychological tests. Of the cirrhotic patients, 14 were unaffected, and 11 had covert HE (CHE) and 8 overt HE (OHE). Global cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen (CMRO2) were noninvasively measured by phase-contrast and T2-relaxation-under-spin-tagging MRI. Correlations were performed between MR measurements, hematocrits, ammonia levels, Child-Pugh scores and neuropsychological test scores. Compared with the values in healthy subjects, CBF was higher in unaffected patients, the same in CHE patients and lower in OHE patients, OEF was higher in all patients, and CMRO2 was the same in unaffected and CHE patients and lower in OHE patients. Hematocrit was negatively correlated with CBF and OEF, but not with CMRO2. Ammonia level was negatively correlated with CBF and CMRO2, and Child-Pugh score was negatively correlated with CMRO2. The severity-associated alterations in cirrhotic patients indicate that homeostasis of oxygen delivery and oxidative metabolism in HE is regulated by multiple mechanisms. These physiological alterations appeared to be associated with the degree of anemia, ammonia level, and liver function. • CBF, OEF and CMRO2 did not change monotonically with HE progression. • Anemia possibly contributed to CBF and OEF changes in cirrhotic patients. • Liver dysfunction mainly contributed to changes in CMRO2 in cirrhotic patients.

Oxygenation-Sensitive Magnetic Resonance Imaging in Acute Ischemic Stroke Using T2'/R2' Mapping: Influence of Relative Cerebral Blood Volume.

Quantitative T2'/R2' mapping detect locally increased concentrations of deoxygenated hemoglobin-causing a decrease of T2' and increase of R2'-and might reflect increased cerebral oxygen extraction fraction. Because increases of (relative) cerebral blood volume (rCBV) may influence T2' and R2' through accumulation of deoxygenated hemoglobin, we aimed to investigate the impact of rCBV on T2'/R2' in patients with ischemic stroke. Data from patients with acute internal carotid artery and middle cerebral artery occlusion were analyzed. T2', R2', and rCBV were measured within the ischemic core, slightly and severely hypoperfused areas, and their relationship was examined. A strong negative correlation with rCBV was found for R2' (r=-0.544; P=0.002), and T2' correlated positively with rCBV (r=0.546; P=0.001) in time-to-peak-delayed areas. T2'/R2' within hypoperfused tissue remained unchanged at normal or elevated rCBV levels. T2' decrease/R2' increase within hypoperfused areas in ischemic stroke is not caused by local elevations of rCBV but most probably only by increased cerebral oxygen extraction fraction. However, considering rCBV is crucial to assess extent of oxygen extraction fraction changes by means of T2'/R2'.

Mapping the pharmacological modulation of brain oxygen metabolism: The effects of caffeine on absolute CMRO2 measured using dual calibrated fMRI

This study aims to map the acute effects of caffeine ingestion on grey matter oxygen metabolism and haemodynamics with a novel MRI method. Sixteen healthy caffeine consumers (8 males, age=24.7±5.1) were recruited to this randomised, double-blind, placebo-controlled study. Each participant was scanned on two days before and after the delivery of an oral caffeine (250mg) or placebo capsule.Our measurements were obtained with a newly proposed estimation approach applied to data from a dual calibration fMRI experiment that uses hypercapnia and hyperoxia to modulate brain blood flow and oxygenation. Estimates were based on a forward model that describes analytically the contributions of cerebral blood flow (CBF) and of the measured end-tidal partial pressures of CO2 and O2 to the acquired dual-echo GRE signal. The method allows the estimation of grey matter maps of: oxygen extraction fraction (OEF), CBF, CBF-related cerebrovascular reactivity (CVR) and cerebral metabolic rate of oxygen consumption (CMRO2). Other estimates from a multi inversion time ASL acquisition (mTI-ASL), salivary samples of the caffeine concentration and behavioural measurements are also reported.We observed significant differences between caffeine and placebo on average across grey matter, with OEF showing an increase of 15.6% (SEM±4.9%, p<0.05) with caffeine, while CBF and CMRO2 showed differences of −30.4% (SEM±1.6%, p<0.01) and −18.6% (SEM±2.9%, p<0.01) respectively with caffeine administration. The reduction in oxygen metabolism found is somehow unexpected, but consistent with a hypothesis of decreased energetic demand, supported by previous electrophysiological studies reporting reductions in spectral power with EEG.Moreover the maps of the physiological parameters estimated illustrate the spatial distribution of changes across grey matter enabling us to localise the effects of caffeine with voxel-wise resolution. CBF changes were widespread as reported by previous findings, while changes in OEF were found to be more restricted, leading to unprecedented mapping of significant CMRO2 reductions mainly in frontal gyrus, parietal and occipital lobes.In conclusion, we propose the estimation framework based on our novel forward model with a dual calibrated fMRI experiment as a viable MRI method to map the effects of drugs on brain oxygen metabolism and haemodynamics with voxel-wise resolution.

Quantifying the changes in oxygen extraction fraction and cerebral activity caused by caffeine and acetazolamide

A quantitative estimate of cerebral blood oxygen saturation is of critical importance in the investigation of cerebrovascular disease. We aimed to measure the change in venous oxygen saturation (Yv) before and after the intake of the vaso-dynamic agents caffeine and acetazolamide with high spatial resolution using susceptibility mapping. Caffeine and acetazolamide were administered on separate days to five healthy volunteers to measure the change in oxygen extraction fraction. The internal streaking artifacts in the susceptibility maps were reduced by giving an initial susceptibility value uniformly to the structure-of-interest, based on a priori information. Using this technique, Yv for normal physiological conditions, post-caffeine and post-acetazolamide was measured inside the internal cerebral veins as YNormal = 69.1 ± 3.3%, YCaffeine = 60.5 ± 2.8%, and YAcet = 79.1 ± 4.0%. This suggests that susceptibility mapping can serve as a sensitive biomarker for measuring reductions in cerebro-vascular reserve through abnormal vascular response. The percentage change in oxygen extraction fraction for caffeine and acetazolamide were found to be +27.0 ± 3.8% and −32.6 ± 2.1%, respectively. Similarly, the relative changes in cerebral blood flow in the presence of caffeine and acetazolamide were found to be −30.3% and + 31.5%, suggesting that the cerebral metabolic rate of oxygen remains stable between normal and challenged brain states for healthy subjects.

Abstract 35: Transfusion Relieves Cerebral Metabolic Stress in Children with Sickle Cell Disease

Introduction: Transfusions (Tx) are the mainstay of stroke prevention in children with sickle cell disease (SCD), but the pathophysiology conferring this neuroprotection is not well understood. Hypothesis: Tx relieves cerebral metabolic stress by improving arterial oxygen content, thereby lowering chronically-elevated cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in children with SCD at risk for stroke. Methods: Children with SCD on chronic Tx therapy underwent two brain MRIs with measurement of CBF via pseudocontinuuous arterial spin labeling and OEF via asymmetric spin echo sequence within 24 hours of exchange Tx. To determine how Tx may reduce regions of elevated OEF, we set absolute OEF thresholds (45, 47.5, 50%) and compared tissue volumes above each threshold pre- and post-Tx using nonparametric paired statistics. Results: Twelve children with SCD (6-21 yrs) underwent MRIs. Tx raised Hb and lowered CBF and OEF (Figure), suggesting that elevated CBF and OEF may be markers of metabolic stress relieved by Tx. While CBF correlates with age in healthy children, pre-Tx CBF correlation with age was lost (τ= -0.42, p=0.07), but regained post-Tx (τ= -0.76, p=0.001). Also, absolute change in OEF diminished with increasing age (τ=. -0.75, p=0.003). Regions with very high OEF were found in the periventricular white matter, a common area of infarcts in SCD (Figure, average OEF maps pre- and post-Tx). Tx reduced the volume of these brain regions defined by all three OEF thresholds (Table), suggesting that Tx reduces brain regions at high risk for stroke. Conclusion: Tx in SCD children improves arterial oxygen content by increasing Hb, allowing CBF and OEF to fall, thus relieving metabolic stress globally and regionally. The absolute change in OEF correlates with age, suggesting that the efficacy of Tx may be age-dependent.

Abstract WP417: Oxygen Extraction Fraction Measured With MRI is Reduced After Blood Transfusion in Adults With Sickle Cell Anemia

Introduction: Blood transfusion for primary stroke prevention is well established in children but not adults with sickle cell anemia (SCA). Secondary stroke prevention in young adults with SCA is generally accepted. However blood transfusion therapy does not prevent all infarcts and recurrent assessment of cerebral physiology is likely necessary to portend stroke risk. Hypothesis: Oxygen extraction fraction (OEF), which reflects the balance of oxygen consumed to oxygen delivered, can be evaluated routinely noninvasively in vivo using MRI and reduces following blood transfusion; if confirmed, routine MRI-based OEF screening could be applied to evaluate impact of blood transfusion and other therapies on tissue-level impairment. Methods: The noninvasive T 2 -relaxation-under-spin-tagging (TRUST)-MRI method (duration=1min12s) was applied in adults with SCA (n=5) and age and race-matched control (n=11) volunteers. SCA volunteers were scanned pre- and post-transfusion and controls at two time points to assess healthy OEF reproducibility and hypothesized changes after transfusion, respectively. OEF changes were contrasted with symptoms, vasculopathy, and perfusion. A Kruskal-Wallis test with two-sided p&lt;0.05 was used to evaluate significant differences. Results: In adults with SCA, mean age 33±3 years (y) OEF was significantly elevated (p&lt;0.01, OEF=0.53±0.09) relative to controls (mean age 27±5y, OEF=0.32±0.06). OEF was not significantly different at follow-up for controls (OEF=0.33±0.05), but was reduced (OEF=0.44±0.05; p=0.021) following transfusion in SCA volunteers (Figure). Reduction in OEF is inversely correlated with increase in hematocrit post-transfusion. Conclusion: Noninvasive MRI can quickly detect expected reductions in OEF after blood transfusion. Ongoing work is focused on understanding relationships between OEF, changes in symptomatology and stroke risk in SCA. OEF has been predictive of stroke risk in other patient groups.

Noninvasive measurement of renal oxygen extraction fraction under the influence of respiratory challenge.

To demonstrate the feasibility of using a susceptibility-based magnetic resonance imaging (MRI) technique for measuring renal oxygen extraction fraction (OEF) changes under the influence of carbogen (97% O2 , 3% CO2 ) breathing. Eight New Zealand White rabbits were included in this study with local animal care committee approval. For OEF measurement, an asymmetric spin echo (ASE) sequence was used to acquire source images and a susceptibility model was utilized for OEF estimation at 3.0T. Within-session and between-day tests were conducted to evaluate the reproducibility of this OEF measurement. OEF changes were measured under respiratory challenge with alternated air and carbogen (97% O2 , 3% CO2 ) breathing. For comparison, blood samples were collected for the measurement of pO2 . The within-session coefficients of variation (CVs) of renal OEF measurements were 6.62% in cortex and 5.92% in medulla, while between-day CVs were 7.52% in cortex and 8.03% in medulla. Under carbogen breathing, renal OEFs decreased significantly from 0.32 ± 0.03 to 0.28 ± 0.02 (P < 0.01) in cortex, and from 0.34 ± 0.04 to 0.31 ± 0.03 (P < 0.01) in medulla. No statistical difference of relative OEF change was seen between cortex and medulla (P = 0.93). In addition, negative correlation between renal OEF and blood pO2 was found (r = 0.68 (P < 0.05) in cortex, and r = 0.64 (P < 0.05) in medulla). This study demonstrates the feasibility of using a susceptibility-based OEF measurement method for the evaluation of renal oxygenation changes induced by carbogen breathing. J. Magn. Reson. Imaging 2016;44:230-237.