Asymmetric Spin-echo Sequences Research Articles

Abstract WMP63: Oxygen Metabolic Stress Attributes Intrinsic Vulnerability to Watershed Regions in Healthy Individuals

Introduction: Physiological imaging studies in patients with severe steno-occlusive carotid disease (SSCD) reveal hemodynamic compromise as a mechanism underlying watershed infarcts (WI). However, it is unclear if the watershed region (WR) is intrinsically vulnerable in healthy individuals. We measured cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in healthy individuals to determine if the WR was under metabolic stress, and therefore an intrinsically vulnerable region. Methods: To define a common WR, we created an “average WI density map” using MRIs from patients with diffusion restriction ipsilateral to SSCD from a single academic center (7/10 to 8/20). WI density maps were created using 5%, 10% and 15% incidence thresholds. Maps were overlaid onto coregistered CBF and OEF maps generated from pseudo-continuous arterial spin labeling (pCASL) and asymmetric spin echo sequences, respectively, performed on healthy controls aged <55 with no vascular risk factors. OEF was normalized to whole brain values. White matter OEF and CBF was compared within vs. outside the WR using the Kruskal Wallis test. Results: 47 MRIs (mean age 62 years, 55 % females) were used to create average WI density maps using 3 thresholds (Fig A). Average CBF and OEF maps were created from 29 healthy volunteers (mean age 39 years, 59 % females). WI maps were superimposed on the CBF and OEF maps from healthy controls. OEF was higher (p<0.001), and CBF lower (p<0.001) within compared to outside the watershed regions, regardless of incidence threshold used (10% threshold shown in Fig. B-C). Conclusion: Increased OEF and decreased CBF suggest oxygen metabolic stress in the WR, suggesting that the deep white matter may be intrinsically vulnerable even in healthy individuals. Indeed, several brain pathologies (WI, white matter hyperintensities of presumed vascular origin, and multiple sclerosis lesions) are known to fall within this region.

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait.

Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P=0.053) and correlated with SCI volume (ρ=0.49, P=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

Dynamic R2' Imaging can Be a Biomarker for Diagnosing and Staging Early Acute Kidney Injury in Animals.

Background: Early diagnosis of acute kidney injury (AKI) is essential in clinical settings. None of the current biomarkers are widely applied. The combination of pulse-shifting multi-echo asymmetric spin-echo sequence (psMASE) and a modified hemodynamic response imaging (HRI) technique is promising. The purpose of this study was to evaluate the feasibility of psMASE combined with HRI in detecting early ischemic AKI in animal models of different severities.Methods: Twenty rabbits were divided into four groups (mild, moderate, and severe AKI and control groups). Transarterial embolization with different doses of microspheres was performed to establish AKI animal models of different severities. The 3T psMASE and HRI scans of kidneys were conducted. The R2*, R2, and R2' during room air and gas stimulation were acquired and the difference of R2' (dR2') was evaluated in different AKI groups.Results: The values were not different in R2* and R2 during room air and in R2* and R2, and R2' during gas stimulation. The value of R2' was significantly different during room air (P = 0.014), but the difference was only found between control and moderate/severe AKI groups (P = 0.032 and 0.022). The values of dR2' were different among groups (P < 0.0001) and differences between every two groups except comparison of moderate and severe AKI groups were significant (P < 0.01).Conclusion: The dR2' imaging acquired by a combination of renal psMASE and HRI technique can serve as a potential quantitative biomarker for early detection and staging of AKI.

Cerebral Metabolic Stress Is Lower in Patients with Sickle Cell Anemia on Hydroxyurea Therapy

Hydroxyurea (HU) is the only medication available with neuroprotective potential in sickle cell anemia (SCA), yet the physiological mechanisms of this effect remain unclear. We utilized MRI to measure cerebral blood flow (CBF) and oxygen extraction fraction (OEF) to test our hypothesis that HU therapy relieves ongoing cerebral metabolic stress by decreasing OEF in patients with SCA. Brain MRI measured CBF (pseudo-continuous arterial spin labeling), OEF (asymmetric spin echo sequence that measures voxel-wise tissue deoxyhemoglobin) and vasculopathy (magnetic resonance angiography) in prospectively enrolled participants with SCA. FMRIB9s Linear Image Registration Tool individually co-registered CBF and OEF maps to corresponding T1 images, and FMRIB9s Automated Segmentation Tool segmented gray and white matter (GM and WM). For analysis, participants were cohorted by SCA therapy they were receiving at the time of the MRI. Group comparisons between SCA without HU, SCA with HU, and SCA pre-transfusion (pre-tx; MRI up to 24 hours before chronic tx therapy) were made with Kruskal-Wallis or chi-squared test, followed by pairwise comparisons with Mann-Whitney U test. Bivariate correlations were described with Spearman9s rho. Significance was specified as p-value Seventy-nine participants with SCA (70 HbSS, 9 HbSβ 0 thalassemia) underwent MRI. There was no significant difference in age (p = 0.965) or sex (p = 0.471) among treatment cohorts. Hemoglobin (Hb) was significantly different between cohorts (p = 0.001). While the SCA without HU cohort had a significantly lower Hb than both SCA with HU (p = 0.010) and SCA pre-tx (p There was no difference in GM (p = 0.680) or WM (p = 0.736) CBF among the 3 cohorts, even after controlling for age with multiple regression. However, there was a significant difference in GM OEF among cohorts (p To investigate potential mechanisms of metabolic stress reduction, we evaluated the relationship between OEF, total Hb, % Hb A, % Hb F and % Hb S. OEF and Hb were strongly correlated in both GM and WM (GM: spearman9s rho = -0.857, p 2 = 0.737, p = 0.003), and for WM OEF (total Hb: β = -0.041, p 2 = 0.719, p We report the first investigation into the effects of HU on cerebral oxygen metabolism in SCA. Our data suggest that HU mitigates ongoing cerebral metabolic stress by improving cerebral oxygen delivery, allowing reduction in OEF without altering CBF; however, the degree of OEF correction is not as strong as chronic tx therapy. Longitudinal evaluation of these cohorts is needed to determine if the improvement in OEF by HU is sufficient for prevention of stroke and cognitive dysfunction in patients with SCA. Disclosures Fields: Proclara Biosciences: Equity Ownership. Hulbert: Pfizer: Other: Spouse employment at Pfizer.

Quantification of myocardial oxygen extraction fraction: A proof-of-concept study.

To demonstrate a proof of concept for the measurement of myocardial oxygen extraction fraction (mOEF) by a cardiovascular magnetic resonance technique. The mOEF measurement was performed using an electrocardiogram-triggered double-echo asymmetric spin-echo sequence with EPI readout. Seven healthy volunteers (22-37 years old, 5 females) were recruited and underwent the same imaging scans at rest on 2 different days for reproducibility assessment. Another 5 subjects (23-37 years old, 4 females) underwent cardiovascular magnetic resonance studies at rest and during a handgrip isometric exercise with a 25% of maximal voluntary contraction. Both mOEF and myocardial blood volume values were obtained in septal regions from respective maps. The reproducibility was excellent for the measurements of mOEF in septal myocardium (coefficient of variation: 3.37%) and moderate for myocardial blood volume (coefficient of variation: 19.7%). The average mOEF and myocardial blood volume of 7 subjects at rest were 0.61 ± 0.05 and 11.0 ± 4.3%, respectively. The mOEF agreed well with literature values that were measured by PET in healthy volunteers. In the exercise study, there was no significant change in mOEF (0.61 ± 0.06 vs 0.62 ± 0.07) or myocardial blood volume (12 ± 6% vs 13 ± 4%) from rest to exercise, as expected. The implemented cardiovascular magnetic resonance method shows potential for the quantitative assessment of mOEF in vivo. Future technical work is needed to improve image quality and to further validate mOEF measurements.

Cerebral Metabolic Stress Is Increased in Children with Sickle Cell Anemia Compared to Anemic Controls

Children with sickle cell anemia (SCA) experience a host of neurologic complications, including cognitive dysfunction, silent and overt stroke. Oxygen extraction fraction (OEF), the percent of oxygen removed from the blood into the brain tissue, can increase to compensate for decreased oxygen delivery and maintain the cerebral metabolic rate of oxygen utilization (CMRO2), as stroke occurs with a decrease in CMRO2. Elevated OEF is an independent predictor for ischemic injury in adults without SCA. We have previously shown that OEF is increased in children with SCA compared to healthy controls. Furthermore, the region of the brain with greatest elevation in OEF in SCA co-localizes with the regions at greatest risk for stroke, and OEF indirectly correlates with hemoglobin. However, it remains unclear if OEF is only elevated due to decreased arterial oxygen content with severe anemia in SCA, or if other factors contribute to this ongoing cerebral metabolic stress. We prospectively obtained brain MRIs in children with SCA, children with non-sickle cell anemia (ACTL) and healthy controls (CTL) to test our hypothesis that all children with anemia would have elevated OEF compared to controls, but those with SCA would have more elevated OEF than children with non-sickle cell anemia. Brain MRI measured voxel-wise OEF with an asymmetric spin echo sequence. OEF processing is described in Fields et al. Blood. 2019; 133(22):2436-2444. Group comparisons were made with a Mann-WhitneyUor chi-square tests. General linear models were used to understand the difference in whole brain (WB), gray matter (GM) and white matter (WM) OEF between cohorts while controlling for hemoglobin. Table 1 describes the 78 participants (20 CTL, 17 ACTL, 41 SCA). The CTL cohort includes 11 HbAA and 9 HbAS participants; the ACTL cohort includes 4 hereditary spherocytosis, 1 congenital dyserythropoietic anemia, 1 beta thalassemia intermedia, 6 iron deficiency, 4 aplastic anemia and 1 loxoscelism participant; the SCA cohort includes 36 HbSS and 5 HbS beta thalassemia null participants. Hemoglobin was lower in the ACTL (p &amp;lt; 0.001) and SCA (p &amp;lt; 0.001) cohorts compared to CTL, but was not different between the ACTL and SCA cohorts (p = 0.682). Ninety percent of the SCA cohort was receiving hydroxyurea at a median dose of 29.1 [21.5-33.1] mg/kg/day, and none were receiving chronic transfusions. Thirty-four percent of the SCA cohort had a history of silent cerebral infarct, while none had a history of overt stroke or vasculopathy identified on screening MRA. OEF was significantly elevated in the ACTL cohort compared to the CTL cohort, but significantly lower than the SCA cohort in the WB, GM and WM (Table 1, Figure 1). Final general linear models predicting WB, GM and WM OEF used a quadratic fit for hemoglobin, and included hemoglobin, hemoglobin2, and cohort as covariates. After accounting for hemoglobin and hemoglobin2(indicating that the relationship between hemoglobin and OEF is not linear), OEF is significantly higher in the SCA cohort compared to the ACTL cohort in WB, GM and WM, while there was not a significant difference in OEF between the ACTL and CTL cohorts (Table 2, Figure 2). The volume of WM with elevated OEF was significantly higher in the ACTL cohort compared to the CTL cohort (OEF 35%: p &amp;lt; 0.001, OEF 37%: p &amp;lt; 0.001, OEF 39%: p &amp;lt; 0.001), but lower in ACTL cohort compared to the SCA cohort (OEF 35%: p = 0.032, OEF 37%: p = 0.028, OEF 39%: p = 0.029). We conclude that OEF is significantly higher in children with SCA compared to age- and sex-matched children that are equally anemic for reasons other than SCA. While severity of anemia was a significant predictor of OEF, cohort (SCA vs. ACTL) remained an independent predictor of OEF across the WB, GM and WM while accounting for hemoglobin. These data suggest that further investigation is required to understand additional covariates contributing to increased cerebral metabolic stress, as measured by OEF, in children with SCA, as these may be clinical targets to reduce OEF and provide further neuroprotection in this vulnerable population. Disclosures Ford: Bluebird Bio: Honoraria. Lee:Biogen: Research Funding. Fields:Global Blood Therapeutics: Other: Speaking engagement without financial compensation; Proclara Biosciences: Current equity holder in private company; Bluebird Bio: Honoraria.

Abstract TMP112: Increased Large Vessel Diameter is Associated With Increased Cerebral Metabolic Stress in Children With Sickle Cell Anemia

Background: Children with sickle cell anemia (SCA) invoke compensatory mechanisms to meet cerebral oxygen demand in the setting of low oxygen carrying capacity. Whereas cerebral blood flow (CBF) is largely regulated by cerebral arterioles as one compensatory mechanism, we sought to determine if the cross-sectional area of the large in-flow arteries was also increased. Methods: Children and young adults with SCA underwent 3 Tesla magnetic resonance angiography (MRA) and imaging (MRI) with pseudocontinuous arterial spin labeling (pCASL) and asymmetric spin echo sequence to measure CBF and oxygen extraction fraction (OEF) respectively. Using the double oblique method, we measured artery diameters and calculated the area (A) of the vessel as A=πr 2 . The total inflow area (A T-inflow ) was the summation of the areas of distal portions of both internal carotid arteries and basilar artery. CBF, OEF, arterial oxygen content [(CaO 2 ) = 1.36*Hemoglobin*%saturation on pulse oximetry] and A T-inflow were compared between groups with nonparametric statistics. Spearman’s correlation determined relationship of A T-inflow with other variables. Results: Data was available for 29 subjects with SCA (median age 15 years (range 9-26), 45% male) and 17 age-matched controls (15y (range 9-18), 47% male) underwent scanning. Children with SCA had larger A T-inflow (36 [29, 40] mm 2 ) compared to age-matched controls (29 [26, 31] mm 2 , p=0.01). CBF and OEF were higher (p=0.001, p=0.002), and CaO 2 was lower (p&lt;0.001) in SCA compared to controls. A T-inflow positively correlated with CBF (p=0.002) and OEF (p&lt;0.001), and negatively correlated with CaO 2 (p=0.02; Figure ). Conclusion: Increased cross sectional area of large cerebral arteries may provide an additional compensatory mechanism in SCA to augment CBF and aid in meeting cerebral oxygen demand. Further work is needed to determine if MRA measurements provide a non-invasive precursor to increased cerebral metabolic stress and stroke risk.

Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia

AbstractBlood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.

Abstract WP400: Magnetic Resonance-Derived Oxygen Extraction Fraction in White Matter Hyperintensities Compared to Normal Appearing White Matter

Introduction: White matter hyperintensities (WMH), a common neuroradiological feature seen with aging, increases the risk of stroke, dementia, disability and mortality. The underlying pathophysiology leading to WMH is incompletely understood. Here, we examined the role of regional cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in WMH. Methods: Subjects with WMH (n=9) and age-matched controls (n=9) were imaged in a 3T MRI Scanner. OEF was obtained using an asymmetric spin echo sequence while CBF was obtained with pseudo-continuous arterial spin labeling. WMH were graded according to Fazekas et al. For tissue-type quantification, CBF and OEF images were segmented to classify whole brain (WB), gray matter (GM), white matter (WM), white matter hyperintensities (WMH), and normal appearing white matter (NAWM). Results: CBF and OEF in WB, GM and WM did not differ between cohorts. However, differences emerged when comparing the WMH and NAWM segmented tissues. Specifically, CBF in WMH was less than half that seen in NAWM in the WMH group, and similarly lower than normal WM in controls. Moreover, OEF in WMH was higher compared to NAWM and WM in controls, but this did not reach statistical significance (Table). Conclusions: CBF and OEF did not differ between subjects with or without WMH. However, within the WMH group, regions of WMH had significantly lower but not absent CBF and trends towards higher OEF compared to NAWM and normal WM in controls. These data suggest that regions of WMH do not represent irreversibly infarcted tissue, but rather, may be viable tissue under chronic metabolic stress. Increased OEF in WMH may be a marker of salvageable brain tissue; However, additional work is needed to confirm these results.

Dynamic measurement of oxygen extraction fraction using a multiecho asymmetric spin echo (MASE) pulse sequence.

PurposeThe oxygen extraction fraction (OEF), an important parameter for assessing brain oxygen metabolism, is a key marker of brain health. Dynamic measurement of the OEF is currently limited by the long acquisition time. In this study, a noninvasive method for rapidly and effectively assessing dynamic changes in the OEF during brain stimulation is proposed.MethodsA novel pulse sequence using the multi‐echo asymmetric spin echo with an echo‐planar imaging acquisition scheme was developed to improve the temporal resolution of functional OEF measurements. A theoretical formulation that describes the multi‐echo asymmetric spin echo signal dephasing phenomena in the presence of deoxygenated hemoglobin was established. A functional motor experiment was performed using human subjects, in which both OEF maps using the multi‐echo asymmetric spin echo sequence and blood oxygenation level–dependent maps using a ‐weighted gradient‐echo echo‐planar imaging sequence were generated and compared.ResultsThe activation maps for both OEF and blood oxygenation level–dependent maps revealed significant changes in the motor cortex. Our results, which were consistent with the previous reports, showed that the average relative changes in the OEF and blood oxygenation level–dependent signal were −22% and 2.0%, respectively.ConclusionObtaining dynamic OEF measurements during functional experiments with the proposed multi‐echo asymmetric spin echo method is feasible. Magn Reson Med 80:1118–1124, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Abstract 171: Cerebral Blood Flow and Oxygen Extraction Fraction are Age-dependent in Children and Young Adults with and without Sickle Cell Disease

Introduction: Children with sickle cell disease (SCD) are a high risk population for pediatric stroke. Young children with SCD have a higher stroke incidence than older children. Cerebral oxygen metabolism, the product of CBF, OEF and arterial oxygen content (CaO 2 , [oxygen saturation (SpO 2 ) x hemoglobin (Hb) x 1.36]) is age-dependent in healthy children, peaking at 5-9 years of age. CBF is age-dependent, but OEF variation across childhood is not well-studied. In non-SCD adults, elevated OEF confers higher stroke risk. Children with SCD have higher CBF and OEF than healthy controls, but also have lower CaO 2 . It is unknown if age independently influences CBF and OEF. We hypothesized that age, sex and CaO 2 influence components of cerebral oxygen metabolism, as measured by MRI. Methods: Subjects with SCD and sibling/relative controls without SCD underwent brain MRI with measurement of CBF and OEF by pseudocontinuous arterial spin labeling and asymmetric spin echo sequences, respectively. Blood samples were obtained for Hb and hematocrit values. A fast inversion recovery sequence measured T1 values in the superior sagittal sinus. A multiple regression model determined significant factors influencing CBF and OEF (age, sex, CaO 2 ). Results: We scanned 25 subjects without SCD (ages 6-27) and 56 subjects with SCD (ages 5-28). In multiple regression analysis, age (p=0.0009) and CaO 2 (p &lt; 0.0001) were significantly predictive of CBF, controlling for sex. Age (p=0.027) and CaO 2 (p&lt;0.0001), were also significantly predictive of OEF, controlling for sex. Conclusion: Age is an independent predictor of CBF and OEF. Younger children have higher CBF and OEF, even after controlling for the lower CaO 2 associated with SCD. This may explain the increased stroke incidence in young children with SCD.

Evaluation of renal oxygenation change under the influence of carbogen breathing using a dynamic R2 , R2 ' and R2 * quantification approach.

The purpose of this study is to demonstrate the feasibility of dynamic renal R2 /R2 '/R2 * measurements based on a method, denoted psMASE-ME, in which a periodic 180° pulse-shifting multi-echo asymmetric spin echo (psMASE) sequence, combined with a moving estimation (ME) strategy, is adopted. Following approval by the institutional animal care and use committee, a block design of respiratory challenge with interleaved air and carbogen (97% O2 , 3% CO2 ) breathing was employed in nine rabbits. Parametrical R2 /R2 '/R2 * maps were computed and average R2 /R2 '/R2 * values were measured in regions of interest in the renal medulla and cortex. Bland-Altman plots showed good agreement between the proposed method and reference standards of multi-echo spin echo and multi-echo gradient echo sequences. Renal R2 , R2 ' and R2 * decreased significantly from 16.2±4.4s-1 , 9.8±5.2s-1 and 25.9±5.0s-1 to 14.9±4.4s-1 (p<0.05), 8.5±4.1s-1 (p<0.05) and 23.4±4.8s-1 (p<0.05) in the cortex when switching the gas mixture from room air to carbogen. In the renal medulla, R2 , R2 ' and R2 * also decreased significantly from 12.9±4.7s-1 , 15.1±5.8s-1 and 27.9±5.3s-1 to 11.8±4.5s-1 (p<0.05), 14.2±4.2s-1 (p<0.05) and 25.8±5.1s-1 (p<0.05). No statistically significant differences in relative R2 , R2 ' and R2 * changes were observed between the cortex and medulla (p=0.72 for R2 , p=0.39 for R2 ' and p=0.61 for R2 *). The psMASE-ME method for dynamic renal R2 /R2 '/R2 * measurements, together with the respiratory challenge, has potential use in the evaluation of renal oxygenation in many renal diseases.

Simultaneous dynamic R2 R2', and R2* measurement using periodic π pulse shifting multiecho asymmetric spin echo sequence moving estimation strategy: A feasibility study for lower extremity muscle.

The purpose of this study was to demonstrate the feasibility of simultaneous dynamic R2 , R2', and R2* measurement of lower extremity muscle by means of a new method in which the periodic π pulse shifting multiecho asymmetric spin echo (psMASE) sequence is adopted together with a moving estimation (ME) strategy. The psMASE sequence is a modification of the multiecho asymmetric spin echo sequence determined by shifting the 180 ° refocusing pulse periodically. ME strategy is introduced to improve the temporal resolution of the simultaneous dynamic measurement of R2 , R2', and R2*. Reproducibility measurements and comparison with reference methods were conducted. Furthermore, this method was tested on 10 healthy volunteers with the dynamic imaging of lower extremity muscles during a cuff occlusion release paradigm. Both phantom and in vivo comparisons demonstrated that psMASE-ME-based R2 and R2* had good agreement with those calculated by multiecho spin echo and gradient echo sequences. Scan-rescan tests showed good reproducibility. Moreover, muscle R2 , R2', and R2* increased obviously from rest to cuff occlusion and decreased significantly after cuff release. It is feasible to obtain high temporally resolved R2 , R2', and R2* simultaneously with the proposed psMASE-ME method. Magn Reson Med 77:766-773, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Abstract WMP97: Regional Cerebral Oxygen Extraction is Elevated in Tissue at High Risk of Stroke in Pediatric Sickle Cell Disease

Introduction: Children with sickle cell disease (SCD) are at high risk of stroke. Hemispheric oxygen extraction fraction (OEF) is a predictor of stroke in adults with carotid occlusion, but OEF has not been evaluated as a predictor of stroke in children with SCD. Hypothesis: OEF is elevated in SCD children compared to controls within a region at high risk of stroke as defined by an infarct heat-map created from a separate retrospective SCD cohort. Methods: A prospective MRI study enrolled 37 children aged 5-21: 17 with SCD and no stroke, 12 with SCD and silent infarcts (median infarct volume=0.3ml), and 8 sibling controls. None were on transfusions or had overt stroke history. Voxel-wise OEF was measured using an asymmetric spin echo sequence. In a separate retrospective cohort of 67 SCD children with overt and silent stroke, infarct regions on FLAIR were manually outlined and coregistered to an average T1 map to create an infarct heat-map (Fig A) which was used to define a “high risk” ROI (defined by &gt;3% infarct density). This ROI was aligned to individual OEF maps from the prospective cohort (Fig B, average OEF map). OEF within the “high risk” ROI was compared between SCD children and controls; and between SCD children with and without infarction using Mann Whitney U tests. Results: The infarct heat-map from the retrospective cohort (Fig A) and the average OEF map from the prospective SCD cohort (Fig B) demonstrate striking co-localization of infarct density and elevated OEF. Within the “high risk” ROI, OEF was higher in SCD children compared to controls (39% [36, 46] vs. 23% [22, 27], p&lt;0.0001 (Fig C). OEF within this “high risk” ROI did not differ between SCD children with and without infarcts (40% [38, 47] vs. 38% [35, 46], p=0.6). Conclusion: OEF in SCD children is elevated in the internal borderzone, a region with high stroke risk in SCD. Regional OEF may be a marker of cerebral metabolic stress that could be exploited to stratify stroke risk in this vulnerable population.

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.

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.

Elevations in MR Measurements of Whole Brain and Regional Cerebral Blood Flow and Oxygen Extraction Fraction Suggest Cerebral Metabolic Stress in Children with Sickle Cell Disease Unaffected By Overt Stroke

Positron emission tomography (PET) studies have shown that the brain increases cerebral blood flow (CBF) and oxygen extraction fraction (OEF, the fraction of oxygen brain tissue extracts from blood) when oxygen delivery is compromised in adult ischemic stroke. Children with sickle cell disease (SCD) have higher CBF compared to healthy children, suggesting that autoregulatory mechanisms, compensating for compromised oxygen delivery, may underlie the pathophysiology of ischemic stroke in SCD. Until now, evaluation of cerebral oxygen metabolism in children with SCD has been limited to measurement of CBF due to the radiation risks of PET. We used a MR sequence that measures voxel-wise OEF to test our hypothesis that children with sickle cell disease will have elevated whole brain and regional OEF when compared to typically developing, sibling controls without SCD.Thirty-six participants, 8 controls and 28 with SCD (26 HbSS and 2 HbSB0), ages 5-21 years, were recruited from St. Louis Children's Hospital. Participants underwent brain MRI with measurement of CBF via pseudo-continuous arterial spin labeling and OEF via a novel processing of asymmetric spin echo sequence that measures tissue deoxyhemoglobin. CBF and OEF maps were individually co-registered to corresponding T1 images with FMRIB's Linear Image Registration Tool, and gray and white matter were segmented with FMRIB's Automated Segmentation Tool. Visual inspection identified a region of high OEF within the deep white matter of the frontal and parietal lobes in the majority of subjects (figure 1 a,b). OEF maps from control and SCD participants were coregistered and averaged into a single map, and then an OEF threshold of 47.5% was applied to demarcate this "high OEF region" (figure 1c). Hemoglobin (Hb) and hematocrit were obtained in SCD participants, while these values were assumed for the controls. Arterial oxygen content (CaO2) was calculated as 1.36 x Hb x SpO2. Comparisons were made with a Mann-Whitney U test or Student's t-test. Bivariate correlations were tested with Kendall's tau b. Bonferroni correction was used in determining significance. Multivariate linear regression modeling with block entry described covariates associated with CBF.The control and SCD cohorts did not differ in age, gender or SpO2. SCD participants demonstrated higher whole brain, gray matter and white matter CBF and OEF when compared to controls (table 1, figure 1a-b), but there was no difference in whole brain or segmented measures of CBF and OEF between SCD participants with structurally normal brain MRIs (n=16) and silent infarcts (n=12). SCD participants' OEF was higher within the "high OEF region" when compared to controls (table 1), but the regional OEF did not differ between SCD participants with structurally normal brain MRIs versus silent infarcts. Whole brain CBF negatively correlated with age (b = -0.554, p < 0.001), while whole brain OEF did not (b= 0.014, p = 0.921). Lower CaO2 correlated with higher whole brain CBF (b = -0.329, p < 0.016) and higher whole brain OEF (b = -0.587, p < 0.001). CaO2 remained a predictor (β = -0.38, p = 0.009) of CBF when controlling for age (β = -0.63, p < 0.001).We report the first whole brain, segmented and regional analysis of oxygen metabolism, including CBF and OEF, in a pediatric SCD cohort unaffected by overt stroke. Elevation in both CBF and OEF in response to low arterial oxygen content suggests children with SCD are chronically compensating to meet the brain's metabolic demands. OEF is more elevated in children with SCD when compared to healthy controls within the "high OEF region," which coincides with previously reported locations of silent infarcts. We propose that the "high OEF region" provides a tissue signature of vulnerable, metabolically stressed brain that is at risk for future stroke. [Display omitted] [Display omitted] DisclosuresFields:Neurophage: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Noninvasive measurement of lower extremity muscle oxygen extraction fraction under cuff compression paradigm.

To demonstrate the feasibility of using a susceptibility-based MRI technique with asymmetric spin-echo (ASE) sequence to assess the lower extremity muscle oxygen extraction fraction (OEF) alternations under cuff compression paradigm. Approved by the local institutional human study committee, nine healthy young volunteers participated in this study. All the ASE scans were conducted using a 3 Tesla clinical MRI scanner during resting state (pre), 1-3 min (post1) and 3-5 min (post2) after a pressure of 50 mmHg above individual systolic blood pressure imposed on the thigh. Moreover, near-infrared spectroscopy (NIRS) measurements were performed on the same day under the same cuff compression protocol to verify the accuracy of this susceptibility-based method. In all volunteers, the mean MRI based OEF in gastrocnemius (GAS) muscle increased significantly from 0.28 ± 0.02 (pre) to 0.31 ± 0.03 (post1, P < 0.05) and 0.31 ± 0.03 (post2, P < 0.05). In addition, mean OEF in soleus (SOL) muscle went up from 0.31 ± 0.01 (pre) to 0.33 ± 0.03 (post1, P = 0.14) and 0.37 ± 0.04 (post2, P < 0.05). For comparison, NIRS measured 1-%HbO2 (percentage of deoxyhemoglobin concentration within total hemoglobin) in GAS rose significantly from 0.29 ± 0.03 (pre) to 0.31 ± 0.04 (post1, P < 0.05) and 0.31 ± 0.04 (post2, P < 0.05), which confirmed the accuracy of the MRI-based OEF. This susceptibility-based OEF quantification technique together with cuff compression paradigm could provide a noninvasive, quantifiable and effective tool for measuring skeletal muscle oxygenation.

Abstract T P370: Blood Transfusions in Pediatric Sickle Cell Disease Normalize Cerebral Blood Flow While Maintaining Constant Cerebral Oxygen Metabolism

Background: Chronic blood transfusions (Tx) reduces stroke risk in pediatric sickle cell disease (SCD). Cerebral blood flow (CBF) is elevated in SCD, likely representing a compensatory mechanism to maintain cerebral oxygen metabolism (CMRO2) in the setting of reduced arterial oxygen content (CaO2) from chronic anemia. When exhausted compensatory mechanisms are unable to meet oxygen demands, stroke ensues. We measured MR-derived CBF and oxygen extraction fraction (OEF) pre- and post-Tx, hypothesizing that Tx ‘resets’ the CBF baseline by increasing CaO2 via increased hemoglobin (Hb), while maintaining cerebral oxygen delivery and metabolism. Methods: SCD children on chronic Tx were enrolled in a prospective, observational MRI study. MR-CBF and MR-OEF were acquired before and 2 hours after exchange Tx. MR-CBF and MR-OEF were measured using pseudocontinuous arterial spin labelling and a novel asymmetric spin echo sequence, respectively. CaO2 =1.35 x [Hb] x SaO2. CMRO2 = CaO2 x CBF x OEF. Results: Two SCD children underwent MRI pre- and post-Tx (six more are anticipated prior to ISC). For subject #1 (18 yo F with overt stroke), mean global CBF was 128 and 98 ml/min/100g pre- and post-Tx, respectively, indicating a 24% CBF reduction. For subject #2 (6 yo F with elevated transcranial Doppler velocities), mean global CBF was 189 and 129 ml/min/100g pre- and post-Tx, respectively, a 32% CBF reduction (Fig). Both Hb and CaO2 were increased after Tx, resulting in unchanged oxygen delivery (CaO2 x CBF) post-Tx. Moreover, OEF and CMRO2 were not significantly different pre- and post-Tx, consistent with our hypothesis that CBF increases to maintain oxygen delivery. Conclusions: Elevated CBF is likely a compensatory mechanism to maintain constant oxygen delivery in SCD children who have chronically low CaO2. In our subjects, Tx improved CaO2, allowing CBF to normalize. This reduced hemodynamic stress likely contributes to the lower stroke risk in chronically transfused SCD children.

Fast accurate MR thermometry using phase referenced asymmetric spin‐echo EPI at high field

A novel highly accurate method for MR thermometry, effective at high field, is introduced and validated, which corrects for slow and fast field fluctuations by means of reference images. An asymmetric spin-echo echo planar imaging sequence was made frequency-selective to water or a reference substance by controlling the slice-select gradient polarity and the duration of the excitation and refocusing radiofrequency pulses. Images were acquired pairwise, and the temperature-sensitive water images were corrected for field fluctuations using the reference images. In a phantom radiofrequency heating experiment, dissolved dimethyl sulfoxide was used as a reference substance. Temperature stability was tested in vivo on the human brain, referenced using subcutaneous scalp fat. Water and fat phase images were acquired only 50 ms apart. Bloch simulations validated the frequency selection accuracy. Asymmetric spin-echo imaging using a simple frequency selection method provides highly accurate referenced MR thermometry in phantoms and in vivo at 7 T. Effects of field fluctuations caused by field drift, breathing, and heart beat were corrected. The technique is highly robust against B1 inhomogeneities. Frequency selection using gradient-reversal can enable fast accurate referenced in vivo MR thermometry, assisting thermal characterization of radiofrequency coils and possibly in vivo SAR monitoring.