Elevated Oxygen Extraction Fraction Research Articles

Comparison of cerebral oxygen extraction fraction using ASE and TRUST methods in patients with sickle cell disease and healthy controls

Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD.

Brain Frontal-Lobe Misery Perfusion in COVID-19 ICU Survivors: An MRI Pilot Study.

Post-acute COVID-19 syndrome (PCS) is highly prevalent. Critically ill patients requiring intensive care unit (ICU) admission are at a higher risk of developing PCS. The mechanisms underlying PCS are still under investigation and may involve microvascular damage in the brain. Cerebral misery perfusion, characterized by reduced cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF) in affected brain areas, has been demonstrated in cerebrovascular diseases such as carotid occlusion and stroke. This pilot study aimed to examine whether COVID-19 ICU survivors exhibited regional misery perfusion, indicating cerebral microvascular damage. In total, 7 COVID-19 ICU survivors (4 female, 20-77 years old) and 19 age- and sex-matched healthy controls (12 female, 22-77 years old) were studied. The average interval between ICU admission and the MRI scan was 118.6 ± 30.3 days. The regional OEF was measured using a recently developed technique, accelerated T2-relaxation-under-phase-contrast MRI, while the regional CBF was assessed using pseudo-continuous arterial spin labeling. COVID-19 ICU survivors exhibited elevated OEF (β = 5.21 ± 2.48%, p = 0.047) and reduced relative CBF (β = -0.083 ± 0.025, p = 0.003) in the frontal lobe compared to healthy controls. In conclusion, misery perfusion was observed in the frontal lobe of COVID-19 ICU survivors, suggesting microvascular damage in this critical brain area for high-level cognitive functions that are known to manifest deficits in PCS. Physiological biomarkers such as OEF and CBF may provide new tools to improve the understanding and treatment of PCS.

Topographic mapping of oxygen extraction and cerebral venous blood volume fraction in Brain tumors using quantitative BOLD: A case report

Background: While oxygen extraction fraction (OEF) reflects the underlying variations in cerebral brain oxygen metabolism, tissue voxels having elevated volume fraction of blood vessel network with deoxygenated blood, will apparently contribute to higher cerebral venous blood volume fraction (CVBVF). This Case report examines the difference in intra and peri-tumoral topographical patterns of OEF and CVBVF in cases of a meningioma tumor (Case-I) and a low- grade glioma (Case-II). Methods: Using a “static dephasing regime” BOLD model, we use the BOLD signal model containing parameters representing OEF and CVBVF. For each voxel in the region of interest, the parameters are solved by non-linearly fitting the signal model using paired differences between logarithms of the measured echo signal after inhomogeneity correction. Results: OEF and CVBVF maps in Case-I reveals an interesting phenomenon in the peritumoral parenchyma showing reduced OEF and increased CVBVF levels. The uniformly low CVBVF and elevated OEF in Case-II indicates that even with less density of vasculature, the region extracts higher amount of oxygen. Conclusion: While topographic mapping using qBOLD revealed elevated levels of intra-tumoral OEF for both cases, the pattern of CVBVF variation was uniformly low in Case-II.

The Effect of Tucaresol on Translational MRI Estimates of Cerebral Physiology in Townes SCD Mice

Sickle Cell Disease (SCD) is characterized by severe hemolytic anemia and low Hct. This contributes to elevated cerebral cerebrometabolic strain, as evidenced by increased cerebral blood flow (CBF), increased blood oxygen extraction fraction (OEF), and increased incidence of silent cerebral infarct. Recent reports have shown that approved and experimental therapies ameliorate these physiological indicators of strain in SCD patients using advanced MRI-based techniques (Fields, et al., Blood, 2019; Hulbert, et al., Blood 2022), but the effect on these same MRI endpoints has not been demonstrated in animal models of SCD. The purpose of this work was to perform these same measurements in Townes SCD mice treated with tucaresol, which is known to increase the oxygen affinity hemoglobin, thus building a translational platform for non-invasive assessment of these endpoints to support characterization of novel therapies and their relationship to cerebrometabolic strain that leads to end organ damage in the brain. All animal procedures were performed under an IACUC-approved protocol. Forty-three male Townes SCD mice were assigned to two treatment groups (n=21 / 22, mean age = 8.1±0.8 / 8.4 ±0.6 weeks, mean weight = 26±2 / 26±2 g). Animals were anesthetized and scanned on a 9.4 T Bruker MRI scanner at MGH. CBF was measured using a pseudo-continuous arterial spin labeling sequence (pCASL) (Hirschler, et al., NMR in Biomedicine, 2018), and OEF was estimated from a T2 measurement in the superior sagittal sinus using a TRUST sequence (Wei, et al., Magn. Reson. Med., 2018) and a hematocrit measure which was taken from a tail vein bleed immediately following the scan. Following anesthesia recovery from the first imaging timepoint, animals were placed in cages according to group assignment and drinking water was replaced by one of two masked dosing solutions. prepared off-site by an independent team, containing either 1.14 mM tucaresol or pH and color-matched water. The tucaresol concentration was chosen to approximate an oral dose of 60 mg/kg/day comparable to a clinical dose and be consistent with previous studies. After two weeks of ad lib exposure to the dosing solutions, the scanning and blood sampling procedure was repeated. A terminal cardiac punch was also performed under anesthesia to assess tucaresol blood exposure. Due to technical challenges Hct measures were not performed in the first five animals from each group, and two animals had Hct measures at only the second timepoint. CBF is reported in whole bilateral striatum. Whole blood analysis revealed tucaresol exposures of 0.1-0.6 mM in the active arm. While still within the range for hemoglobin modification, the exposures were similar but somewhat lower than the exposures of 0.5-1.6 mM reported from oral gavage at 30 mg/kg twice per day in SCD mice (Knee et al. Blood, 2016). Table 1 shows CBF, Hct, and OEF values at baseline and after two weeks of dosing for each group. OEF values assume arterial oxygen saturation of 1. Spaghetti plots in figure 1 display changes in these values for individual animals. CBF elevations are observed very early in clinical SCD populations and begin to plateau as the disease progresses, but OEF has been shown to increase as the disease progresses (Juttukunda, et al., J. Magn. Reson. Imaging, 2019). As a result, therapeutic interventions in advanced disease may be expected to first affect OEF, with decreases in CBF to follow. That may, in part explain why a treatment effect was observed with OEF and not with CBF. Additionally, the proximity of the labeling plane of inflowing arterial blood to the brain tissue being perfused and the high carotid artery flow rate in these animals means that the CBF measure by pCASL MRI is considerably more challenging in mice than in humans. The sensitivity of MRI-derived OEF to therapeutic intervention in mice is similar to what has been reported in SCD patients, where elevated OEF is particularly associated with regions of the brain at highest risk for developing silent infarct. CBF and OEF are currently being evaluating for an approved HbS modifier (NCT05228821). The ability to use the same techniques in both mice and humans to non-invasively and quantitatively demonstrate the amelioration of the cerebrophysiological compensatory measures that precede end CNS organ damage is a valuable step in characterizing potential benefit of novel therapeutics beyond standard regulatory endpoints associated with pain crises.

Abstract 129: Cerebral Oxygen Extraction Fraction Predicts White Matter Lesion Progression In Patients With A Monogenic Cerebral Small Vessel Disease

Background: A rare, monogenic cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), is associated with progressive cerebral ischemia and accelerated vascular cognitive impairment, resulting in premature death. We hypothesized that low cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF), as metrics of microvascular ischemia, would predict growth of white matter lesions (WML) and other neuroimaging manifestations of cSVD. Methods: We prospectively performed sequential brain MRI in a cohort of RVCL-S participants. Pseudocontinuous arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal appearing white matter (NAWM), respectively. WMLs were manually delineated on FLAIR. WM volumes were segmented and quantified. Diffusion tensor imaging (DTI) was used to measure NAWM mean diffusivity (MD). Results: Each of 14 RVCL-S participants underwent a median of 4.5 scans (IQR 3 - 6.75) with a median of 6.5 months (IQR 5.8 - 8.6) between scans performed over 2.9 years (IQR 2.0 - 4.2). Elevated NAWM OEF from the previous MRI, but not CBF, was associated with WML growth (ρ = 0.672, p < 0.0001), WM atrophy (ρ = 0.654, p < 0.0001), and increased MD (ρ = 0.714, p < 0.0001, Figure). After adjusting for age, sex, previous WML volume, and participant, previous OEF remained an independent predictor of WML growth (β = 7.04 (1.08, 13.01), p = 0.021). NAWM OEF was not retained in the mixed models predicting WM atrophy and MD. Conclusion: We found evidence that hypoxic-ischemic physiology, as measured by elevated OEF in NAWM, independently predicted WML growth. Previous OEF was associated with WM atrophy and decrease in microstructural integrity on follow-up. This work suggests that ischemia in normal brain regions may be a harbinger of disease progression in patients with RVCL-S, an inherited cSVD. Additionally, OEF may serve as a potential predictive biomarker in sporadic cSVD.

Cerebral oxygen metabolic stress is increased in children with sickle cell anemia compared to anemic controls.

Patients with sickle cell anemia (SCA) experience cerebral metabolic stress with an increase in oxygen extraction fraction (OEF) to compensate for reduced oxygen carrying capacity due to anemia. It remains unclear if anemia alone drives this metabolic stress. Using MRI, we collected voxel-wise OEF measurements to test our hypothesis that OEF would be elevated in anemic controls without SCA (AC) compared to healthy controls (HC), but OEF would be even higher in SCA compared to AC. Brain MRIs (N=159) were obtained in 120 participants (34 HC, 27 AC, 59 SCA). While hemoglobin was lower in AC versus HC (p < 0.001), hemoglobin was not different between AC and SCA cohorts (p=0.459). Whole brain OEF was higher in AC compared to HC (p < 0.001), but lower compared to SCA (p=0.001). Whole brain OEF remained significantly higher in SCA compared to HC (p=0.001) while there was no longer a difference between AC versus HC (p=0.935) in a multivariate model controlling for age and hemoglobin. OEF peaked within the border zone regions of the brain in both SCA and AC cohorts, but the volume of white matter with regionally elevated OEF in AC was smaller (1.8%) than SCA (58.0%). While infarcts colocalized within regions of elevated OEF, more SCA participants had infarcts than AC (p < 0.001). We conclude that children with SCA experience elevated OEF compared to AC and HC after controlling for the impact of anemia, suggesting that there are other pathophysiologic factors besides anemia contributing to cerebral metabolic stress in children with SCA.

Oxygen Metabolic Stress and White Matter Injury in Patients With Cerebral Small Vessel Disease.

Chronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth. In this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions. In a cohort of 42 participants (age 50-80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions. Chronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression.

Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease.

ObjectiveTo determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD).MethodsControl participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location.ResultsOf 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g, p < 0.001), increased OEF (0.35 vs 0.25, p < 0.001), increased MD (0.76 vs 0.72 × 10−3 mm2s−1, p = 0.005), and decreased FA (0.40 vs 0.42, p = 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19, p = 0.035), but not CBF (β = 0.00, p = 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort.ConclusionElevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD.

Cerebral Hemodynamics and Executive Function in Sickle Cell Anemia.

Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen extraction fraction are associated with lower executive function in individuals with sickle cell anemia. Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance: P<0.05). Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts. Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.

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.

Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease.

Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = -0.760 [95% CI = -1.297, -0.224]), default mode (p = 0.012, parameter estimate = -0.417 [95% CI = -0.731, -0.104]), and cingulo-opercular (p = 0.009, parameter estimate = -0.883 [95% CI = -1.517, -0.250]) networks decreased. We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020;88:995-1008.

Detection of hemodynamic impairment on 15O gas PET using visual assessment of arterial spin-labeling MR imaging in patients with moyamoya disease

It is unclear whether the visual assessment of noninvasive arterial spin labeling magnetic resonance imaging (ASL) can identify instances of hemodynamic compromise including an elevated oxygen extraction fraction (OEF) measured by 15O-gas positron emission tomography (PET). Here we evaluated the relationship between a four-point visual assessment system referred to as 'ASL scores' using ASL with two postlabeling delays (PLDs; 1525 ms and 2525 ms) and some quantitative hemodynamic parameters measured by PET. We retrospectively evaluated the cases of 18 Japanese patients with moyamoya disease who underwent ASL and PET. We compared the patients' regional ASL scores on two ASL images to the regional values of PET parameters, and we observed a significant trend in accord with the presumed clinical severity among all PET parameters and ASL scores (p < .003). The ASL score of the long PLD (2525 ms) showed the highest specificity (98.5%) for elevated OEF. Our results suggest that hemodynamic impairment (including elevated OEF) in patients with moyamoya disease may be grossly assessed by a visual assessment of noninvasive ASL images, which can be easily obtained in clinical settings.

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.

Asymmetric Cortical Vessel Sign Indicates Hemodynamic Deficits in Adult Patients with Moyamoya Disease

Asymmetric cortical vessel sign (ACVS) on susceptibility-weighted imaging (SWI) indicates elevated concentration of deoxyhemoglobin and elevated oxygen extraction fraction in patients with cerebral ischemia. This study aimed to clarify whether ACVS is associated with impaired hemodynamics and hyperperfusion syndrome in patients with moyamoya disease (MMD). Consecutive adult patients with MMD were enrolled. ACVS data on SWI and perfusion data using dynamic perfusion computed tomography were obtained and evaluated preoperatively and on postoperative days 2 and180. A total of 24 patients with MMD were enrolled. Of 11 (45.83%) patients showing positive ACVS before surgery, 8 turned negative on postoperative day 2 and 9 showed absence of ACVS 180 days after surgery. Regions of interest showing positive ACVS had lower cerebral blood flow (CBF, P<0.001), increased cerebral blood volume (P= 0.021), prolonged time to peak (P<0.001), and mean transit time (P= 0.009). No patients with hemorrhagic symptoms showed positive ACVS(P= 0.041) and patients with positive ACVS showed more increase in CBF (P<0.004). In patients with MMD, ACVS on SWI indicates severe impairment in hemodynamics and is associated with more increase in CBF after bypass surgery. Hence, ACVS on SWI might be considered as a neuroimaging marker for the evaluation of hemodynamics in patients with MMD.

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

Abstract 51: Aging and Metabolic Stress Are Associated With Disrupted White Matter Integrity in Children and Young Adults With Sickle Cell Disease

Introduction: Silent cerebral infarcts (SCIs) in sickle cell disease (SCD) begin in early childhood and increase with age, affecting 50% by age 30. SCIs often occur in the watershed area, where cerebral blood flow (CBF) is low, and oxygen extraction fraction (OEF) is high. Diffusion tensor imaging (DTI) measures white matter integrity; lower fractional anisotropy (FA) and higher mean diffusivity (MD) may precede the appearance of SCIs. We hypothesized that age and oxygen metabolic stress, defined by elevated watershed OEF, are associated with disruption of white matter integrity as measured by FA and MD. Methods: Children and young adults with and without SCD were recruited for brain MRI (T1, FLAIR, pseudocontinuous arterial spin label (CBF), asymmetric spin echo (OEF) and DTI). We averaged CBF maps of non-SCD participants and created a watershed region of interest (ROI), defined as CBF &lt;30% of mean gray matter CBF, which was applied to individual maps. All SCIs were outlined and excluded. We evaluated age and SCD as predictors of FA and MD. Within the watershed ROI, we evaluated OEF and age as predictors of FA and MD. Results: Fifty SCD and 53 control participants, age 6-39 years, underwent MRI. Within all normal appearing white matter, FA decreased (p&lt;0.001) and MD increased (p&lt;0.001) with advancing age. MD, but not FA, changed at a faster rate with advancing age in SCD compared to controls (p=0.02). Within the watershed region, OEF significantly predicted FA (p=0.002) and MD (p &lt;0.001), after adjusting for age. Conclusion: Disruption of white matter integrity worsens with early life aging, particularly in SCD. Oxygen metabolic stress within the watershed region, a region at high risk for SCIs, is associated with lower FA and higher MD, suggesting OEF may provide an early tissue marker of ischemic vulnerability in SCD, prior to developing SCIs.

Elevated brain oxygen extraction fraction in preterm newborns with anemia measured using noninvasive MRI.

To test the hypothesis that cerebral oxygen extraction fraction (OEF) is elevated and inversely related to hematocrit level in anemic former very-low-birth-weight infants near term. Prospective study of non-sedated preterm infants (post-menstrual age = 36 ± 2 weeks) over a range of hematocrits (0.23-0.49). Anatomical (T1-W, T2-W, and diffusion-weighted), cerebral blood flow (CBF), and OEF 3-T MRI were utilized. Statistical analysis included Spearman's rank-order correlation testing between study variables and intraclass correlation coefficients (ICC) calculated between consecutively acquired OEF scans. Consecutive OEF measurements showed moderate-to-good agreement (ICC = 0.71; 95% CI = 0.40-0.87). OEF increased with worsening anemia (ρ = -0.58; p = 0.005), and OEF and basal ganglia CBF were positively correlated (ρ = 0.49; p = 0.023). Noninvasive OEF MRI has moderate-to-good repeatability in non-sedated former preterm infants nearing term-equivalent age. Strong correlation of elevated OEF with anemia suggests hemodynamic compensation for anemia and could establish OEF as a useful biomarker of transfusion threshold for preterm infants.

Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease.

To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO2) in children with SCD. Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps. Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort. Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.

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 109: Non-invasive Detection of Capillary Arteriovenous Shunting in Patients With Sickle Cell Anemia

Introduction: High blood velocity can cause rapid erythrocyte transit through capillaries, reducing efficiency of oxygen delivery to tissue (capillary arteriovenous shunting). Arterial spin labeling (ASL) is an MRI technique that utilizes magnetic labeling of arterial blood water for CBF quantitation. Labeled water that traverses capillaries without exchanging with tissue leads to hyperintense venous signal indicative of arteriovenous shunting. We hypothesized that venous hyperintensity is present in sickle cell anemia (SCA) adults, correlates with flow velocity, and corresponds with clinical impairment and oxygen extraction fraction (OEF). Methods: ASL for shunting determination, TRUST for OEF measurement, phase contrast angiography for velocity assessment, and FLAIR / MRA for infarct / vasculopathy evaluation were performed at 3T in adults with SCA (n=36) and age- and race-matched controls (n=11). Three reviewers assessed for hyperintensity in the superior sagittal sinus on ASL images (Fig) and assigned scores of 0 (none), 1 (mild, focal), 2 (significant, focal), or 3 (significant, diffuse). Shunting scores were compared with the presence of clinical impairment (prior infarcts, stenosis&gt;50%, or severe disease requiring transfusions) and OEF. Results: Interobserver agreement was excellent (Fleiss’ κ=0.91). Consensus shunting score in SCA adults (1.2±1.1) was higher (p&lt;0.01) than controls (0.1±0.3), Median age 27.6 y, 57% F. Elevated shunting scores were observed in SCA adults with (1.23±1.07) vs. without (1.07±1.16) clinical impairment. A trend (p=0.068) for elevated OEF was observed in those with shunting scores ≥2 (0.44±0.07) vs. those with shunting scores ≤1 (0.40±0.07). Cervical flow velocity was elevated in subjects with shunting scores ≥2 (30.2±4.8 cm/s) vs. ≤1 (25.3±4.8 cm/s). Conclusion: Venous hyperintensity in ASL images may indicate capillary arteriovenous shunting and may reflect higher clinical impairment and elevated OEF.