Oxygen Extraction Fraction Research Articles

Assessment of functional shunting in patients with sickle cell disease.

Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption. Functional cerebrovascular shunting is defined as reduced oxygen offloading due to the rapid transit of blood through the capillaries caused by increased flow and has been suggested as a potential mechanism underlying reduced oxygenation and SCI. We investigated the venous arterial spin labeling signal (VS) in the sagittal sinus as a proxy biomarker of cerebral functional shunting, and its association with hemodynamic imaging and hematological laboratory parameters. We included 28 children and 38 adults with SCD, and ten healthy racematched adult controls. VS, cerebral blood flow (CBF), velocity in the brain feeding arteries, oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) were measured before and after acetazolamide administration. VS was higher in patients with SCD compared to controls (P<0.01) and was increased after acetazolamide administration in all groups (P<0.01). VS was primarily predicted by CBF (P<0.01), but CBF-corrected VS was also associated with decreased CMRO2 (P<0.01). Additionally, higher disease severity defined by low hemoglobin and increased hemolysis was associated with higher CBF-corrected VS. Finally, CMRO2 was negatively correlated with fetal hemoglobin, and positively correlated with lactate dehydrogenase, which could be explained by changes in oxygen affinity. These findings provide evidence for cerebral functional shunting and encourage future studies investigating the potential link to aberrant capillary exchange in SCD.

Cerebral oxygen extraction fraction MRI: Techniquesand applications.

The human brain constitutes 2% of the body's total mass but uses 20% of the oxygen. The rate of the brain's oxygen utilization can be derived from a knowledge of cerebral blood flow and the oxygen extraction fraction (OEF). Therefore, OEF is a key physiological parameter of the brain's function and metabolism. OEF has been suggested to be a useful biomarker in a number of brain diseases. With recent advances in MRI techniques, several MRI-based methods have been developed to measure OEF in the human brain. These MRI OEF techniques are based on the T2 of blood, the blood signal phase, the magnetic susceptibility of blood-containing voxels, the effect of deoxyhemoglobin on signal behavior in extravascular tissue, and the calibration of the BOLD signal using gas inhalation. Compared to 15 O PET, which is considered the "gold standard" for OEF measurement, MRI-based techniques are non-invasive, radiation-free, and are more widely available. This article provides a review of these emerging MRI-based OEF techniques. We first briefly introduce the role of OEF in brain oxygen homeostasis. We then review the methodological aspects of different categories of MRI OEF techniques, including their signal mechanisms, acquisition methods, and data analyses. The strengths and limitations of the techniques are discussed. Finally, we review key applications of these techniques in physiological and pathological conditions.

Ongoing Exercise Intolerance Following COVID-19: A Magnetic Resonance-Augmented Cardiopulmonary Exercise Test Study.

BackgroundOngoing exercise intolerance of unclear cause following COVID‐19 infection is well recognized but poorly understood. We investigated exercise capacity in patients previously hospitalized with COVID‐19 with and without self‐reported exercise intolerance using magnetic resonance–augmented cardiopulmonary exercise testing.Methods and ResultsSixty subjects were enrolled in this single‐center prospective observational case‐control study, split into 3 equally sized groups: 2 groups of age‐, sex‐, and comorbidity‐matched previously hospitalized patients following COVID‐19 without clearly identifiable postviral complications and with either self‐reported reduced (COVIDreduced) or fully recovered (COVIDnormal) exercise capacity; a group of age‐ and sex‐matched healthy controls. The COVIDreducedgroup had the lowest peak workload (79W [Interquartile range (IQR), 65–100] versus controls 104W [IQR, 86–148]; P=0.01) and shortest exercise duration (13.3±2.8 minutes versus controls 16.6±3.5 minutes; P=0.008), with no differences in these parameters between COVIDnormal patients and controls. The COVIDreduced group had: (1) the lowest peak indexed oxygen uptake (14.9 mL/minper kg [IQR, 13.1–16.2]) versus controls (22.3 mL/min per kg [IQR, 16.9–27.6]; P=0.003) and COVIDnormal patients (19.1 mL/min per kg [IQR, 15.4–23.7]; P=0.04); (2) the lowest peak indexed cardiac output (4.7±1.2 L/min per m2) versus controls (6.0±1.2 L/min per m2; P=0.004) and COVIDnormal patients (5.7±1.5 L/min per m2; P=0.02), associated with lower indexed stroke volume (SVi:COVIDreduced 39±10 mL/min per m2 versus COVIDnormal 43±7 mL/min per m2 versus controls 48±10 mL/min per m2; P=0.02). There were no differences in peak tissue oxygen extraction or biventricular ejection fractions between groups. There were no associations between COVID‐19 illness severity and peak magnetic resonance–augmented cardiopulmonary exercise testing metrics. Peak indexed oxygen uptake, indexed cardiac output, and indexed stroke volume all correlated with duration from discharge to magnetic resonance–augmented cardiopulmonary exercise testing (P<0.05).ConclusionsMagnetic resonance–augmented cardiopulmonary exercise testing suggests failure to augment stroke volume as a potential mechanism of exercise intolerance in previously hospitalized patients with COVID‐19. This is unrelated to disease severity and, reassuringly, improves with time from acute illness.

Magnetic resonance imaging metrics of oxygen extraction fraction: Contradictions or insight into pathophysiological mechanisms?

Magnetic resonance imaging metrics of oxygen extraction fraction: Contradictions or insight into pathophysiological mechanisms?

Functional photoacoustic microscopy of hemodynamics: a review.

Functional blood imaging can reflect tissue metabolism and organ viability, which is important for life science and biomedical studies. However, conventional imaging modalities either cannot provide sufficient contrast or cannot support simultaneous multi-functional imaging for hemodynamics. Photoacoustic imaging, as a hybrid imaging modality, can provide sufficient optical contrast and high spatial resolution, making it a powerful tool for in vivo vascular imaging. By using the optical-acoustic confocal alignment, photoacoustic imaging can even provide subcellular insight, referred as optical-resolution photoacoustic microscopy (OR-PAM). Based on a multi-wavelength laser source and developed the calculation methods, OR-PAM can provide multi-functional hemodynamic microscopic imaging of the total hemoglobin concentration (CHb), oxygen saturation (sO2), blood flow (BF), partial oxygen pressure (pO2), oxygen extraction fraction, and metabolic rate of oxygen (MRO2). This concise review aims to systematically introduce the principles and methods to acquire various functional parameters for hemodynamics by photoacoustic microscopy in recent studies, with characteristics and advantages comparison, typical biomedical applications introduction, and future outlook discussion.

Oxygen extraction fraction (OEF) assesses cerebral oxygen metabolism of deep gray matter in patients with pre-eclampsia.

The objective of this study was to compare oxygen extraction fraction (OEF) values in the deep gray matter (GM) of pre-eclampsia (PE) patients, pregnant healthy controls (PHCs), and non-pregnant healthy controls (NPHCs) to explore their brain oxygen metabolism differences in GM. Forty-seven PE patients, forty NPHCs, and twenty-one PHCs were included. Brain OEF values were computed from quantitative susceptibility mapping (QSM) plus quantitative blood oxygen level-dependent magnitude (QSM + qBOLD = QQ)-based mapping. One-way ANOVA was used to compare mean OEF values in the three groups. The area under the curve of the mean OEF value in each region of interest was estimated using a receiver operating characteristic curve analysis. We found that the mean OEF values in the thalamus, putamen, caudate nucleus, pallidum, and substantia nigra were significantly different in these three groups (F = 5.867, p = 0.004; F = 5.142, p = 0007; F = 6.158, p = 0.003; F = 6.319, p = 0.003; F = 5.491, p = 0.005). The mean OEF values for these 5 regions were higher in PE patients than in NPHCs and in PHCs (p < 0.05). The AUC of these ROIs ranged from 0.673 to 0.692 (p < 0.01) and cutoff values varied from 35.1 to 36.6%, indicating that the OEF values could discriminate patients with and without PE. Stepwise multivariate analysis revealed that the OEF values correlated with hematocrit in pregnant women (r = 0.353, p = 0.003). OEF values in the brains of pregnant women can be measured in clinical practice using QQ-based OEF mapping for noninvasive assessment of hypertensive disorders. • Pre-eclampsia is a hypertensive disorder associated with abnormalities in brain oxygen extraction. • Oxygen extraction fraction (OEF) is an indicator of brain tissue viability and function. QQ-based mapping of OEF is a new MRI technique that can noninvasively quantify brain oxygen metabolism. • OEF values in the brains of pregnant women can be measured for noninvasive assessment of hypertensive disorders in clinical practice.

Brain oxygen extraction and neural tissue susceptibility are associated with cognitive impairment in older individuals.

We investigated the effects of aging, white matter hyperintensities (WMH), and cognitive impairment on brain iron levels and cerebral oxygen metabolism, known to be altered in Alzheimer's disease (AD), using quantitative susceptibility mapping and MR-based cerebral oxygen extraction fraction (OEF). In 100 individuals over the age of 50 (68/32 cognitively impaired/intact), OEF and neural tissue susceptibility (χn ) were computed retrospectively from MRI multi-echo gradient echo data, obtained on a 3 Tesla MRI scanner. The effects of age and WMH on OEF and χn were assessed within groups, and OEF and χn were assessed between groups, using multivariate regression analyses. Cognitively impaired subjects were found to have 19% higher OEF and 34% higher χn than cognitively intact subjects in the cortical gray matter and several frontal, temporal, and parietal regions (p<.05). Increased WMH burden was significantly associated with decreased OEF in the cognitively impaired, but not in the cognitively intact. Older age had a stronger association with decreased OEF in the cognitively intact group. Both older age and increased WMH burden were significantly associated with increased χn in temporoparietal regions in the cognitively impaired. Higher brain OEF and χn in cognitively impaired older individuals may reflect altered oxygen metabolism and iron in areas with underlying AD pathology. Both age and WMH have associations with OEF and χn but are modified by the presence of cognitive impairment.

Clinical Imaging of the Penumbra in Ischemic Stroke: From the Concept to the Era of Mechanical Thrombectomy.

The ischemic penumbra is defined as the severely hypoperfused, functionally impaired, at-risk but not yet infarcted tissue that will be progressively recruited into the infarct core. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. Intravenous thrombolysis and mechanical thrombectomy for selected patients with large vessel occlusion has been shown to improve functional outcome. Given the varying speed of infarct core progression among individuals, a therapeutic window tailored to each patient has recently been proposed. Recent studies have demonstrated that reperfusion therapies are beneficial in patients with a persistent ischemic penumbra, beyond conventional time windows. As a result, mapping the penumbra has become crucial in emergency settings for guiding personalized therapy. The penumbra was first characterized as an area with a reduced cerebral blood flow, increased oxygen extraction fraction and preserved cerebral metabolic rate of oxygen using positron emission tomography (PET) with radiolabeled O2. Because this imaging method is not feasible in an acute clinical setting, the magnetic resonance imaging (MRI) mismatch between perfusion-weighted imaging and diffusion-weighted imaging, as well as computed tomography perfusion have been proposed as surrogate markers to identify the penumbra in acute ischemic stroke patients. Transversal studies comparing PET and MRI or using longitudinal assessment of a limited sample of patients have been used to define perfusion thresholds. However, in the era of mechanical thrombectomy, these thresholds are debatable. Using various MRI methods, the original penumbra definition has recently gained a significant interest. The aim of this review is to provide an overview of the evolution of the ischemic penumbra imaging methods, including their respective strengths and limitations, as well as to map the current intellectual structure of the field using bibliometric analysis and explore future directions.

The Association Between Pregnancy-Induced Hypertension and Neonatal Cerebral Metabolism, Hemodynamics, and Brain Injury as Determined by Physiological Imaging

Pregnancy-induced hypertension (PIH) is common and may affect maternal and children’s healthcare. However, the neurobiological status of neonates born from mothers with PIH has yet to be elucidated. The present study employed physiological imaging to investigate the association between maternal PIH and a number of neonatal health parameters, including cerebral metabolism, hemodynamics, and pathophysiological vulnerabilities. Following the acquisition of ethical approval, we recruited 16 neonates with maternal PIH and 22 normal neonates (non-PIH) as controls. All neonates underwent magnetic resonance imaging (MRI) of the brain. Phase-contrast (PC) MRI and T2-relaxation-under-spin-tagging (TRUST) MRI were performed to determine global cerebral blood flow, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2). These physiological parameters were then compared between PIH neonates and controls. Linear regression analysis was performed to investigate the associations between maternal PIH and each of the physiological parameters. Receiver operating characteristic curves (ROCs) were used to determine whether maternal systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) which could facilitate the diagnosis of neonatal brain injuries. PIH neonates showed significantly lower OEF (25.5 ± 8.8% vs. 32.6 ± 7.3%, P = 0.01) and CMRO2 (29.7 ± 9.4 vs. 40.9 ± 15.0 μmol/100 g/min, P = 0.01) compared to the controls. Maternal blood pressure levels [PIH or non-PIH groups, each one standard deviation (SD) increase in SBP, DBP, and MAP, respectively] were negatively associated with OEF [regression coefficient (β) = −7.9, P = 0.007; β = −4.2, P = 0.004; β = −3.6, P = 0.02; β = −4.0, P = 0.008, respectively). Furthermore, each one SD increase in maternal DBP and MAP was negatively associated with CMRO2 (β = −4.7, P = 0.03; β = −4.4, P = 0.04, respectively). The areas under the curves (AUCs) with 95% confidence intervals (CIs) for maternal SBP, DBP, and MAP were 0.90 (0.80–0.97), 0.85 (0.73–0.97), and 0.89 (0.76–0.99), respectively. The AUC values for maternal SBP, DBP, and MAP indicated good diagnostic ability for identifying neonatal brain injuries. The present study demonstrated that maternal PIH may be associated with a lower oxygen extraction and lower cerebral metabolism in neonates.

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.

Brain Oxygen Extraction and Metabolism in Pediatric Patients With Sickle Cell Disease: Comparison of Four Calibration Models.

Sickle cell disease (SCD) is an inherited hemoglobinopathy with an increased risk of neurological complications. Due to anemia and other factors related to the underlying hemoglobinopathy, cerebral blood flow (CBF) increases as compensation; however, the nature of alterations in oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in SCD remains controversial, largely attributed to the different calibration models. In addition, limited studies have been done to investigate oxygen metabolism in pediatric patients. Thus, this study used a non-invasive T2-based MR oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST) MRI, to measure oxygen homeostasis in pediatric patients with SCD using four different calibration models and examined its relationship to hematological measures. It was found that, compared with controls, SCD patients showed an increased CBF, unchanged total oxygen delivery and increased venous blood T2. The results of OEF and CMRO2 were dependent on the calibration models used. When using sickle-specific, hemoglobin S (HbS) level-dependent calibration, there was a decreased OEF and CMRO2, while the bovine model showed an opposite result. OEF and CMRO2 were also associated with hemoglobin and HbS level; the direction of the relationship was again dependent on the model. Future studies with in vivo calibration are needed to provide more accurate information on the T2-Yv relationship.

Penumbra Detection With Oxygen Extraction Fraction Using Magnetic Susceptibility in Patients With Acute Ischemic Stroke.

BackgroundThe oxygen extraction fraction (OEF) has been applied to identify ischemic penumbral tissue, but is difficult to use in an urgent care setting. This study aimed to investigate whether an OEF map generated via magnetic resonance quantitative susceptibility mapping (QSM) could help identify the ischemic penumbra in patients with acute ischemic stroke.Materials and MethodsThis prospective imaging study included 21 patients with large anterior circulation vessel occlusion who were admitted <24 h after stroke onset and 21 age-matched healthy controls. We identified the ischemic penumbra as the region with a Tmax of >6 s during dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) and calculated the perfusion-core mismatch ratio between the ischemic penumbra and infarct core volumes. The OEF values were measured based on magnetic susceptibility differences between the venous structures and brain tissues using rapid QSM acquisition. Volumes with increased OEF values were compared to the ischemic penumbra volumes using an anatomical template.ResultsEleven patients had a perfusion-core mismatch ratio of ≥1.8, and reperfusion therapy was recommended. In these patients, the volumes with increased OEF values of >51.5%, which was defined using the anterior circulation territory OEF values from the 21 healthy controls, were positively correlated with the ischemic penumbra volumes (r = 0.636, 95% CI: 0.059 to 0.895, P = 0.035) and inversely correlated with the 30-day change in the National Institutes of Health Stroke Scale scores (r = −0.624, 95% CI: −0.891 to −0.039, P = 0.041).ConclusionTissue volumes with increased OEF values could predict ischemic penumbra volumes based on DSC-MRI, highlighting the potential of the QSM-derived OEF map as a penumbra biomarker to guide treatment selection in patients with acute ischemic stroke.

Comparison of MRI methods for measuring whole-brain oxygen extraction fraction under different geometric conditions at 7T.

Background and PurposeCerebral tissue oxygenation is a critical brain viability parameter, and the magnetic properties of hemoglobin offer the opportunity to noninvasively quantify oxygen extraction fraction (OEF) by magnetic resonance imaging (MRI). Ultrahigh‐field MRI shows advantages such as increased sensitivity to magnetic susceptibility differences and improved signal‐to‐noise ratio that can be translated into smaller voxel size, but also increased sensitivity to static and B1 field inhomogeneities. The aim was to produce a systematic comparison of three MRI‐based methods for estimation of OEF.MethodsOEF estimates in 16 healthy subjects were obtained at 7T utilizing susceptometry‐based oximetry (SBO), quantitative susceptibility mapping (QSM), and transverse relaxation rate (R2*). Two major draining veins, that is, the superior sagittal sinus (SSS) and the straight sinus (SS), were investigated, including mutual agreement between the methods in each of the two different vessels, agreement between vessels as well as potential vessel angle and vessel size dependences.ResultsVery good correlation (r = .88) was found between SBO‐based and QSM‐based OEF estimates in SSS. Only QSM showed a moderate correlation (r = .61) between corresponding OEF estimates in SSS and SS. For SBO, a trend of increasing OEF estimates was observed as the SS vessel angle relative to the main magnetic field increased. No obvious size dependence could be established for any method. The R2*‐based OEF estimates were reasonable (35%‐36%), but the observed range was somewhat low.ConclusionThe results indicate that QSM is a promising candidate for assessment of OEF estimates, for example, providing reasonably robust estimates across a wide range of vessel orientations.

Comparative Analysis of Blood T2 Values Measured by T2 -TRIR and TRUST.

Venous blood oxygenation (Yv), which can be derived from venous blood T2 (T2 b), combined with oxygen-extraction fraction (OEF) and cerebral metabolic rate of oxygen, is considered indicative for tissue viability and brain functioning and frequently assessed in patients with sickle cell disease. Recently, T2 -Prepared-Blood-Relaxation-Imaging-with-Inversion-Recovery (T2 -TRIR) was introduced allowing for simultaneous measurements of blood T2 and T1 (T1 b), potentially improving Yv estimation by overcoming the need to estimate hematocrit. To optimize and compare T2 -TRIR with T2 -relaxation-under-spin-tagging (TRUST) sequence. Prospective. A total of 12 healthy volunteers (six female, 27 ± 3 years old) and 7 patients with sickle cell disease (five female, 32 ± 12 years old). 3 T; turbo field echo planar imaging (TFEPI), echo planar imaging (EPI), and fast field echo (FFE). T2 b, Yv, and OEF from TRUST and T2 -TRIR were compared and T2 -TRIR-derived T1 b was assessed. Within- and between-session repeatability was quantified in the controls, whereas sensitivity to hemodynamic changes after acetazolamide (ACZ) administration was assessed in the patients. Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, mixed linear model, Bland-Altman analysis and correlation analysis. Sidak multiple-comparison correction was performed. Significance level was 0.05. In controls, T2 b from T2 -TRIR (70 ± 11 msec) was higher compared to TRUST (60 ± 8 msec). In patients, T2 b values were lower pre- compared to post-ACZ administration (TRUST: 80 ± 15 msec and 106 ± 23 msec and T2 -TRIR: 95 ± 21 msec and 125 ± 36 msec). Consequently, Yv and OEF were lower and higher pre- compared to post-ACZ administration (TRUST Yv: 68% ± 7% and 77% ± 8%, T2 -TRIR Yv: 74% ± 8% and 80% ± 6%, TRUST OEF: 30% ± 7% and 21% ± 8%, and T2 -TRIR OEF: 25% ± 8% and 18% ± 6%). TRUST and T2 -TRIR are reproducible, but T2 -TRIR-derived T2 b values are significantly higher compared to TRUST, resulting in higher Yv and lower OEF estimates. This bias might be considered when evaluating cerebral oxygen homeostasis. 2 TECHNICAL EFFICACY: Stage 2.

Abnormal oxidative metabolism in the cuprizone mouse model of demyelination: An in vivo NIRS-MRI study

Disruptions in oxidative metabolism may occur in multiple sclerosis and other demyelinating neurological diseases. The impact of demyelination on metabolic rate is also not understood. It is possible that mitochondrial damage may be associated with many such neurological disorders. To study oxidative metabolism with one model of demyelination, we implemented a novel multimodal imaging technique combining Near-Infrared Spectroscopy (NIRS) and MRI to cuprizone mouse model. The cuprizone model is used to study demyelination and may be associated with inhibition of mitochondrial function. Cuprizone mice showed reduced oxygen extraction fraction (−39.1%, p ≤ 0.001), increased tissue oxygenation (6.4%, p ≤ 0.001), and reduced cerebral metabolic rate of oxygen in cortical gray matter (−62.1%, p ≤ 0.001). These changes resolved after the cessation of cuprizone exposure and partial remyelination. A decrease in hemoglobin concentration (−34.4%, p ≤ 0.001), but no change in cerebral blood flow were also observed during demyelination. The oxidized state of the mitochondrial enzyme, Cytochrome C Oxidase (CCO) increased (46.3%, p ≤ 0.001) while the reduced state decreased (−34.4%, p ≤ 0.05) significantly in cuprizone mice. The total amount of CCO did not change significantly during cuprizone exposure. Total CCO did decline after recovery both in control (−23.1%, p ≤ 0.01) and cuprizone (−28.8%, p ≤ 0.001) groups which may relate to age. A reduction in the magnetization transfer ratio, indicating demyelination, was found in the cuprizone group in the cerebral cortex (−3.2%, p ≤ 0.01) and corpus callosum (−5.5%, p ≤ 0.001). In summary, we were able to detect evidence of altered CCO metabolism during cuprizone exposure, consistent with a mitochondrial defect. We observed increased oxygenation and reduced metabolic rate associated with reduced myelination in the gray and white matter. The novel multimodal imaging technique applied here shows promise for noninvasively assessing parameters associated with oxidative metabolism in both mouse models of neurological disease and for translation to study oxidative metabolism in the human brain.

Cerebrovascular Reserve (CVR) and Stages of Hemodynamic Compromise.

The concept of hemodynamic compromise (HC) is used to detect brain regions under ischemic stress by impaired ability to dilate in response to a vasodilatory challenge for cerebrovascular reserve (CVR). The vasodilatory challenges are either inhaled CO2 or a carbonic anhydrase inhibitor acetazolamide (AZ) with measurements of cerebral blood flow (CBF) before and during the challenge. The rationale for CVR is that the brain under ischemic stress is vasodilated and the increase in CBF is attenuated. However, regional oxygen extraction fraction (OEF) by positron emission tomography (PET) is the gold standard for measurement of HC. We showed a strong correlation between CVR and OEF and the OEF response (OEFR) before and after vasodilation in patients with acute ischemic stroke. These observations suggest that CVR measurements alone identify brain regions under ischemic stress without the need for expensive, time consuming and difficult PET OEF.

The Clinical Applications of Oxygen Extraction Fraction (OEF) Metrics: A Systematic Review

The Clinical Applications of Oxygen Extraction Fraction (OEF) Metrics: A Systematic Review

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.

Correlation Between Cerebral Tissue Oxygen Saturation and Oxygen Extraction Fraction During Anesthesia: Monitoring Cerebral Metabolic Demand-supply Balance During Vasopressor Administration.

The speculation that cerebral tissue oxygen saturation (SctO 2 ) measured using tissue near-infrared spectroscopy reflects the balance between cerebral metabolic rate of oxygen and cerebral oxygen delivery has not been validated. Our objective was to correlate SctO 2 with cerebral oxygen extraction fraction (OEF) measured using positron emission tomography; OEF is the ratio between cerebral metabolic rate of oxygen and cerebral oxygen delivery and reflects the balance between these 2 variables. This cohort study was based on data collected in a previously published trial assessing phenylephrine versus ephedrine treatment in anesthetized patients undergoing brain tumor surgery. The variables of interest were measured twice over the healthy hemisphere before surgery: the first measurement performed after anesthesia induction and the second measurement performed after induction of a ∼20% increase in blood pressure using either phenylephrine or ephedrine. Data from 24 patients were analyzed. The overall vasopressor-induced relative changes in SctO 2 (ΔSctO 2 ) and OEF (ΔOEF) were 3.16% [interquartile range, -0.73% to 6.04%] and -12.5% [interquartile range, -24.0% to -6.19%], respectively. ΔSctO 2 negatively correlated with ΔOEF after phenylephrine treatment (Spearman rank correlation coefficient [ rs ]=-0.76; P =0.007), ephedrine treatment ( rs =-0.76; P =0.006), and any treatment ( rs =-0.79; P <0.001). ΔSctO 2 significantly associated with ΔOEF based on multivariable analysis with ΔOEF, relative changes in mean arterial pressure, arterial blood oxygen tension, and the bispectral index as covariates ( P =0.036). The negative correlation between changes in SctO 2 and OEF suggests that SctO 2 may reflect the cerebral metabolic demand-supply balance during vasopressor treatment. The generalizability of our findings in other clinical scenarios remains to be determined.

Heterogeneity of tau deposition and microvascular involvement in MCI and AD.

Recent preclinical and clinical studies have highlighted the role of tau pathology in the impaired cerebrovascular function frequently observed in mild cognitive impairment (MCI) and Alzheimer's disease (AD). These studies typically report on cerebrovascular abnormalities, disease severity, and/or tau deposition in only a few brain regions susceptible to AD pathology. Animal models of tauopathy demonstrate extended tau-driven alterations in capillary physiology, including aberrant angiogenesis, suggesting the interaction between tau and perfusion may be more complex and heterogeneous than others have presented. This study is the first to date to inspect the extent of heterogeneity in microvascular perfusion associated with tau deposition in MCI and AD patients. Seven subjects with cognitive impairment received Flortaucipir positron emission tomography (PET) imaging to measure tau neurofibrillary tangle deposition. Microvascular perfusion was quantified using spin-echo dynamic susceptibility contrast (SE-DSC) magnetic resonance imaging (MRI), which is particularly sensitive to signal from capillaries (radius <10µm). To evaluate macrovascular perfusion for comparison, gradient echo DSC (GE-DSC) and pseudocontinuous arterial spin labeling (PCASL) magnetic resonance imaging (MRI) were also acquired. Cerebral blood flow (CBF) maps were derived from SE-DSC, GE-DSC, and PCASL imaging. Capillary transit heterogeneity (CTH) and oxygen extraction fraction (OEF) maps were derived from SE-DSC and GE-DSC MRI. Functional maps were visually inspected in volumetric slices and cortical surface projections, with summary statistics calculated across cortical surface vertices per subject. Across the seven subjects with MCI or AD (6 MCI/1 AD, 4M/3F, ages 66-85), high tau-PET standardized uptake value ratio (SUVR) signal was primarily observed in the inferior and middle temporal and parietal cortices, with marked uptake in the occipital cortex in one subject. Tau accumulation was spatially associated with highly variable patterns of CBF and OEF throughout the cortex, with marked CTH hotspots in the periventricular white matter of several subjects. Cortical thickness patterns were consistent across subjects despite the microvascular perfusion heterogeneity, indicating that such vascular changes are unlikely to be driven by atrophy alone. Preliminary multi-modal imaging data suggest complex associations between tau pathology and microvascular perfusion abnormalities beyond regions susceptible to AD.