Oxygen Extraction Fraction Research Articles

Deteriorated regional calf microcirculation measured by contrast-free MRI in patients with diabetes mellitus and relation with physical activity.

Objective:To evaluate regional calf muscle microcirculation in people with diabetes mellitus (DM) with and without foot ulcers, compared to healthy control people without DM, using contrast-free magnetic resonance imaging methods.Methods:Three groups of subjects were recruited: non-DM controls, DM, and DM with foot ulcers (DM + ulcer), all with ankle brachial index (ABI) > 0.9. Skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in calf muscle were measured at rest and during a 5-min isometric ankle plantarflexion exercise. Subjects completed the Yale physical activity survey.Results:The exercise SMBF (ml/min/100 g) of the medial gastrocnemius muscle were progressively impaired: 63.7 ± 18.9 for controls, 42.9 ± 6.7 for DM, and 36.2 ± 6.2 for DM + ulcer, p < 0.001. Corresponding exercise SMOEF was the lowest in DM + ulcers (0.48 ± 0.09). Exercise SMBF in the soleus muscle was correlated moderately with the Yale physical activity survey (r = 0.39, p < 0.01).Conclusions:Contrast-free MR imaging identified progressively impaired regional microcirculation in medial gastrocnemius muscles of people with DM with and without foot ulcers. Exercise SMBF in the medial gastrocnemius muscle was the most sensitive index and was associated with HbA1c. Lower exercise SMBF in the soleus muscle was associated with lower Yale score.

Noninvasive Evaluation of Renal Hypoxia by Multiparametric Functional MRI in Early Diabetic Kidney Disease.

Renal hypoxia, which caused by a mismatch between oxygen delivery and oxygen demand, may be the primary pathophysiological pathway driving diabetic kidney disease (DKD). Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) could detect hypoxia, but can be limited in distinguishing increased oxygen consumption or decreased blood supply. To explore multiparametric functional MRI in evaluating mechanism of the hypoxia changes in early stage of DKD. Prospective. Thirty-five New Zealand White rabbits were divided into control group (n=5) and alloxan-induced diabetes mellitus (DM) groups (DM3 group: n=15, DM7 group: n=15). 3 T MRI/BOLD, arterial spin labeling (ASL), and asymmetric spin-echo (ASE). The renal oxygenation level (R2*), renal blood flow (RBF), and oxygen extraction fraction (OEF) were evaluated by BOLD, ASL, and ASE MRI, respectively. The regions of interest were manually drawn including cortex, outer stripes of outer medulla (OS), and inner stripes of outer medulla (IS). Analysis of variance, independent-sample t-test, and paired-sample t-test were applied for comparisons among groups, between groups, and within the same group. P < 0.05 was considered statistically significant. All renal regions of DM3 group at Day 3 after DM induction showed significantly higher R2* and OEF values compared to baseline. The RBF values showed no statistically significant difference (P=0.62, 0.76, 0.09 in cortex, OS, and IS, respectively). For DM7 group at Day 7, R2*, OEF, and RBF values showed no statistically significant difference compared to baseline (P=0.06, 0.05, 0.06 of R2*; 0.70, 0.64, 0.68 of OEF; and 0.33, 0.58, 0.48 of RBF in cortex, OS, and IS, respectively). BOLD MRI could detect renal hypoxia in early stage of DKD rabbit model, which was mainly revealed by increased oxygen consumption, but not affected by renal blood flow change. 2 Technical Efficacy Stage: 1.

Normalization of Cerebral Hemodynamics after Hematopoietic Stem Cell Transplant in Children with Sickle Cell Anemia

▪BackgroundChildren with Sickle Cell Anemia (SCA) are at high risk for overt or silent strokes, and this risk may be mitigated by hematopoietic stem cell transplant (HSCT). Our research group has shown that when cerebral oxygen delivery is compromised due to anemia in SCA, the cerebral blood flow (CBF) and brain oxygen extraction fraction (OEF) increase to maintain brain tissue oxygen delivery. We used novel magnetic resonance imaging (MRI) sequences to measure OEF and CBF in children with SCA treated with HSCT, testing the hypothesis that after HSCT, OEF and CBF will be similar to control values.MethodsChildren with SCA were enrolled in a pilot prospective, observational study of MRI-measured OEF and CBF. Brain MRI exams were performed without sedation on a 3T Siemens scanner. The MRI protocol included fluid-attenuated inverse recovery (FLAIR) sequences in two planes to evaluate for strokes, asymmetric spin echo to measure tissue-level OEF, and pseudo-continuous arterial spin labeling perfusion-weighted imaging to measure CBF. HSCT recipients underwent paired brain MRI 1-2 months before and >1 year after HSCT. Controls, non-anemic siblings of SCA patients, had a single brain MRI. Pre- and post-HSCT CBF and OEF were compared within subjects and between the HSCT and control cohorts using non-parametric tests. Bivariate correlations between OEF or CBF and hemoglobin (Hb) or Hb S concentrations were tested with Spearman's rho. The level of significance was specified as p < 0.05 after adjustment by the Benjamini-Hochberg procedure.ResultsFour children (two male, median age 10 years, range 8-21 years) underwent HSCT: one had prior overt stroke, one had silent strokes, and two had no neuroimaging abnormalities. All received a reduced intensity preparative regimen of alemtuzumab, melphalan, and fludarabine. One subject received marrow from an HLA-matched unrelated donor without Hb S trait; two received marrow from HLA-identical siblings. One child who had rejected a HSCT from an HLA-identical sibling underwent re-conditioning with antithymocyte globulin and cyclophosphamide and received CD-34-selected peripheral stem cells from the same donor. All sibling donors had Hb S trait. Brain MRIs of 20 non-anemic sibling controls of median age 11 years (range 6-17 years) were included for comparison.Median OEF and CBF were significantly elevated pre-HSCT compared to controls (OEF median 0.355 vs 0.288, p = 0.012; CBF median 99.8 vs 65.1 ml/100 g/min, p = 0.018; Figure). Median post-HSCT OEF and CBF were lower than pre-HSCT values (OEF median 0.270 vs 0.355, CBF median 65.1 vs 99.8 ml/100 g/min, p = 0.13 for both), but these analyses had low power to detect significant differences due to the small sample size. Post-HSCT, recipients' OEF and CBF were similar to controls (OEF median 0.270 vs 0.288, p=0.18; CBF median CBF 65.1 vs 75.8 ml/100 g/min, p = 0.42). None of the HSCT recipients had new overt or silent strokes on FLAIR imaging or developed severe acute or chronic GVHD after HSCT.Pre-HSCT, recipients were anemic compared to controls (median Hb 9.8 vs 12.8 g/dl, p = 0.018). Pre-HSCT Hb S concentrations were lower than expected for SCA due to recent red blood cell transfusions (median 50.6%, range 39.7-77.6%). At the post-HSCT imaging timepoint, recipients' anemia had resolved (median Hb 12.4 g/dl, range 11.3-15.7 g/dl), and Hb S concentrations were consistent with their donors' levels. When all pre- and post-HSCT measurements were compared, OEF had a strong negative correlation with Hb (Spearman's rho = -0.905, p = 0.002) and a strong positive correlation with Hb S concentration (Spearman's rho = 0.970, p < 0.001). CBF had a weaker negative correlation with Hb (Spearman's rho = -0.714, p = 0.047) and positive correlation with Hb S concentration (Spearman's rho = 0.731, p = 0.040).ConclusionIn this cohort, children with SCA had normalization of OEF and CBF after successful HSCT. OEF elevation was strongly correlated with Hb S concentration and inversely correlated with Hb concentration in these HSCT recipients. Our data suggest that when curative HSCT corrects hemolytic anemia, OEF and CBF normalize. This physiologic change may provide protection against strokes following HSCT for SCA. [Display omitted] DisclosuresHulbert:Pfizer: Other: Spouse employment at Pfizer. Fields:Proclara Biosciences: Equity Ownership.

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.

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.

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

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

Cerebral Metabolic Alterations in Transgenic and Hemizygous Murine Models of Sickle Cell Disease

BACKGROUND: In SCD, the mechanisms leading to the high incidence of acute stroke in both children and adults remain controversial, while the effects of chronic hypoxia, hyperemia and oxidative stress upon the sickle brain are poorly understood. In limited studies, elevation of brain N-acetyl-aspartate (NAA) has been observed in SCD inflicted children (Steen RG and Ogg RJ, AJNR, 2005). We recently presented evidence that NAA is elevated in one mild murine model (NY1DD) of SCD (Cui MH, NMR Biomed., 2017); we proposed that alterations in NAA are linked to neuronal metabolism and may be indicative of a compensatory increase in mitochondrial energy utilization. Here we present data obtained in additional animal models of SCD that further support these hypotheses.METHODS: Control animals (C57BL6) were compared to sickle animals; the BERK mouse expressing various levels of fetal hemoglobin (HbF, BERK-G) ; the BERK-TX mouse, based on C57BL6 mice irradiated to lethal levels and subsequently infused with nucleated cells from the bone-marrow of BERK mice; and the BERK-HEMI (Hemizygous sickle transgenic animals with murine a knockout, human HbS (aHbS) and a mouse b human S transgene (mb/hS). BERK-HEMI exhibit low O2 affinity hemoglobin (P50 ~ 57).Cerebral measurements were conducted using MRI/MRS methods at 9.4 Tesla. We measuredcerebral blood flow (CBF), cerebral oxygen extraction (using blood level oxygen dependent MRI during a short bolus of hyperoxia [BOLD-RHO]), brain microstructural integrity (from Diffusion Tensor Imaging [DTI] fractional isotropy [FA]) and tissue inflammation (from DTI mean diffusivity [MD]). Magnetic Resonance Spectroscopy (MRS) in the thalamus provided NAA, glutamate (Glu), myoinositial (Ins), and other metabolite measures.RESULTS: MRI and MRS findings exhibit increasing NAA, Glu and BOLD-RHO which seem to suggest a metabolic adjustment not just to anemia but to some other factor(s) (Figure 1); BERK-HEMI animals exhibit the most significant metabolic changes while the BERK-G animals (with low gamma) had the highest CBF and worst anemia, although NAA in the BERK-G appeared similar to WT levels. Evolving changes in the BERK-TX animal after transplant (Figures 2 and 3) suggest a phase of increasing NAA while HbSS and CBF peak. These changes inversely correlate with decreasing Ins. Oxygen extraction and brain inflamation appear to rise after NAA stabilizes or drops. Full BERK-like systemic pathology is established by 12 weeks post transplant but in brain > 12 weeks are required.CONCLUSIONS: NAA was not elevated where the anemia and CBF were the highest (BERK-G and advanced BERK-TX). Instead, NAA was highest in NY1DD and BERK-HEMI (both without significant anemia), in early BERK-TX, where CBF was mildly elevated. This suggests that something other than anemia was driving the NAA elevations. Possibilities include chronic mild hypoxia (from low Hb O2 affinity, reperfusion injury, or ROS). The changes evident in the early post-transplant BERK-TX brain suggest that CBF is driven by HbSS expression and not anemia, since hematocrit remains relatively stable (after an initial drop). This finding suggests likely candidates to be ROS activity, Hb O2 affinity, blood products or degredation in oxygen carrying capacity. The compensatory alterations in energy homeostasis (increased NAA and Glu, decreased Ins and other metabolite changes) may reflect a shift toward increased neuronal glycolysis or increased GSH production and recycling, both of which require increased mitochondrial energy utilization. Decreases in Ins may be related to altered astrocyte/neuronal homeostasis, or the increased cerebrovascular activity. In the advanced stages of the BERK-TX transition, NAA and glutamate levels drop, CBF plateaus, oxygen extraction is high, cerebral inflammation increases and neuronal structure is degraded, all of which are consistent with a system failure, which further predispose the brain to cerebrovascular injury and may explain why NAA increases have been observed only in children with SCD and not adults. If so, the decline of pediatric NAA levels to its “normalization” in adult patients may signal emergence of cerebral dysfunction and impaired cognition (Strouse JJ et al., Blood, 2006) and are consistent with elevations in oxygen extraction fraction and exhaustion of cerebrovascular reserves (Kosinski PD et al; Br. J Haematol., 2017). [Display omitted] DisclosuresAcharya:AIMA: Consultancy. Billett:Janssen Pharmaceutical: Research Funding.

Temporal clustering, tissue composition, and total variation for mapping oxygen extraction fraction using QSM and quantitative BOLD.

To improve the accuracy of quantitative susceptibility mapping plus quantitative blood oxygen level-dependent magnitude (QSM+qBOLD or QQ) based mapping of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) using temporal clustering, tissue composition, and total variation (CCTV). Three-dimensional multi-echo gradient echo and arterial spin labeling images were acquired from 11 healthy subjects and 33 ischemic stroke patients. Diffusion-weighted imaging (DWI) was also obtained from patients. The CCTV mapping was developed for incorporating tissue-type information into clustering of the previous cluster analysis of time evolution (CAT) and applying total variation (TV). The QQ-based OEF and CMRO2 were reconstructed with CAT, CAT+TV (CATV), and the proposed CCTV, and results were compared using region-of-interest analysis, Kruskal-Wallis test, and post hoc Wilcoxson rank sum test. In simulation, CCTV provided more accurate and precise OEF than CAT or CATV. In healthy subjects, QQ-based OEF was less noisy and more uniform with CCTV than CAT. In subacute stroke patients, OEF with CCTV had a greater contrast-to-noise ratio between DWI-defined lesions and the unaffected contralateral side than with CAT or CATV: 1.9 ± 1.3 versus 1.1 ± 0.7 (P = .01) versus 0.7 ± 0.5 (P < .001). The CCTV mapping significantly improves the robustness of QQ-based OEF against noise.

Stroke-Like Lesion in an m.3243A&gt;G Carrier Presenting as Hyperperfusion and Hypometabolism

Carriers of the m.3243A>G variant typically manifest with stroke-like episodes (SLEs), of which the morphological correlate on imaging is the stroke-like lesion (SLL). The pathophysiology of SLLs is poorly understood but acute and chronic stages are delineated. Here we present the case of an m.3243A>G carrier who presented with hypometabolism during his second SLL.The patient was a 56-year-old male who was diagnosed with MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) at the age of 50 upon a third SLE, muscle biopsy, and the detection of the m.3243A>G variant in the muscle. A fluorodeoxyglucose-positron emission tomography (FDG-PET) during the second SLE revealed hypometabolism in the occipital lobes bilaterally. The patient was misdiagnosed for years and was repeatedly exposed to mitochondrion-toxic drugs (metformin, steroids, valproic acid, oxcarbazepine, zolpidem). The previous data and the present findings indicate that the hypometabolism on FDG-PET together with reduced oxygen-extraction fraction (OEF) on OEF-MRI and hyperperfusion on perfusion-weighted imaging (PWI) characterise best the acute stage of an SLL.In conclusion, an acute SLE in m.3243A>G carriers typically manifests with a mismatch between hyperperfusion on PWI or single-photon emission computed tomography (SPECT) and hypometabolism on FDG-PET and hypointensity on OEF-MRI. Since SLEs are not vascular events, they should be managed by a multispecialist approach and not by general or stroke neurologists.

Quantitative assessment of cerebral metabolism and hemodynamics in small-for-gestational-age (SGA) newborns.

Small-for-gestational-age (SGA) newborns represent approximately 10% of births worldwide and 45% of births in some countries. It has been suggested that SGA might cause learning difficulties and behavioral abnormalities in childhood, yet the neurobiological basis for this is poorly understood. In this study, we employed several advanced imaging techniques-including T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), and phase-contrast (PC) MRI-to quantify oxygen extraction fraction (OEF), global cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) to elucidate pathophysiological vulnerabilities of SGA neonates. A total of 41 newborns were enrolled in this study, consisting of 29 SGA and 12 appropriate-for-gestational-age (AGA) neonates. The SGA group was further divided into subgroups with and without abnormalities on structural MRI, denoted as SGA-a (N=17) and SGA-n (N=12). TRUST and PC MRI were performed to determine OEF, CBF, and CMRO2. Linear regression analyses were performed to examine physiological parameters' dependence on scan age, gender, and group. Similar analyses were conducted for birth weight and brain volume. Receiver operating characteristic (ROC) curves were used to test physiological parameters' ability to different diagnostic groups. Regression analysis revealed that CMRO2 was significantly lower (P=0.04) in the SGA group relative to the AGA group. When further stratifying the SGA participants into SGA-a and SGA-n subgroups, the SGA-a subgroup was found to have the most pronounced physiological deficits, with a lower CMRO2 (P=0.004) and lower CBF (P=0.007) than those in the AGA group. Conversely, CMRO2 (P=0.40) and CBF (P=0.90) in the SGA-n subgroup were not different from those of the AGA group. Accordingly, CBF in the SGA-a group was significantly lower (P=0.01) than that of the SGA-n group and CMRO2 also showed a difference (P=0.09). Additionally, CMRO2 (P=0.002) and CBF (P=0.04) showed an age-related increase during this early developmental period. In analyzing the SGA-a subgroup relative to the remaining neonates, the area under curve (AUC) values were 0.6, 0.6, 0.7, 0.8, and 0.5 for birth weight, OEF, CMRO2, CBF, and brain volume, respectively. In analyzing the SGA-a subgroup relative to the SGA-n subgroup, AUC values were 0.5, 0.6, 0.7, 0.8, and 0.5 for birth weight, OEF, CMRO2, CBF, and brain volume. Structural damage in SGA-a neonates is associated with cerebral hemodynamic and metabolic deficits. SGA neonates with normal CBF and CMRO2reveal minimal structural abnormalities. Physiological imaging may help identify SGA patients at high risk of developing irreversible brain damage.

Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study.

Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for "unbiased descriptive classification", biomarkers of neurodegeneration, "N", constitute a critical component in the tri-category "A/T/N" system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2 -relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by -18.7%, p = 0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2 ) (by -17.4%, p = 0.04) and total CMRO2 (by -30.8%, p < 0.001) were observed in Tau4RΔK mice-referred to as the tau AD model-which manifested pronounced neurodegeneration, as measured by diminished brain volume (by -15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild-type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL-Tg [APPSWE]2576Kha (APP) mice-referred to as the amyloid AD model-no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.

Optical Detection of Intracranial Pressure and Perfusion Changes in Neonates With Hydrocephalus

To demonstrate that a novel noninvasive index of intracranial pressure (ICP) derived from diffuse optics-based techniques is associated with intracranial hypertension. We compared noninvasive and invasive ICP measurements in infants with hydrocephalus. Infants born term and preterm were eligible for inclusion if clinically determined to require cerebrospinal fluid (CSF) diversion. Ventricular size was assessed preoperatively via ultrasound measurement of the fronto-occipital (FOR) and frontotemporal (FTHR) horn ratios. Invasive ICP was obtained at the time of surgical intervention with a manometer. Intracranial hypertension was defined as invasive ICP ≥15mmHg. Diffuse optical measurements of cerebral perfusion, oxygen extraction, and noninvasive ICP were performed preoperatively, intraoperatively, and postoperatively. Optical and ultrasound measures were compared with invasive ICP measurements, and their change in values after CSF diversion were obtained. We included 39 infants, 23 with intracranial hypertension. No group difference in ventricular size was found by FOR (P=.93) or FTHR (P=.76). Infants with intracranial hypertension had significantly higher noninvasive ICP (P=.02) and oxygen extraction fraction (OEF) (P=.01) compared with infants without intracranial hypertension. Increased cerebral blood flow (P=.005) and improved OEF (P<.001) after CSF diversion were observed only in infants with intracranial hypertension. Noninvasive diffuse optical measures (including a noninvasive ICP index) were associated withintracranial hypertension. The findings suggest that impaired perfusion from intracranial hypertension was independentof ventricular size. Hemodynamic evidence of the benefits of CSF diversion was seen in infants with intracranial hypertension. Noninvasive optical techniques hold promise for aiding the assessment of CSF diversion timing.

Non-Invasive measurement of the cerebral metabolic rate of oxygen using MRI in rodents

Malfunctions of oxygen metabolism are suspected to play a key role in a number of neurological and psychiatric disorders, but this hypothesis cannot be properly investigated without an in-vivo non-invasive measurement of brain oxygen consumption. We present a new way to measure the Cerebral Metabolic Rate of Oxygen (CMRO2) by combining two existing magnetic resonance imaging techniques, namely arterial spin-labelling and oxygen extraction fraction mapping. This method was validated by imaging rats under different anaesthetic regimes and was strongly correlated to glucose consumption measured by autoradiography.

Reduced global cerebral oxygen metabolic rate in sickle cell disease and chronic anemias.

Anemia is the most common blood disorder in the world. In patients with chronic anemia, such as sickle cell disease or major thalassemia, cerebral blood flow increases to compensate for decreased oxygen content. However, the effects of chronic anemia on oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) are less well understood. In this study, we examined 47 sickle-cell anemia subjects (age 21.7± 7.1, female 45%), 27 non-sickle anemic subjects (age 25.0± 10.4, female 52%) and 44 healthy controls (age 26.4± 10.6, female 71%) using MRI metrics of brain oxygenation and flow. Phase contrast MRI was used to measure resting cerebral blood flow, while T2 -relaxation-under-spin-tagging (TRUST) MRI with disease appropriate calibrations were used to measure OEF and CMRO2 . We observed that patients with sickle cell disease and other chronic anemias have decreased OEF and CMRO2 (respectively 27.4± 4.1% and 3.39 ± 0.71 ml O2 /100 g/min in sickle cell disease, 30.8± 5.2% and 3.53 ± 0.64 ml O2 /100 g/min in other anemias) compared to controls (36.7± 6.0% and 4.00 ± 0.65 ml O2 /100 g/min). Impaired CMRO2 was proportional to the degree of anemia severity. We further demonstrate striking concordance of the present work with pooled historical data from patients having broad etiologies for their anemia. The reduced cerebral oxygen extraction and metabolism are consistent with emerging data demonstrating increased non-nutritive flow, or physiological shunting, in sickle cell disease patients.

Multi-Parametric Evaluation of Cerebral Hemodynamics in Neonatal Piglets Using Non-Contrast-Enhanced Magnetic Resonance Imaging Methods.

Disruption of brain oxygen delivery and consumption after hypoxic-ischemic injury contributes to neonatal mortality and neurological impairment. Measuring cerebral hemodynamic parameters, including cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ), is clinically important. Phase-contrast (PC), velocity-selective arterial spin labeling (VSASL), and T2 -relaxation-under-phase-contrast (TRUPC) are magnetic resonance imaging (MRI) techniques that have shown promising results in assessing cerebral hemodynamics in humans. We aimed to test their feasibility in quantifying CBF, OEF, and CMRO2 in piglets. Prospective. Ten neonatal piglets subacutely recovered from global hypoxia-ischemia (N=2), excitotoxic brain injury (N=6), or sham procedure (N=2). VSASL, TRUPC, and PC MRI acquired at 3.0 T. Regional CBF was measured by VSASL. Global CBF was quantified by both PC and VSASL. TRUPC assessed OEF at the superior sagittal sinus (SSS) and internal cerebral veins (ICVs). CMRO2 was calculated from global CBF and SSS-derived OEF. End-tidal carbon dioxide (EtCO2 ) levels of the piglets were also measured. Brain damage was assessed in tissue sections postmortem by counting damaged neurons. Spearman correlations were performed to evaluate associations among CBF (by PC or VSASL), OEF, CMRO2 , EtCO2 , and the pathological neuron counts. Paired t-test was used to compare OEF at SSS with OEF at ICV. Global CBF was 32.1 ± 14.9 mL/100 g/minute and 30.9 ± 8.3 mL/100 g/minute for PC and VSASL, respectively, showing a significant correlation (r=0.82, P < 0.05). OEF was 54.9 ± 8.8% at SSS and 46.1 ± 5.6% at ICV, showing a significant difference (P < 0.05). Global CMRO2 was 79.1 ± 26.2 μmol/100 g/minute and 77.2 ± 12.2 μmol/100 g/minute using PC and VSASL-derived CBF, respectively. EtCO2 correlated positively with PC-based CBF (r=0.81, P < 0.05) but negatively with OEF at SSS (r=-0.84, P < 0.05). Relative CBF of subcortical brain regions and OEF at ICV did not significantly correlate, respectively, with the ratios of degenerating-to-total neurons (P=0.30, P=0.10). Non-contrast MRI can quantify cerebral hemodynamic parameters in normal and brain-injured neonatal piglets. 1 TECHNICAL EFFICACY STAGE: 2.

Relating Retinal Vascular Oxygen Saturation and Microvasculature Morphology at Progressive Stages of Diabetic Retinopathy.

PurposeDiabetic retinopathy (DR) is a common cause of vision loss in working age adults and presents changes in retinal vessel oxygenation and morphology. The purpose of this study was to test the hypothesis that there is an association of retinal vessel oxygen saturation with vessel density (VD) and tortuosity in DR.MethodsNinety-five subjects were classified in the following groups: nondiabetic control (N = 25), no DR (N = 28), mild nonproliferative DR (NPDR; N = 21), moderate to severe NPDR (N = 14), or treated proliferative DR (PDR; N = 7). Retinal oximetry was performed to measure arterial and venous oxygen saturation (SO2A and SO2V) and calculate oxygen extraction fraction (OEF). Optical coherence tomography angiography (OCTA) was performed for measurements of VD and vessel tortuosity index (VTI).ResultsThere were statistically significant differences in SO2A and SO2V among groups (P < 0.004). SO2A and SO2V were higher in the PDR group compared to the control group and SO2V was also higher in the moderate to severe NPDR group. VD differed significantly among groups (P = 0.003), whereas VTI was not significantly different (P = 0.22). Compared to the control group, VD was lower in moderate to severe NPDR and PDR groups. VD was also lower in the PDR group than that in the no DR group (P = 0.03). There was a significant correlation of VTI with SO2V (r = 0.32, P = 0.002) and OEF (r = −0.35, P = 0.001).ConclusionsRetinal vessel morphology, oxygenation, and tissue oxygen extraction were associated with each other in a cohort of subjects with and without DR.Translational RelevanceThe findings of this study have the potential to improve clinical management of DR by providing better understanding of human disease pathophysiology and propelling future studies to identify multiple image-based biomarkers for improved disease diagnosis and monitoring.

An interictal measurement of cerebral oxygen extraction fraction in MRI-negative refractory epilepsy using quantitative susceptibility mapping.

Oxygen extraction fraction (OEF) can be a factor to identify brain tissue's disability in epileptic patients. This study aimed to assess the OEF's level measurement in refractory epileptic patients (REPs) using a quantitative susceptibility mapping (QSM) method and to determine whether the OEF parameters change. QSM-OEF maps of 26 REPs and 16 healthy subjects were acquired using 3T MRI with a 64-channel coil. Eighteen regions-of-interest (ROIs) were chosen around the cortex in one appropriate slice of the brain and the mean QSM-OEF for each ROI was obtained. The correlations of QSM-OEF among different clinical characteristics of the disease, as well as between the patients and normal subjects, were also investigated. QSM-OEF was shown to be significantly higher in REPs (44.9±5.8) than that in HS (41.9±6.2) (p<0.05). Mean QSM-OEF was statistically lower in the ipsilateral side (44.5±6.6) compared to the contralateral side (46.4±6.8) (P<0.01). QSM-OEF was illustrated to have a strong positive correlation with the attack duration (r=0.6), and a moderate negative correlation with the attack frequency (r=-0.3). Using an optimized support vector machine algorithm, we could predict the disease in subjects having abnormal OEF values in the brain-selected-ROIs with sensitivity, specificity, AUC, and the precision of 0.96, 1, 0.98, and 1, respectively. The results of this study revealed that QSM-OEF of the REPs' brain is higher than that of HS, which indicates that QSM-OEF is associated with disease activity.

Hemodynamic and oxygen-metabolic responses of the awake mouse brain to hypercapnia revealed by multi-parametric photoacoustic microscopy

A widely used cerebrovascular stimulus and common pathophysiologic condition, hypercapnia is of great interest in brain research. However, it remains controversial how hypercapnia affects brain hemodynamics and energy metabolism. By using multi-parametric photoacoustic microscopy, the multifaceted responses of the awake mouse brain to different levels of hypercapnia are investigated. Our results show significant and vessel type-dependent increases of the vessel diameter and blood flow in response to the hypercapnic challenges, along with a decrease in oxygen extraction fraction due to elevated venous blood oxygenation. Interestingly, the increased blood flow and decreased oxygen extraction are not commensurate with each other, which leads to reduced cerebral oxygen metabolism. Further, time-lapse imaging over 2-hour chronic hypercapnic challenges reveals that the structural, functional, and metabolic changes induced by severe hypercapnia (10% CO2) are not only more pronounced but more enduring than those induced by mild hypercapnia (5% CO2), indicating that the extent of brain’s compensatory response to chronic hypercapnia is inversely related to the severity of the challenge. Offering quantitative, dynamic, and CO2 level-dependent insights into the hemodynamic and metabolic responses of the brain to hypercapnia, these findings might provide useful guidance to the application of hypercapnia in brain research.

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.

Regional and interindividual relationships between cerebral perfusion and oxygen metabolism.

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) show large between-subject and regional variability, but the relationships between CBF and CMRO2 measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO2 measures with independent and quantitative PET techniques. We included resting CBF and CMRO2 measurements from 50 healthy volunteers (aged 22-81 yr), and calculated the regional and global values of oxygen delivery (Do2) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO2 measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial Pco2 and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between Do2 and CMRO2, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO2 in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by Pco2 and hemoglobin concentration.NEW & NOTEWORTHY Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO2, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.