Hemodynamic and metabolic changes during hypercapnia with normoxia and hyperoxia using pCASL and TRUST MRI in healthy adults

Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO2). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO2 or O2 does not affect CMRO2. We evaluated the null hypothesis that two common hypercapnic stimuli, ‘CO2 in air’ and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO2 were calculated for room-air, ‘CO2 in air’ and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for ‘CO2 in air’ and carbogen, respectively). CMRO2 decreased for ‘CO2 in air’ (−13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO2 during carbogen did not significantly change. Our findings indicate that ‘CO2 in air’ is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO2 reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.

Hypothermia Suppresses Uncoupling of Oxidative- Phosphorylation after Neonatal Cerebral Hypoxia-Ischemia

Hypothermia is the best available therapy for neonatal hypoxia ischemia (HI) brain injury, but its primary mechanisms remain uncertain. We hypothesize that HI induces, whereas hypothermia represses, uncoupling of oxidative phosphorylation (OXPHOS), an increase of the cerebral metabolic rate of oxygen (CMRO2) despite reduction of the mitochondrial energy output. We used a multiparametric photoacoustic microscopy (PAM) system to compare the effects of HI and post HI hypothermic treatment on CMRO2 in awake 10 day old (P10) mice. Here we show that hypoxia (10% O2) elevated CMRO2, but the addition of unilateral carotid artery ligation suppressed CMRO2 and sparked a rapid overshoot of post HI CMRO2 in the ipsilateral cerebral cortex for at least 2 hours. The post HI surge of CMRO2 was linked to an increase of mitochondrial oxygen consumption and superoxide outburst, despite reduction of the mitochondrial membrane potential. Notably, post HI hypothermia blocked the surge of superoxide and CMRO2, primarily by limiting oxygen extraction fraction (OEF), leading to better preservation of adenosine triphosphate (ATP), creatine (Cr) and N acetylaspartate (NAA) after HI. Mice that did not receive hypothermia exhibited ~80% reduction of CMRO2 at 24 h post HI, coupled to a large cortical infarction. These results suggest that mitigation of post HI uncoupling of OXPHOS is an early and/or pivotal effect of hypothermia. Further, optical measurement of CMRO2 may be a sensitive and noninvasive method to monitor brain damage in hypoxic ischemic encephalopathy (HIE).

Exercise Training Increases Resting Calf Muscle Oxygen Metabolism in Patients with Peripheral Artery Disease

Exercise training can mitigate symptoms of claudication (walking-induced muscle pain) in patients with peripheral artery disease (PAD). One adaptive response enabling this improvement is enhanced muscle oxygen metabolism. To explore this issue, we used arterial-occlusion diffuse optical spectroscopy (AO-DOS) to measure the effects of exercise training on the metabolic rate of oxygen (MRO2) in resting calf muscle. Additionally, venous-occlusion DOS (VO-DOS) and frequency-domain DOS (FD-DOS) were used to measure muscle blood flow (F) and tissue oxygen saturation (StO2), and resting calf muscle oxygen extraction fraction (OEF) was calculated from MRO2, F, and blood hemoglobin. Lastly, the venous/arterial ratio (γ) of blood monitored by FD-DOS was calculated from OEF and StO2. PAD patients who experience claudication (n = 28) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 months of supervised exercise training. Optical measurements were obtained at baseline and at 3 months in both groups. Resting MRO2, OEF, and F, respectively, increased by 30% (12%, 44%) (p < 0.001), 17% (6%, 45%) (p = 0.003), and 7% (0%, 16%) (p = 0.11), after exercise training (median (interquartile range)). The pre-exercise γ was 0.76 (0.61, 0.89); it decreased by 12% (35%, 6%) after exercise training (p = 0.011). Improvement in exercise performance was associated with a correlative increase in resting OEF (R = 0.45, p = 0.02).

Artificial Neural Network-Derived Cerebral Metabolic Rate of Oxygen for Differentiating Glioblastoma and Brain Metastasis in MRI: A Feasibility Study

Glioblastoma may appear similar to cerebral metastasis on conventional MRI in some cases, but their therapies differ significantly. This prospective feasibility study was aimed at differentiating them by applying the quantitative susceptibility mapping and quantitative blood-oxygen-level-dependent (QSM + qBOLD) model to these entities for the first time. We prospectively included 15 untreated patients with glioblastoma (n = 7, median age: 68 years, range: 54–84 years) or brain metastasis (n = 8, median age 66 years, range: 50–78 years) who underwent preoperative MRI including multi-gradient echo and arterial spin labeling sequences. Oxygen extraction fraction (OEF), cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were calculated in the contrast-enhancing tumor (CET) and peritumoral non-enhancing T2 hyperintense region (NET2), using an artificial neural network. We demonstrated that OEF in CET was significantly lower (p = 0.03) for glioblastomas than metastases, all features were significantly higher (p = 0.01) in CET than in NET2 for metastasis patients only, and the ratios of CET/NET2 for CBF (p = 0.04) and CMRO2 (p = 0.01) were significantly higher in metastasis patients than in glioblastoma patients. Discriminative power of a support-vector machine classifier was highest with a combination of two features, yielding an area under the receiver operating characteristic curve of 0.94 with 93% diagnostic accuracy. QSM + qBOLD allows for robust differentiation of glioblastoma and cerebral metastasis while yielding insights into tumor oxygenation.

Reduced magnetic resonance angiography signal intensity in the middle cerebral artery ipsilateral to severe carotid stenosis may be a practical index of high oxygen extraction fraction

Objectives Angiographic “slow flow” in the middle cerebral artery (MCA), caused by carotid stenosis, may be associated with high oxygen extraction fraction (OEF). If the MCA slow flow is associated with a reduced relative signal intensity (rSI) of the MCA on MR angiography, the reduced rSI may be associated with a high OEF. We investigated whether the MCA slow flow ipsilateral to carotid stenosis was associated with a high OEF and aimed to create a practical index to estimate the high OEF. Methods We included patients who underwent digital subtraction angiography (DSA) and MRA between 2015 and 2019 to evaluate carotid stenosis. MCA slow flow by image count using DSA, MCA rSI, minimal luminal diameter (MLD) of the carotid artery, carotid artery stenosis rate (CASr), and whole-brain OEF (wb-OEF) was evaluated. When MCA slow flow was associated with a high wb-OEF, the determinants of MCA slow flow were identified, and their association with high wb-OEF was evaluated. Results One hundred and twenty-seven patients met our inclusion criteria. Angiographic MCA slow flow was associated with high wb-OEF. We identified MCA rSI and MLD as determinants of angiographic MCA slow flow. The upper limits of MCA rSI and MLD for angiographic MCA slow flow were 0.89 and 1.06 mm, respectively. The wb-OEF was higher in patients with an MCA rSI ≤ 0.89 and ipsilateral MLD ≤ 1.06 mm than patients without this combination. Conclusions The combination of reduced MCA rSI and ipsilateral narrow MLD is a straightforward index of high wb-OEF. Key Points • The whole-brain OEF in patients with angiographic slow flow in the MCA ipsilateral to high-grade carotid stenosis was higher than in patients without it. • Independent determinants of MCA slow flow were MCA relative signal intensity (rSI) on MRA or minimal luminal diameter (MLD) of the carotid stenosis. • The wb-OEF was higher in patients with an MCA rSI ≤ 0.89 and ipsilateral MLD ≤ 1.06 mm than patients without this combination.

Application of Cluster Analysis of Time Evolution for Magnetic Resonance Imaging -Derived Oxygen Extraction Fraction Mapping: A Promising Strategy for the Genetic Profile Prediction and Grading of Glioma

Background: The intratumoral heterogeneity of oxygen metabolism and angiogenesis are core hallmarks of glioma, unveiling that genetic aberrations associated with magnetic resonance imaging (MRI) phenotypes may aid in the diagnosis and treatment of glioma.Objective: To explore the predictability of MRI-based oxygen extraction fraction (OEF) mapping using cluster analysis of time evolution (CAT) for genetic profiling and glioma grading.Methods: Ninety-one patients with histopathologically confirmed glioma were examined with CAT for quantitative susceptibility mapping and quantitative blood oxygen level–dependent magnitude-based OEF mapping and dynamic contrast-enhanced (DCE) MRI. Imaging biomarkers, including oxygen metabolism (OEF) and angiogenesis [volume transfer constant, cerebral blood volume (CBV), and cerebral blood flow], were investigated to predict IDH mutation, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status, receptor tyrosine kinase (RTK) subgroup, and differentiation of glioblastoma (GBM) vs. lower-grade glioma (LGG). The corresponding DNA sequencing was also obtained. Results were compared with DCE-MRI using receiver operating characteristic (ROC) analysis.Results: IDH1-mutated LGGs exhibited significantly lower OEF and hypoperfusion than IDH wild-type tumors (all p &lt; 0.01). OEF and perfusion metrics showed a tendency toward higher values in MGMT unmethylated GBM, but only OEF retained significance (p = 0.01). Relative prevalence of RTK alterations was associated with increased OEF (p = 0.003) and perfusion values (p &lt; 0.05). ROC analysis suggested OEF achieved best performance for IDH mutation detection [area under the curve (AUC) = 0.828]. None of the investigated parameters enabled prediction of MGMT status except OEF with a moderate AUC of 0.784. Predictive value for RTK subgroup was acceptable by using OEF (AUC = 0.764) and CBV (AUC = 0.754). OEF and perfusion metrics demonstrated excellent performance in glioma grading. Moreover, mutational landscape revealed hypoxia or angiogenesis-relevant gene signatures were associated with specific imaging phenotypes.Conclusion: CAT for MRI-based OEF mapping is a promising technology for oxygen measurement and along with perfusion MRI can predict genetic profiles and tumor grade in a non-invasive and clinically relevant manner.Clinical Impact: Physiological imaging provides an in vivo portrait of genetic alterations in glioma and offers a potential strategy for non-invasively selecting patients for individualized therapies.

Differences in Hemodynamic Alteration between Atherosclerotic Occlusive Lesions and Moyamoya Disease: A Quantitative 15O-PET Study

To clarify the differences in hemodynamic status between atherosclerotic steno-occlusive lesions (SOL) and moyamoaya disease (MMD), hemodynamic parameters were compared using 15O-PET. Twenty-four patients with unilateral SOL (67 ± 11 y) and eighteen with MMD (33 ± 16 y) were assigned to this study. MMD patients were divided into twelve unilateral and six bilateral lesions. All patients underwent 15O-PET to measure cerebral blood flow (CBF), blood volume (CBV), oxygen extraction fraction (OEF), and metabolic rate (CMRO2). Acetazolamide was administered after the baseline scan and the second 15O-water PET was performed to evaluate cerebrovascular reactivity (CVR). For the CBF calculation in 15O-water PET, the three-weighted integral method was applied based on a one-tissue compartment model with pixel-by-pixel delay correction to measure precise CBF and arterial-to-capillary blood volume (V0). Baseline hemodynamic parameters showed significantly lower CBF, V0, and CMRO2, but greater CBV, OEF, and delay (p < 0.01) in the affected hemispheres than in the unaffected hemispheres. After ACZ administration, both hemispheres showed a significant increase in CBF (p < 0.0001), but not in V0. CVR differed significantly between the hemispheres. The arterial perfusion pressure of the functioning arterial part tended to be reduced after acetazolamide administration in patients with past neurologic events caused by hemodynamic impairment. MMD patients showed greater inactive vascular and venous volumes compared with common atherosclerotic SOL patients. The hemodynamic status of cerebral circulation may vary according to the chronic process of steno-occlusive change and the development of collateral circulation. In order to evaluate physiologic differences between the two diseases, 15O-PET with an acetazolamide challenge test is useful.

Imaging effective oxygen diffusivity in the human brain with multiparametric magnetic resonance imaging

Cerebrovascular diseases can impair blood circulation and oxygen extraction from the blood. The effective oxygen diffusivity (EOD) of the capillary bed is a potential biomarker of microvascular function that has gained increasing interest, both for clinical diagnosis and for elucidating oxygen transport mechanisms. Models of capillary oxygen transport link EOD to measurable oxygen extraction fraction (OEF) and cerebral blood flow (CBF). In this work, we confirm that two well established mathematical models of oxygen transport yield nearly equivalent EOD maps. Furthermore, we propose an easy-to-implement and clinically applicable multiparametric magnetic resonance imaging (MRI) protocol for quantitative EOD mapping. Our approach is based on imaging OEF and CBF with multiparametric quantitative blood oxygenation level dependent (mq-BOLD) MRI and pseudo-continuous arterial spin labeling (pCASL), respectively. We evaluated the imaging protocol by comparing MRI-EOD maps of 12 young healthy volunteers to PET data from a published study in different individuals. Our results show comparably good correlation between MRI- and PET-derived cortical EOD, OEF and CBF. Importantly, absolute values of MRI and PET showed high accordance for all three parameters. In conclusion, our data indicates feasibility of the proposed MRI protocol for EOD mapping, rendering the method promising for future clinical evaluation of patients with cerebrovascular diseases.