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Background: Sleep problem is a common complication of Alzheimer's disease (AD). Extensive preclinical studies have been performed to investigate the AD pathology. However, the pathophysiological consequence of AD complicated by sleep problem remains to be further determined. Purpose: To investigate brain metabolism and perfusion in an AD mouse model complicated by sleep problem, and subsequently identify potential imaging markers to better understand the associated pathophysiology. Methods: We examined the oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2), and cerebral blood flow (CBF) using state-of-the-art MRI techniques in a cohort of 5xFAD model mice. Additionally, neuroinflammation, indicated by activated microglia, was assessed using histology techniques. Sleep fragmentation (SF) was utilized as a representative for sleep problems. Results: SF was associated with significant increases in OEF (P = 0.023) and CMRO2 (P = 0.029), indicating a state of hypermetabolism. CBF showed a significant genotype-by-sleep interaction effect (P = 0.026), particularly in the deep brain regions such as the hippocampus and thalamus. Neuroinflammation was primarily driven by genotype rather than SF, especially in regions with significant interaction effect in CBF measurements. Conclusion: These results suggest that brain metabolism and perfusion measurements are promising markers for studying the co-pathogenesis of AD and SF. [ABSTRACT FROM AUTHOR]

Purpose: There are many approaches to the quantitative BOLD (qBOLD) technique described in the literature, differing in pulse sequences, MRI parameters and data processing. Thus, in this review, we summarized the acquisition methods, approaches used for oxygenation quantification and clinical populations investigated. Methods: Three databases were systematically searched (Medline, Embase, and Web of Science) for published research that used qBOLD methods for quantification of oxygen metabolism. Data extraction and synthesis were performed by one author and reviewed by a second author. Results: A total of 93 relevant papers were identified. Acquisition strategies were summarized, and oxygenation parameters were found to have been investigated in many pathologies such as steno‐occlusive diseases, stroke, glioma, and multiple sclerosis disease. Conclusion: A summary of qBOLD approaches for oxygenation measurements and applications could help researchers to identify good practice and provide objective information to inform the development of future consensus recommendations. [ABSTRACT FROM AUTHOR]

Background: Imaging examination of cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen is crucial for understanding the normal functioning and pathophysiology of the brain. A recently developed method estimates the appearance time of cerebral blood (ATB) pixel-wise from the imaging examination of CBF alone. In this study, we aimed to test the potential of ATB as an indicator of OEF. Results: We retrospectively reviewed patients (n = 62) with suspected cerebrovascular disorders including steno-occlusive disease who underwent positron emission tomography (PET) with 15O-labelled tracers. Regarding the generated OEF and ATB images, a visual assessment was performed to test the consistency of the elevated OEF and delayed ATB. The OEF and ATB values and the absolute differences between their ipsilateral and contralateral sides were extracted and obtained for the entire hemisphere and the middle, anterior, and posterior cerebral arterial regions. Consistency was observed in 52 PET scans (83.9%) in visual assessment. The OEF and ATB values were moderately correlated (r = 0.553, p < 0.001), and the differences between their ipsilateral and contralateral sides were weakly correlated (r = 0.276, p < 0.001). Conclusion: Our results indicate the potential of ATB as an indicator of OEF. [ABSTRACT FROM AUTHOR]

Background: Sleep problem is a common complication of Alzheimer's disease (AD). Extensive preclinical studies have been performed to investigate the AD pathology. However, the pathophysiological consequence of AD complicated by sleep problem remains to be further determined. Purpose: To investigate brain metabolism and perfusion in an AD mouse model complicated by sleep problem, and subsequently identify potential imaging markers to better understand the associated pathophysiology. Methods: We examined the oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2), and cerebral blood flow(CBF) using state-of-the-art MRI techniques in a cohort of 5xFAD model mice. Additionally, neuroinflammation, indicated by activated microglia, was assessed using histology techniques. Sleep fragmentation (SF) was utilized as a representative for sleep problems. Results: SF was associated with significant increases in OEF (P = 0.023) and CMRO2 (P = 0.029), indicating a state of hypermetabolism. CBF showed a significant genotype-by-sleep interaction effect (P = 0.026), particularly in the deep brain regions such as the hippocampus and thalamus. Neuroinflammation was primarily driven by genotype rather than SF, especially in regions with significant interaction effect in CBF measurements. Conclusion: These results suggest that brain metabolism and perfusion measurements are promising markers for studying the co-pathogenesis of AD and SF. [ABSTRACT FROM AUTHOR]

Abstract Background Imaging examination of cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen is crucial for understanding the normal functioning and pathophysiology of the brain. A recently developed method estimates the appearance time of cerebral blood (ATB) pixel-wise from the imaging examination of CBF alone. In this study, we aimed to test the potential of ATB as an indicator of OEF. Results We retrospectively reviewed patients (n = 62) with suspected cerebrovascular disorders including steno-occlusive disease who underwent positron emission tomography (PET) with 15O-labelled tracers. Regarding the generated OEF and ATB images, a visual assessment was performed to test the consistency of the elevated OEF and delayed ATB. The OEF and ATB values and the absolute differences between their ipsilateral and contralateral sides were extracted and obtained for the entire hemisphere and the middle, anterior, and posterior cerebral arterial regions. Consistency was observed in 52 PET scans (83.9%) in visual assessment. The OEF and ATB values were moderately correlated (r = 0.553, p

Abstract Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin‐oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction. We followed four patients for 2–5 months during and/or after voxelotor therapy. This study showed no observable increase in cerebral blood flow or oxygen extraction fraction during treatment.

Isoflurane is one of the most widely used anesthetic agents in rodent imaging studies. However, the impact of isoflurane on brain metabolism has not been fully characterized to date, primarily due to a scarcity of noninvasive technologies to quantitatively measure the brain's metabolic rate in vivo. In this study, using noncontrast MRI techniques, we dynamically measured cerebral metabolic rate of oxygen (CMRO2) under varying doses of isoflurane anesthesia in mice. Concurrently, systemic parameters of heart and respiration rates were recorded alongside CMRO2. Additionally, electroencephalogram (EEG) recording was used to identify changes in neuronal activities under the same anesthetic regimen employed in the MRI experiments. We found suppression of the CMRO2 by isoflurane in a dose‐dependent manner, concomitant with a diminished high‐frequency EEG activity. The degree of metabolic suppression by isoflurane was strongly correlated with the respiration rate, which offers a potential approach to calibrate CMRO2 measurements. Furthermore, the metabolic level associated with neural responses of the somatosensory and motor cortices in mice was estimated as 308.2 μmol/100 g/min. These findings may facilitate the integration of metabolic parameters into future studies involving animal disease models and anesthesia usage. [ABSTRACT FROM AUTHOR]

Objectives: To explore the oxygen metabolism level of different types of lesions in relapsing–remitting multiple sclerosis (RRMS) patients by oxygen extraction fraction (OEF) both cross-sectionally and longitudinally. Methods: Forty-six RRMS patients and forty-one healthy controls (HC) went MRI examination. The quantitative susceptibility mapping (QSM) and OEF map were reconstructed from a 3D multi-echo gradient echo sequence. MS lesions in white matter were classified as contrast-enhancing lesions (CELs) on post-gadolinium T1-weighted sequence, paramagnetic rim lesions (PRLs), hyperintense lesions and non-hyperintense lesions on QSM, respectively. The susceptibility and OEF of different types of lesions were compared. The susceptibility and OEF values were measured and compared among different types of lesions. Among these RRMS patients, seventeen had follow-up MRI and 232 lesions, and baseline to follow-up longitudinal changes in susceptibility and OEF were measured. Results: PRLs had higher susceptibility and lower OEF than CELs, hyperintense lesions, and non-hyperintense lesions. The hyperintense lesions had higher susceptibility and lower OEF than non-hyperintense lesions. In longitudinal changes, PRLs had susceptibility increased (P < 0.001) and OEF decreased (P < 0.001). The hyperintense lesions showed significant decreases in susceptibility (P = 0.020), and non-hyperintense lesions showed significant increases in OEF during follow-up (P = 0.005). Notably, hyperintense lesions may convert to PRLs or non-hyperintense lesions as time progresses, accompanied by changes of OEF and susceptibility in the lesions. Conclusion: This study revealed tissue damage and oxygen metabolism level in different types of MS lesions. The OEF may contribute to further understanding the evolution of MS lesions. [ABSTRACT FROM AUTHOR]

Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (SvO2) in the ICVs. Results revealed a significant reduction in the susceptibility of ICVs (212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb) and a significant increase of SvO2 (74.5 ± 1.89% vs 72.4 ± 2.23%) in patients with RRMS compared with age- and sex-matched healthy controls. Both the susceptibility of ICVs (r = 0.508, p = 0.031) and the SvO2 (r = −0.498, p = 0.036) exhibited a moderate correlation with cognitive decline in these patients assessed by the Paced Auditory Serial Addition Test, while no significant correlation was observed with clinical disability measured by the Expanded Disability Status Scale. The findings suggest that venous susceptibility in ICVs has the potential to serve as a specific indicator of oxygen metabolism and cognitive function in RRMS. [ABSTRACT FROM AUTHOR]

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

One of the goals of this systematic review is to provide a meta-analysis-derived mean OEF of healthy volunteers. Another aim of this study is to indicate the OEF ranges of various neurological pathologies. Potential clinical applications of OEF metrics are presented. Peer-reviewed studies reporting OEF metrics derived from computed tomography (CT)/positron emission tomography (PET) and/or magnetic resonance imaging (MRI) were considered. Databases utilized included MEDLINE, PubMed, EMBASE, Web of Science, and Google Scholar. The Newcastle–Ottawa scoring system was used for evaluating studies. R Studio was utilized for the meta-analysis calculations when appropriate. The GRADE framework was utilized to assess additional findings. Of 2267 potential studies, 165 met the inclusion criteria. The healthy volunteer meta-analysis included 339 subjects and found a mean OEF value of 38.87 (37.38, 40.36), with a prediction interval of 32.40–45.34. There were no statistical differences in OEF values derived from PET versus MRI. We provided a GRADE A certainty rating for the use of OEF metrics to predict stroke occurrence in patients with symptomatic carotid or cerebral vessel disease. We provided a GRADE B certainty rating for monitoring treatment response in Moyamoya disease. Use of OEF metrics in diagnosing and/or monitoring other conditions had a GRADE C certainty rating or less. OEF might have a role in diagnosing and monitoring patients with symptomatic carotid or cerebral vessel disease and Moyamoya disease. While we found insufficient evidence to support measuring OEF metrics in other patient populations, in many cases, further studies are warranted. [ABSTRACT FROM AUTHOR]

Quantitative BOLD (qBOLD) MRI allows evaluation of oxidative metabolism of the brain based purely on an endogenous contrast mechanism. The method quantifies deoxygenated blood volume (DBV) and hemoglobin oxygen saturation level of venous blood (Yv), yielding oxygen extraction fraction (OEF), and along with a separate measurement of cerebral blood flow, cerebral metabolic rate of oxygen (CMRO2) maps. Here, we evaluated our recently reported 3D qBOLD method that rectifies a number of deficiencies in prior qBOLD approaches in terms of repeat reproducibility and sensitivity to hypercapnia on the metabolic parameters, and in comparison to dual-gas calibrated BOLD (cBOLD) MRI for determining resting-state oxygen metabolism. Results suggested no significant difference between test-retest qBOLD scans in either DBV and OEF. Exposure to hypercapnia yielded group averages of 38 and 28% for OEF and 151 and 146 µmol/min/100 g for CMRO2 in gray matter at baseline and hypercapnia, respectively. The decrease of OEF during hypercapnia was significant (p ≪ 0.01), whereas CMRO2 did not change significantly (p = 0.25). Finally, baseline OEF (37 vs. 39%) and CMRO2 (153 vs. 145 µmol/min/100 g) in gray matter using qBOLD and dual-gas cBOLD were found to be in good agreement with literature values, and were not significantly different from each other (p > 0.1). [ABSTRACT FROM AUTHOR]

Introduction: We aimed to demonstrate non-invasive measurements of regional oxygen extraction fraction (OEF) from quantitative BOLD MRI modeling at baseline and after pharmacological vasodilation. We hypothesized that OEF decreases in response to vasodilation with acetazolamide (ACZ) in healthy conditions, reflecting compensation in regions with increased cerebral blood flow (CBF), while cerebral metabolic rate of oxygen (CMRO2) remained unchanged. We also aimed to assess the relationship between OEF and perfusion in the default mode network (DMN) regions that have shown associations with vascular risk factors and cerebrovascular reactivity in different neurological conditions. Material and methods: Eight healthy subjects (47 ± 13 years, 6 female) were scanned on a 3 T scanner with a 32-channel head coil before and after administration of 15 mg/kg ACZ as a pharmacological vasodilator. The MR imaging acquisition protocols included: 1) A Gradient Echo Slice Excitation Profile Imaging Asymmetric Spin Echo scan to quantify OEF, deoxygenated blood volume, and reversible transverse relaxation rate (R2 ') and 2) a multi-post labeling delay arterial spin labeling scan to measure CBF. To assess changes in each parameter due to vasodilation, two-way t-tests were performed for all pairs (baseline versus vasodilation) in the DMN brain regions with Bonferroni correction for multiple comparisons. The relationships between CBF versus OEF and CBF versus R2' were analyzed and compared across DMN regions using linear, mixed-effect models. Results: During vasodilation, CBF significantly increased in the medial frontal cortex (P=0.004), posterior cingulate gyrus (pCG) (P=0.004), precuneus cortex (PCun) (P=0.004), and occipital pole (P=0.001). Concurrently, a significant decrease in OEF was observed only in the pCG (8.8%, P=0.003) and PCun (8.7%,P=0.001). CMRO2 showed a trend of increased values after vasodilation, but these differences were not significant after correction for multiple comparisons. Although R2' showed a slightly decreasing trend, no statistically significant changes were found in any regions in response to ACZ. The CBF response to ACZ exhibited a stronger negative correlation with OEF (β=-0.104±0.027; t=-3.852,P

Objectives: Iron deposition and mitochondrial dysfunction are closely associated with the genesis and progression of Parkinson's disease (PD). This study aims to extract susceptibility and oxygen extraction fraction (OEF) values of deep grey matter (DGM) to explore spatiotemporal progression patterns of brain iron-oxygen metabolism in PD. Methods: Ninety-five PD patients and forty healthy controls (HCs) were included. Quantitative susceptibility mapping (QSM) and OEF maps were computed from MRI multi-echo gradient echo data. Analysis of covariance (ANCOVA) was used to compare mean susceptibility and OEF values in DGM between early-stage PD (ESP), advanced-stage PD (ASP) patients and HCs. Then Granger causality analysis on the pseudo-time-series of MRI data was applied to assess the causal effect of early altered nuclei on iron content and oxygen extraction in other DGM nuclei. Results: The susceptibility values in substantia nigra (SN), red nucleus, and globus pallidus (GP) significantly increased in PD patients compared with HCs, while the iron content in GP did not elevate obviously until the late stage. The mean OEF values for the caudate nucleus, putamen, and dentate nucleus were higher in ESP patients than in ASP patients or/and HCs. We also found that iron accumulation progressively expands from the midbrain to the striatum. These alterations were correlated with clinical features and improved AUC for early PD diagnosis to 0.824. Conclusions: Abnormal cerebral iron deposition and tissue oxygen utilization in PD measured by QSM and OEF maps could reflect pathological alterations in neurodegenerative processes and provide valuable indicators for disease identification and management. Clinical relevance statement: Noninvasive assessment of cerebral iron-oxygen metabolism may serve as clinical evidence of pathological changes in PD and improve the validity of diagnosis and disease monitoring. Key Points: • Quantitative susceptibility mapping and oxygen extraction fraction maps indicated the cerebral pathology of abnormal iron accumulation and oxygen metabolism in Parkinson's disease. • Iron deposition is mainly in the midbrain, while altered oxygen metabolism is concentrated in the striatum and cerebellum. • The susceptibility and oxygen extraction fraction values in subcortical nuclei were associated with clinical severity. [ABSTRACT FROM AUTHOR]

Purpose: The heart is a highly aerobic organ consuming most of the oxygen the body in supporting heart function. Quantitative imaging of myocardial oxygen metabolism and perfusion is essential for studying cardiac physiopathology in vivo. Here, we report a new imaging method that can simultaneously assess myocardial oxygen metabolism and blood flow in the rat heart. Methods: This novel method is based on the 17O‐MRSI combined with brief inhalation of 17O‐isotope labeled oxygen gas for quantitative imaging of myocardial metabolic rate of oxygen consumption (MVO2), myocardial blood flow (MBF), and oxygen extraction fraction (OEF). We demonstrate this imaging method under basal and high workload conditions in rat hearts at 9.4 T. Results: We show that this 17O MRSI–based approach can directly measure and image MVO2 (1.35–4.06 μmol/g/min), MBF (0.49–1.38 mL/g/min), and OEF (0.33–0.44) in the heart of anesthetized rat under basal and high workload (21.6 × 103–56.7 × 103 mmHg • bpm) conditions. Under high workload condition, MVO2 and MBF values in healthy rats approximately doubled, whereas OEF remained unchanged, indicating a strong coupling between myocardial oxygen metabolic demand and supply through blood perfusion. Conclusion: The 17O‐MRSI method has been used to simultaneously image the myocardial metabolic rate of oxygen consumption, blood flow, and oxygen extraction fraction in small animal hearts, which are sensitive to the physiological changes induced by high workload. This approach could provide comprehensive measures that are critical for studying myocardial function in normal and diseased states and has a potential for translation. [ABSTRACT FROM AUTHOR]

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

Background: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv) levels, which in turn can be calculated from venous blood T2 values (T2b). T2b can be measured using different MRI sequences, including T2‐relaxation‐under‐spin‐tagging (TRUST) and T2‐prepared‐blood‐relaxation‐imaging‐with‐inversion‐recovery (T2‐TRIR). The latter measures both T2b and T1 (T1b) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. Purpose: To compare TRUST and T2‐TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. Study Type: Prospective. Population: Twelve healthy volunteers (four female, age 36 ± 10 years). Field Strength/Sequence: A 3T; turbo‐field echo‐planar‐imaging (TFEPI), echo‐planar‐imaging (EPI), and fast‐field‐echo (FFE). Assessment: TRUST‐ and T2‐TRIR‐derived T2b, Yv, OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2‐TRIR was used to estimate Hct (HctTRIR) and compared with venipuncture (HctVP). Statistical Tests: Shapiro–Wilk, one‐sample and paired‐sample t‐test, repeated measures ANOVA, Friedman test, Bland–Altman, and correlation analysis. Bonferroni multiple‐comparison correction was performed. Significance level was 0.05. Results: A significant bias was observed between TRUST‐ and T2‐TRIR‐derived T2b, Yv, and OEF values (−13 ± 11 msec, −5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). Data Conclusion: Given the constant bias, TRUST‐ and T2‐TRIR‐derived venous T2b values can be used interchangeably to estimate Yv, OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2‐TRIR‐derived T1‐values only weakly correlated with Hct from venipuncture. Evidence Level: 2 Technical Efficacy: Stage 2. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases affect up to thirty percent of the adult cancer population. One of the treatment options is stereotactic radiosurgery (SRS). To better understand SRS-related side-effects, we used advanced imaging techniques to study both the vascular and metabolic reserve capacity of the brain in nine patients with brain metastases before and three months after SRS. We observed larger declines in both vascular and metabolic markers in healthy brain regions that received a higher dose of SRS, but also saw substantial variation within- and between individuals. Our case analysis showed that the markers used in this study were able to pick up differences between patients who had either tumor growth or tumor shrinkage three months after SRS. These preliminary findings suggest there are no immediate detrimental effects on healthy brain tissue following SRS, but larger groups with a longer follow-up are needed to investigate potential late side-effects. Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = −0.286, p < 0.001), CMRO2 (rrm = −0.254, p < 0.001), and CVR (rrm = −0.346, p < 0.001), but not in OEF (rrm = −0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to evaluate the whole-brain pattern of oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) perturbation in Alzheimer's disease (AD) and investigate the relationship between regional cerebral oxygen metabolism and global cognition. Methods: Twenty-six AD patients and 25 age-matched healthy controls (HC) were prospectively recruited in this study. Mini-Mental State Examination (MMSE) was used to evaluate cognitive status. We applied the QQ-CCTV algorithm which combines quantitative susceptibility mapping and quantitative blood oxygen level-dependent models (QQ) for OEF calculation. CBF map was computed from arterial spin labeling and CMRO2 was generated based on Fick's principle. Whole-brain and regional OEF, CBF, and CMRO2 analyses were performed. The associations between these measures in substructures of deep brain gray matter and MMSE scores were assessed. Results: Whole brain voxel-wise analysis showed that CBF and CMRO2 values significantly decreased in AD predominantly in the bilateral angular gyrus, precuneus gyrus and parieto-temporal regions. Regional analysis showed that CBF value decreased in the bilateral caudal hippocampus and left rostral hippocampus and CMRO2 value decreased in left caudal and rostral hippocampus in AD patients. Considering all subjects in the AD and HC groups combined, the mean CBF and CMRO2 values in the bilateral hippocampus positively correlated with the MMSE score. Conclusion: CMRO2 mapping with the QQ-CCTV method - which is readily available in MR systems for clinical practice - can be a potential biomarker for AD. In addition, CMRO2 in the hippocampus may be a useful tool for monitoring cognitive impairment.

Purpose: Asymmetric spin echo (ASE) MRI is a method for measuring regional oxygen extraction fraction (OEF); however, extravascular tissue models have been shown to under‐estimate OEF. The hypothesis investigated here is that the addition of a vascular‐space‐occupancy (VASO) pre‐pulse will more fully suppress blood water signal and provide global OEF values more consistent with physiological expectation and 15O positron emission tomography (PET)‐validated T2‐relaxation‐under‐spin‐tagging (TRUST) OEF measures. Methods: Healthy adults (n = 14; age = 27.7 ± 5.2 y; sex = 7/7 male/female) were scanned at 3.0T. Multi‐echo ASE without inter‐readout refocusing (ASERF−), multi‐echo ASE with inter‐readout refocusing (ASERF+), and single‐echo VASO‐ASE were acquired twice each with common spatial resolution = 3.44 × 3.44 × 3.0 mm and τ = 0–20 ms (interval = 0.5 ms). TRUST was acquired twice sequentially for independent global OEF assessment (τCPMG = 10 ms; effective TEs = 0, 40, 80, and 160 ms; spatial resolution = 3.4 × 3.4 × 5 mm). OEF intraclass‐correlation‐coefficients (ICC), summary statistics, and group‐wise differences were assessed (Wilcoxon rank‐sum; significance: two‐sided p < 0.05). Results: ASERF+ (OEF = 36.8 ± 1.9%) and VASO‐ASE (OEF = 34.4 ± 2.3%) produced OEF values similar to TRUST (OEF = 36.5 ± 4.6%, human calibration model; OEF = 32.7 ± 4.9%, bovine calibration model); however, ASERF− yielded lower OEF (OEF = 26.1 ± 1.0%; p < 0.01) relative to TRUST. VASO‐ASE (ICC = 0.61) yielded lower ICC compared to other ASE variants (ICC >0.89). Conclusion: VASO‐ASE and TRUST provide similar OEF values; however, VASO‐ASE spatial coverage and repeatability improvements are required. [ABSTRACT FROM AUTHOR]

Purpose: To verify whether arterial transit time (ATT) mapping can correct arterial spin labeling-cerebral blood flow (ASL-CBF) values and to verify whether ATT is a parameter that correlates with positron emission tomography (PET)-oxygen extraction fraction (OEF) and PET-mean transit time (MTT). Methods: Eleven patients with unilateralmajor cerebral artery stenosis or occlusion underwent MRI and PET in the chronic or asymptomatic phase. ASL-MRI acquisitions were conducted with each of two post-label delay (PLD) settings (0.7s and 2.0s) using a pseudo-continuous ASL pulse sequence and 3D-spin echo spiral readout with vascular crusher gradient. ATT maps were obtained using a low-resolution pre-scan approach with five PLD settings. Using the ASL perfusion images and ATT mapping, ATT-corrected ASL-CBF images were obtained. Four kinds of ASL-CBFmethods (PLD 0.7s with or withoutATT correction and PLD 2.0s with or withoutATT correction) were compared to PET-CBF, using vascular territory ROIs. ATT and OEF were compared for all ROIs, unaffected side ROIs, and affected side ROIs, respectively. ATT and MTT were compared by the ratio of the affected side to the unaffected side. Transit time-based ROIs were used for the comparison with ATT. Results: Comparing ASL-CBF and PET-CBF, the correlation was higher with ATT correction than without correction, and for a PLD of 2.0s compared with 0.7s. The best correlation was for PLD of 2.0s with ATT correction (R² = 0.547). ROIs on the affected side showed a low but significant correlation between ATT and PET-OEF (R² = 0.141). There was a low correlation between the ATT ratio and the MTT ratio (R² = 0.133). Conclusion: Low-resolution ATT correction may increase the accuracy of ASL-CBF measurements in patients with unilateral major cerebral artery stenosis or occlusion. In addition, ATT itself might have a potential role in detecting compromised hemodynamic state. [ABSTRACT FROM AUTHOR]

Oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are key cerebral physiological parameters to identify at-risk cerebrovascular patients and understand brain health and function. PET imaging with [15O]-oxygen tracers, either through continuous or bolus inhalation, provides non-invasive assessment of OEF and CMRO2. Numerous tracer delivery, PET acquisition, and kinetic modeling approaches have been adopted to map brain oxygenation. The purpose of this technical review is to critically evaluate different methods for [15O]-gas PET and its impact on the accuracy and reproducibility of OEF and CMRO2 measurements. We perform a meta-analysis of brain oxygenation PET studies in healthy volunteers and compare between continuous and bolus inhalation techniques. We also describe OEF metrics that have been used to detect hemodynamic impairment in cerebrovascular disease. For these patients, advanced techniques to accelerate the PET scans and potential synthesis with MRI to avoid arterial blood sampling would facilitate broader use of [15O]-oxygen PET for brain physiological assessment.

Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3 ± 3.4%) versus the contralateral hemisphere (25.5 ± 3.1%) of patients with large diffusion-perfusion lesion mismatch (P = 0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI (P = 0.004), suggesting compensation for reduced flow. Patients with perfusion-diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2 ± 0.1 at baseline that normalized (decreased) to 1.0 ± 0.1 at follow-up three days later (P = 0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time. Clinical trial registration: Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; clinicaltrials.org : NCT02077582.

Normal pressure hydrocephalus (NPH) is a neurodegenerative disease that is potentially reversible by shunt surgery in approximately 60% of patients. Imaging may provide a means to investigate brain tissue viability and oxygen metabolism in NPH patients. Oxygen extraction fraction (OEF) mapping was generated from 3D multi-echo gradient echo MRI (mGRE) data using QQ-CCTV algorithm and cerebral blood flow (CBF) using 3D arterial spin labeling (ASL) MRI data, thereby calculating the cerebral metabolic rate of oxygen (CMRO 2 = CBF × OEF × [H] a) in 16 NPH patients. Regression analyses using cortical gray matter and deep gray matter regions were conducted with age, gender, CSF stroke volume and normalized ventricular volume as independent variables. OEF showed significant negative correlations with normalized brain ventricular volumes in the whole brain (p = 0.004, q = 0.01), cortical gray matter (p = 0.004, q = 0.01), caudate (p = 0.02, q = 0.04), and pallidum (p = 0.03, q = 0.04), but no significant correlation with CSF stroke volume (q > 0.05). There was no significant finding with CBF or CMRO 2. In NPH patients, low OEF in several regions was significantly correlated with large ventricular volumes, indicating decreased tissue oxygen metabolism with increased NPH severity. OEF mapping may provide a functional understanding of neurodegeneration in NPH and may improve monitoring of disease course and treatment outcomes. • Oxygen extraction fraction mapping in normal pressure hydrocephalus patients • Oxygen extraction fraction is feasible using multiecho gradient echo MRI. • Declined oxygen extraction fraction is correlated with enlarged brain ventricles. • Oxygen extraction fraction provides understanding of neurodegeneration. [ABSTRACT FROM AUTHOR]

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion‐induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)‐weighted pseudocontinuous ASL and OEF imaging with T2‐relaxation‐under‐spin‐tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin‐F, hemoglobin‐A, and hemoglobin‐S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two‐sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion‐induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD. [ABSTRACT FROM AUTHOR]

This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2). The first section is devoted to describing blood magnetic susceptibility and its effect on the MRI signal. Blood circulating in the vasculature can have diamagnetic (oxyhemoglobin) or paramagnetic properties (deoxyhemoglobin). The overall balance between oxygenated and deoxygenated hemoglobin determines the induced magnetic field which, in turn, modulates the transverse relaxation decay of the MRI signal via additional phase accumulation. The following sections of this review then illustrate the principles underpinning susceptibility-based techniques for quantifying OEF and CMRO2. Here, it is detailed whether these techniques provide global (OxFlow) or local (Quantitative Susceptibility Mapping - QSM, calibrated BOLD - cBOLD, quantitative BOLD - qBOLD, QSM+qBOLD) measurements of OEF or CMRO2, and what signal components (magnitude or phase) and tissue pools they consider (intravascular or extravascular). Validations studies and potential limitations of each method are also described. The latter include (but are not limited to) challenges in the experimental setup, the accuracy of signal modeling, and assumptions on the measured signal. The last section outlines the clinical uses of these techniques in healthy aging and neurodegenerative diseases and contextualizes these reports relative to results from gold-standard PET.

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

Introduction: Oxygen extraction fraction (OEF) reflects the balance between oxygen delivery and consumption. We longitudinally measured OEF in older adults to examine the relationship with markers of Alzheimer's disease (AD) and vascular pathology. Methods: One hundred thirty‐seven participants were studied at two time‐points at an interval of 2.16 years. OEF was measured using T2‐relaxation‐under‐spin‐tagging (TRUST) magnetic resonance imaging (MRI). The association between OEF and vascular risks, white matter hyperintensities (WMH), cerebrospinal fluid (CSF) measures of amyloid beta (Aβ), total tau (t‐tau), and phosphorylated tau 181 (p‐tau181) was examined. Results: OEF increased from baseline to follow‐up. The increase in OEF was more prominent in individuals with high vascular risks compared to those with low vascular risks, and was associated with progression of vascular risks and the growth in WMH volume. OEF change was not related to CSF markers of AD pathology or their progression. Discussion: Longitudinal OEF change in older adults is primarily related to vascular pathology. [ABSTRACT FROM AUTHOR]

Objective: The primary objectives of this pilot study were to assess cognition and cerebral metabolic rate of oxygen (CMRO2) consumption in people with severe obesity before (baseline), and again, 2- and 14-weeks after sleeve gastrectomy bariatric surgery. Methods: Six people with severe/class 3 obesity (52 ± 10 years, five females, body mass index (BMI) = 41.9 ± 3.9 kg/m2), and 10 normal weight sex- and agematched healthy controls (HC) (48 ± 6 years, eight females, 22.8 ± 1.9 kg/m2). Global CMRO2 was measured non-invasively using MRI and cognition using the Integneuro testing battery. Results: Following a sleeve gastrectomy induced weight loss of 6.4 ± 2.5 kg (% total-body-weight-lost = 5.4) over two-weeks, cognition total scores improved by 0.8 ± 0.5 T-scores (p=0.03, 15.8% improvement from baseline). Weight loss over 14-weeks post-surgery was 15.4 ± 3.6 kg (% total-bodyweight-lost = 13.0%) and cognition improved by 1.1 ± 0.4 (p=0.003, 20.6% improvement from baseline). At 14-weeks, cognition was 6.4 ± 0.7, comparable to 6.0 ± 0.6 observed in the HC group. Baseline CMRO2 was significantly higher compared to the HC (230.4 ± 32.9 vs. 177.9 ± 33.9 µmol O2/100 g/min, p=0.02). Compared to baseline, CMRO2 was 234.3 ± 16.2 µmol O2/100 g/min at 2-weeks after surgery (p=0.8, 1.7% higher) and 217.3 ± 50.4 at 14-weeks (p=0.5, 5.7% lower) after surgery. 14-weeks following surgery, CMRO2 was similar to HC (p=0.17). Conclusion: Sleeve gastrectomy induced weight loss was associated with an increase in cognition and a decrease in CMRO2 observed 14-weeks after surgery. The association between weight loss, improved cognition and CMRO2 decrease should be evaluated in larger future studies. [ABSTRACT FROM AUTHOR]

• Volume, CBF and CMRO 2 of brain gray matter decline at certain age ranges. • CBF declines dispersedly while CMRO 2 declines widely across the cortex during aging. • OEF and CBF are negatively coupled across the cortex. • Females have smaller brain volumes but higher CBF and CMRO 2 than males. Background: Brain structure, oxygenation and perfusion are important factors in aging. Coupling between regional cerebral oxygen consumption and perfusion also reflects functions of neurovascular unit (NVU). Their trajectories and sex differences during normal aging important for clinical interpretation are still not well defined. In this study, we aim to investigate the relationship between brain structure, functions and age, and exam the sex disparities. Method : A total of 137 healthy subjects between 20∼69 years old were enrolled with conventional MRI, structural three-dimensional T 1 -weighted imaging (3D-T 1 WI), 3D multi-echo gradient echo sequence (3D-mGRE), and 3D pseudo-continuous arterial spin labeling (3D-pCASL). Oxygen extraction fraction (OEF) and cerebral blood flow (CBF) were respectively reconstructed from 3D-mGRE and 3D-pCASL images. Cerebral metabolic rate of oxygen (CMRO 2) were calculated as follows: CMR O 2 = CBF · OEF · [ H ] a , [ H ] a =7.377 μmol/mL. Brains were segmented into global gray matter (GM), global white matter (WM), and 148 cortical subregions. OEF, CBF, CMRO 2 , and volumes of GM/WM relative to intracranial volumes (rel_GM/rel_WM) were compared between males and females. Generalized additive models were used to evaluate the aging trajectories of brain structure and functions. The coupling between OEF and CBF was analyzed by correlation analysis. P or P FDR < 0.05 was considered statistically significant. Results : Females had larger rel_GM, higher CMRO 2 and CBF of GM/WM than males (P < 0.05). With control of sex, CBF of GM significantly declined between 20 and 32 years, CMRO 2 of GM declined subsequently from 33 to 41 years and rel_GM decreased significantly at all ages (R2 = 0.27, P < 0.001; R2 = 0.17, P < 0.001; R2 = 0.52, P < 0.001). In subregion analysis, CBF declined dispersedly while CMRO 2 declined widely across most subregions of the cortex during aging. Robust negative coupling between OEF and CBF was found in most of the subregions (r range = -0.12∼-0.48, P FDR < 0.05). Conclusion : The sex disparities, age trajectories of brain structure and functions as well as the coupling of NVU in healthy individuals provide insights into normal aging which are potential targets for study of pathological conditions. [ABSTRACT FROM AUTHOR]

The study investigated the sensitivity of a novel MRI-based OEF mapping, quantitative susceptibility mapping plus quantitative blood oxygen level-dependent imaging (QSM+qBOLD or QQ), to physiological changes, particularly increased oxygen extraction fraction (OEF) by using hyperventilation as a vasoconstrictive stimulus. While QQ’s sensitivity to decreased OEF during hypercapnia has been demonstrated, its sensitivity to increased OEF levels, crucial for cerebrovascular disorders like vascular dementia and Parkinson’s disease, remains unexplored. In comparison with a previous QSM-based OEF, we evaluated QQ’s sensitivity to high OEF values. MRI data were obtained from 11 healthy subjects during resting state (RS) and hyperventilation state (HV) using a 3 T MRI with a three-dimensional multi-echo gradient echo sequence (mGRE) and arterial spin labeling (ASL). Region of interest (ROI) analysis and paired t-tests were used to compare OEF, CMRO2 and CBF between QQ and QSM. Similar to QSM, QQ showed higher OEF during HV compared to RS: in cortical gray matter, QQ-OEF and QSM-OEF was 36.4   ±   4.7% and 35.3   ±   12.5% at RS and 45.0   ±   11.6% and 45.0   ±   14.8% in HV, respectively. These findings demonstrate QQ’s ability to detect physiological changes and suggest its potential in studying brain metabolism in neurological disorders. [ABSTRACT FROM AUTHOR]

The medial temporal lobe (MTL) is a key area implicated in many brain diseases, such as Alzheimer's disease. As a functional biomarker, the oxygen extraction fraction (OEF) of MTL may be more sensitive than structural atrophy of MTL, especially at the early stages of diseases. However, there is a lack of non-invasive techniques to measure MTL-OEF in humans. The goal of this work is to develop an MRI technique to assess MTL-OEF in a clinically practical time without using contrast agents. The proposed method measures venous oxygenation (Yv) in the basal veins of Rosenthal (BVs), which are the major draining veins of the MTL. MTL-OEF can then be estimated as the arterio-venous difference in oxygenation. We developed an MRI sequence, dubbed arterial-suppressed accelerated T2-relaxation-under-phase-contrast (AS-aTRUPC), to quantify the blood T2 of the BVs, which was then converted to Yv through a well-established calibration model. MTL-OEF was calculated as (Ya−Yv)/Ya × 100%, where Ya was the arterial oxygenation. The feasibility of AS-aTRUPC to quantify MTL-OEF was evaluated in 16 healthy adults. The sensitivity of AS-aTRUPC in detecting OEF changes was assessed by a caffeine ingestion (200 mg) challenge. For comparison, T2-relaxation-under-spin-tagging (TRUST) MRI, which is a widely used global OEF technique, was also acquired. The dependence of MTL-OEF on age was examined by including another seven healthy elderly subjects. The results showed that in healthy adults, MTL-OEF of the left and right hemispheres were correlated (P=0.005). MTL-OEF was measured to be 23.9±3.6% (mean±standard deviation) and was significantly lower (P

Background: We aimed to investigate whether combined phosphorous (31P) magnetic resonance spectroscopic imaging (MRSI) and quantitative T2′ mapping are able to detect alterations of the cerebral oxygen extraction fraction (OEF) and intracellular pH (pHi) as markers the of cellular energy metabolism in cerebral small vessel disease (SVD). Materials and methods: 32 patients with SVD and 17 age-matched healthy control subjects were examined with 3-dimensional 31P MRSI and oxygenation-sensitive quantitative T2′ mapping (1/T2′ = 1/T2* - 1/T2) at 3 Tesla (T). PHi was measured within the white matter hyperintensities (WMH) in SVD patients. Quantitative T2′ values were averaged across the entire white matter (WM). Furthermore, T2′ values were extracted from normal-appearing WM (NAWM) and the WMH and compared between patients and controls. Results: Quantitative T2′ values were significantly increased across the entire WM and in the NAWM in patients compared to control subjects (149.51 ± 16.94 vs. 138.19 ± 12.66 ms and 147.45 ± 18.14 vs. 137.99 ± 12.19 ms, p

White matter lesions (WML) have been linked to cognitive decline in aging as well as in Alzheimer's disease. While hypoperfusion is frequently considered a cause of WMLs due to the resulting reduction in oxygen availability to brain tissue, such reductions could also be caused by impaired oxygen exchange. Here, we tested the hypothesis that venous hyperintense signal (VHS) in arterial spin labeling (ASL) magnetic resonance imaging (MRI) may represent a marker of impaired oxygen extraction in aging older adults. In participants aged 60–80 years (n = 30), we measured cerebral blood flow and VHS with arterial spin labeling, maximum oxygen extraction fraction (OEFmax) with dynamic susceptibility contrast, and WML volume with T1-weighted MRI. We found a significant interaction between OEFmax and VHS presence on WML volume (p = 0.02), where lower OEFmax was associated with higher WML volume in participants with VHS, and higher OEFmax was associated with higher WML volume in participants without VHS. These results indicate that VHS in perfusion-weighted ASL data may represent a distinct cerebrovascular aging pattern involving oxygen extraction inefficiency as well as hypoperfusion. [ABSTRACT FROM AUTHOR]

Purpose: The simultaneous quantification of T2 and T2* maps based on fast sequences for combined GE and SE acquisition has rekindled research and clinical interest by offering a wide range of attractive applications, e.g., dynamic tracking of oxygen extraction fraction (OEF). However, previously published methods based on EPI‐readouts have been hindered by resolution and the number of acquired echoes. Methods: This work presents a novel 10‐echo GE‐SE EPIK (EPI with keyhole) sequence for the rapid quantification of T2'. T2/T2* maps from the GE‐SE EPIK sequence were validated using three phantoms and 15 volunteers at 3T. The incorporation of a sliding window approach, combined with the full sampling of the k‐space center inherent to EPIK, enables a high effective temporal resolution. That is, for an eight‐slice breath‐hold experiment, a temporal sampling rate of eight reconstructed slices per 1.1 s. Results: In comparison with repeated single‐echo SE, multi‐echo GE, and spectroscopy methods, the GE‐SE EPIK sequence shows good agreement in quantifying T2/T2* values, while the gray matter/white matter separation yielded the expected contrast differentiation. The OEF was calculated with a view to an initial application with clinical relevance, producing results comparable to those in the literature and with good sensitivity in breath‐hold experiments. Conclusions: GE‐SE EPIK provides increased resolution and more echoes, including two SEs, than comparable sequences. Moreover, GE‐SE EPIK achieves this within an acquisition time of 57 s for 20 slices (matrix size = 128×128; FOV = 24 cm) and with a reasonably short TE for the final echo (114 ms). The sequence can dynamically track OEF changes in a breath‐hold experiment. [ABSTRACT FROM AUTHOR]

Objectives: 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. Methods: 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. Results: 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). Conclusion: 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. Key points: • 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. [ABSTRACT FROM AUTHOR]

Background and Purpose: The oxygen extraction fraction is an essential biomarker for the assessment of brain metabolism. A recently proposed method combined with quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude enables noninvasive mapping of the oxygen extraction fraction. Our study investigated the oxygen extraction fraction mapping variations of single-delay and multi-delay arterial spin-labeling., Materials and Methods: A total of twenty healthy participants were enrolled. The multi-echo spoiled gradient-echo, multi-delay arterial spin-labeling, and magnetization-prepared rapid gradient echo sequences were acquired at 3.0 T. The mean oxygen extraction fraction was generated under a single delay time of 1780 ms, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume. The results were compared via paired t tests and the Wilcoxon test. Linear regression analyses were used to investigate the relationships among the oxygen extraction fraction, cerebral blood flow, and venous cerebral blood volume., Results: The oxygen extraction fraction estimate with multi-delay arterial spin-labeling yielded a significantly lower value than that with single-delay arterial spin-labeling. The average values for the whole brain under single-delay arterial spin-labeling, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume were 41.5 ± 1.7 % (P < 0.05), 41.3 ± 1.9 % (P < 0.001), and 40.9 ± 1.9 % (N = 20), respectively. The oxygen extraction fraction also showed a significant inverse correlation with the venous cerebral blood volume under steady-state conditions when multi-delay arterial spin-labeling was used (r = 0.5834, p = 0.0069)., Conclusion: These findings suggest that the oxygen extraction fraction is significantly impacted by the arterial spin-labeling methods used in the quantitative susceptibility mapping plus the quantitative blood oxygen level-dependent model, indicating that the differences should be accounted for when employing oxygen extraction fraction mapping based on this model in diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Venous blood oxygenation (Yv), which can be derived from venous blood T2 (T2b), 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 (T1b), potentially improving Yv estimation by overcoming the need to estimate hematocrit. Purpose: To optimize and compare T2‐TRIR with T2‐relaxation‐under‐spin‐tagging (TRUST) sequence. Study Type: Prospective. Population: 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). Field Strength/Sequence: 3 T; turbo field echo planar imaging (TFEPI), echo planar imaging (EPI), and fast field echo (FFE). Assessment: T2b, Yv, and OEF from TRUST and T2‐TRIR were compared and T2‐TRIR‐derived T1b 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. Statistical Tests: 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. Results: In controls, T2b from T2‐TRIR (70 ± 11 msec) was higher compared to TRUST (60 ± 8 msec). In patients, T2b 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%). Data Conclusion: TRUST and T2‐TRIR are reproducible, but T2‐TRIR‐derived T2b 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. Evidence Level: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is caused by a single amino acid mutation in hemoglobin, causing chronic anemia and neurovascular complications. However, the effects of chronic anemia on oxygen extraction fraction (OEF), especially in deep brain structures, are less well understood. Conflicting OEF values have been reported in SCD patients, but have largely attributed to different measurement techniques, faulty calibration, and different locations of measurement. Thus, in this study, we investigated the reliability and agreement of two susceptibility-based methods, quantitative susceptibility mapping (QSM) and complex image summation around a spherical or a cylindrical object (CISSCO), for OEF measurements in internal cerebral vein (ICV), reflecting oxygen saturation in deep brain structures. Both methods revealed that SCD patients and non-sickle anemia patients (ACTL) have increased OEF in ICV (42.6% ± 5.6% and 30.5% ± 3.6% in SCD by CISSCO and QSM respectively, 37.0% ± 4.1% and 28.5% ± 2.3% in ACTL) compared with controls (33.0% ± 2.3% and 26.8% ± 1.8%). OEF in ICV varied reciprocally with hematocrit (r 2 = 0.92, 0.53) and oxygen content (r 2 = 0.86, 0.53) respectively. However, an opposite relationship was observed for OEF measurements in sagittal sinus (SS) with the widely used T2-based oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST), in the same cohorts (31.2% ± 6.6% in SCD, 33.3% ± 5.9% in ACTL and 36.8% ± 5.6% in CTL). Importantly, we demonstrated that hemoglobin F and other fast moving hemoglobins decreased OEF by TRUST and explained group differences in sagittal sinus OEF between anemic and control subjects. These data demonstrate that anemia causes deep brain hypoxia in anemia subjects with concomitant preservation of cortical oxygenation, as well as the key interaction of the hemoglobin dissociation curve and cortical oxygen extraction. [ABSTRACT FROM AUTHOR]

Purpose: Quantitative susceptibility mapping (QSM) enables cerebral venous characterization and physiological measurements, such as oxygen extraction fraction (OEF). The exquisite sensitivity of QSM to deoxygenated blood makes it possible to image small veins; however partial volume effects must be addressed for accurate quantification. We present a new method, Iterative Cylindrical Fitting (ICF), to estimate voxel-based partial volume effects for susceptibility maps and use it to improve OEF quantification of small veins with diameters between 1.5 and 4 voxels. Materials and Methods: Simulated QSM maps were generated to assess the performance of the ICF method over a range of vein geometries with varying echo times and noise levels. The ICF method was also applied to in vivo human brain data to assess the feasibility and behavior of OEF measurements compared to the maximum intensity voxel (MIV) method. Results: Improved quantification of OEF measurements was achieved for vessels with contrast to noise greater than 3.0 and vein radii greater than 0.75 voxels. The ICF method produced improved quantitative accuracy of OEF measurement compared to the MIV approach (mean OEF error 7.7 vs. 12.4%). The ICF method provided estimates of vein radius (mean error

Sickle cell disease (SCD) is caused by a single amino acid mutation in hemoglobin, causing chronic anemia and neurovascular complications. However, the effects of chronic anemia on oxygen extraction fraction (OEF), especially in deep brain structures, are less well understood. Conflicting OEF values have been reported in SCD patients, but have largely attributed to different measurement techniques, faulty calibration, and different locations of measurement. Thus, in this study, we investigated the reliability and agreement of two susceptibility-based methods, quantitative susceptibility mapping (QSM) and complex image summation around a spherical or a cylindrical object (CISSCO), for OEF measurements in internal cerebral vein (ICV), reflecting oxygen saturation in deep brain structures. Both methods revealed that SCD patients and non-sickle anemia patients (ACTL) have increased OEF in ICV (42.6% ± 5.6% and 30.5% ± 3.6% in SCD by CISSCO and QSM respectively, 37.0% ± 4.1% and 28.5% ± 2.3% in ACTL) compared with controls (33.0% ± 2.3% and 26.8% ± 1.8%). OEF in ICV varied reciprocally with hematocrit (r2 = 0.92, 0.53) and oxygen content (r2 = 0.86, 0.53) respectively. However, an opposite relationship was observed for OEF measurements in sagittal sinus (SS) with the widely used T2-based oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST), in the same cohorts (31.2% ± 6.6% in SCD, 33.3% ± 5.9% in ACTL and 36.8% ± 5.6% in CTL). Importantly, we demonstrated that hemoglobin F and other fast moving hemoglobins decreased OEF by TRUST and explained group differences in sagittal sinus OEF between anemic and control subjects. These data demonstrate that anemia causes deep brain hypoxia in anemia subjects with concomitant preservation of cortical oxygenation, as well as the key interaction of the hemoglobin dissociation curve and cortical oxygen extraction.

Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) can be measured using arterial spin labeling (ASL) and quantitative susceptibility mapping (QSM) sequences, respectively. ASL and QSM sequences were performed on 13 healthy participants and 46 patients with unilateral or bilateral Middle cerebral artery (MCA) occlusion. M1–M3 and M4–M6 correspond to anterior, lateral, and posterior MCA territories within the insular ribbon and centrum semiovale, respectively. In patients with unilateral MCA occlusion, significant decreases in CBF were observed in the lesions in M1, M3, M5 and M6 regions, as well as in the contralateral M3 and M5 regions. The OEF of the lesion in the M1–M4 and M6 regions, and the contralateral M1–M3 regions were significantly higher. Additionally, the cerebral metabolic rate of oxygen (CMRO2) in the lesions of the M3 and M6 regions, and the contralateral M3 region, were significantly lower compared to the corresponding regions of healthy participants. For patients with bilateral MCA occlusion, the CMRO2 in the left M5 region and the right M3 and M6 regions were significantly lower than that in the corresponding regions of healthy participants. In conclusion, abnormal hemodynamics occur in the contralateral hemisphere of patients with unilateral MCA occlusion. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate whether the spatial coefficient of variation of arterial spin labeling (ASL-CoV) acquired in clinical settings can be used to estimate the hemodynamic disturbances measured with 15O-gas positron emission tomography (PET), especially an increased oxygen extraction fraction (OEF), in patients with moyamoya disease. Methods: We evaluated 68 adult patients with moyamoya disease who underwent ASL (postlabeling delay (PLD) = 1525 ms and 2525 ms) and PET. Regional values were measured using the middle cerebral artery territorial atlas divided into proximal, middle, and distal regions based on the arterial transit time, and correlations of ASL-CoV with cerebral blood flow, cerebral blood volume, mean transit time, and OEF, as well as the relationship between increased OEF and ASL-CoV, were evaluated. Results: Regardless of the choice of region and PLD, ASL-CoV was significantly correlated with PET-measured parameters, including OEF (|ρ|= 0.30–0.80, P < 0.001). Regions with an increased OEF showed a significantly higher ASL-CoV than regions with a nonincreased OEF (P ≤ 0.03) regardless of the choice of region and PLD. The accuracy of identification of an increased OEF was highest when using a PLD of 1525 ms and the middle region (area under the curve = 0.750; using a cutoff value of 31.27, sensitivity = 97.4%, specificity = 41.7%, negative predictive value = 92.6%, and positive predictive value = 67.9%). Conclusion: ASL-CoV may help identify patients with increased OEF. [ABSTRACT FROM AUTHOR]

The cerebral cortex has a number of conserved morphological and functional characteristics across brain regions and species. Among them, the laminar differences in microvascular density and mitochondrial cytochrome c oxidase staining suggest potential laminar variability in the baseline O2 metabolism and/or laminar variability in both O2 demand and hemodynamic response. Here, we investigate the laminar profile of stimulus-induced intravascular partial pressure of O2 (pO2) transients to stimulus-induced neuronal activation in fully awake mice using two-photon phosphorescence lifetime microscopy. Our results demonstrate that stimulus-induced changes in intravascular pO2 are conserved across cortical layers I–IV, suggesting a tightly controlled neurovascular response to provide adequate O2 supply across cortical depth. In addition, we observed a larger change in venular O2 saturation (ΔsO2) compared to arterioles, a gradual increase in venular ΔsO2 response towards the cortical surface, and absence of the intravascular "initial dip" previously reported under anesthesia. This study paves the way for quantification of layer-specific cerebral O2 metabolic responses, facilitating investigation of brain energetics in health and disease and informed interpretation of laminar blood oxygen level dependent functional magnetic resonance imaging signals. [ABSTRACT FROM AUTHOR]