T2-relaxation-under-spin-tagging Research Articles

MR Assessment of Acute Changes of Cerebral Perfusion, Metabolism, and Blood-Brain Barrier Permeability in Response to Aerobic Exercise.

It remains unclear how a single bout of exercise affects brain perfusion, oxygen metabolism, and blood-brain barrier (BBB) permeability. Addressing this unresolved issue is essential to understand the acute changes in cerebral physiology induced by aerobic exercise. To dynamically monitor the acute changes in cerebral physiology subsequent to a single aerobic exercise training session using noninvasive MRI measurements. Prospective. Twenty-three healthy participants (18-35 years, 10 females/13 males) were enrolled and divided into 10-minute exercising (N = 10) and 20-minute exercising (N = 13) groups. 3.0 T/Phase Contrast (PC) MRI (gradient echo), T2-Relaxation-Under-Spin-Tagging (TRUST) MRI (gradient echo EPI), Water-Extraction-with-Phase-Contrast-Arterial-Spin-Tagging (WEPCAST) MRI (gradient echo EPI) and T1-weighted magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) (gradient echo). A baseline MR measurement plus four repeated MR measurements immediately after 10 or 20 minutes moderate running exercise. MR measurements included cerebral blood flow (CBF) as measured by PC MRI, venous oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO2) as assessed by TRUST MRI, water extraction fraction (E), and BBB permeability-surface-area product (PS) as determined by WEPCAST MRI. The time dependence of the physiological parameters was studied with a linear mixed-effect model. Additionally, pairwise t-tests comparison of the physiological parameters at each time point was conducted. A P-value of <0.05 was considered statistically significant. There was an initial drop (8.22 ± 2.60%) followed by a recovery in CBF after exercise, while Yv revealed a significant decrease (6.37 ± 0.92%), i.e., an increased oxygen extraction, and returned to baseline at later time points. CMRO2 showed a trend of increase (5.68 ± 3.04%) and a significant interaction between time and group. In addition, E increased significantly (3.86% ± 0.89) and returned to baseline level at later time points, while PS remained elevated (13.33 ± 4.79%). A single bout of moderate aerobic exercise can induce acute alterations in cerebral perfusion, metabolism, and BBB permeability. 2 TECHNICAL EFFICACY: Stage 2.

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model.

Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/INK4a. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

Vessel-specific quantification of cerebral venous oxygenation with velocity-encoding preparation and rapid acquisition.

Non-invasive measurement of cerebral venous oxygenation (Yv) is of critical importance in brain diseases. The present work proposed a fast method to quantify regional Yv map for both large and small veins. A new sequence was developed, referred to as TRU-VERA (T2 relaxation under velocity encoding and rapid acquisition, which isolates blood spins from static tissue with velocity-encoding preparation, modulates the T2 weighting of venous signal with T2-preparation and utilizes a bSSFP readout to achieve fast acquisition with high resolution. The sequence was first optimized to achieve best sensitivity for both large and small veins, and then validated with TRUST (T2 relaxation under spin tagging), TRUPC (T2 relaxation under phase contrast), and accelerated TRUPC MRI. Regional difference of Yv was evaluated, and test-retest reproducibility was examined. Optimal Venc was determined to be 3 cm/s, while recovery time and balanced SSFP flip angle within reasonable range had minimal effect on SNR efficiency. Venous T2 measured with TRU-VERA was highly correlated with T2 from TRUST (R2 = 0.90), and a conversion equation was established for further calibration to Yv. TRU-VERA sequences showed consistent Yv estimation with TRUPC (R2 = 0.64) and accelerated TRUPC (R2 = 0.79). Coefficient of variation was 0.84% for large veins and 2.49% for small veins, suggesting an excellent test-retest reproducibility. The proposed TRU-VERA sequence is a promising method for vessel-specific oxygenation assessment.

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

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

Assessment of Neurocognitive Functioning in Sickle Cell Disease and Thalassemia and the Association with Silent Cerebral Infarcts and Cerebral Hemodynamics and Oxygen Metabolism

Introduction Neurocognitive impairment is a significant problem in patients with sickle cell disease (SCD), affecting various life domains such as academic achievement, career progress, and general life quality. The cause of this impairment is not yet fully understood, however, it has been linked to silent cerebral infarcts (SCIs) and irregularities in blood perfusion and oxygenation, particularly in children with SCD. Previous research has identified cognitive deficits in adults with SCD, but the relationship with SCIs has not been thoroughly explored in this age group. This study aimed to examine the neurocognitive functioning among adult patients with three types of inherited chronic anemia (severe SCD, mild SCD, and thalassemia) and healthy controls. Additionally, we investigated potential associations of neurocognitive performance with cerebral perfusion and oxygenation, and SCIs. Methods This study included 70 severe SCD patients (60 HbSS, 10 HbSβ 0), 22 mild SCD patients (14 HbSC, 8 HbSβ +), 16 thalassemia patients (6 NTDT, 10 TDT), and 29 healthy controls. We assessed neurocognitive functioning through eight tasks divided into seven neurocognitive domains such as attention, processing speed, nonverbal IQ, working memory, verbal learning, visual memory, and fine motor dexterity. Each task score was standardized using published norm data, converted into Z-scores, and used to compute the mean Z-score per domain. SCIs were assessed and segmented using FLAIR MRI scans. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were derived using time-encoded pseudo-continuous arterial spin labeling (te-pCASL) and T 2-relaxation-under-spin-tagging (TRUST) techniques, respectively. Cerebral metabolic rate of oxygen (CMRO 2) was calculated from the CBF, OEF and oxygen content (calculated from hemoglobin and arterial saturation). One-sample t-tests or one-sample Wilcoxon-signed rank tests were used to compare the seven neurocognitive domains of each group with normative test data and ANOVA was used to compare these domains between participant groups. Independent-sample t-tests or Mann-Whitney U tests were used to compare the neurocognitive domains between patients with and without SCIs. Lastly, correlation analyses explored the relationships between the neurocognitive domains and SCI volume, CBF, OEF, and CMRO 2. Results In the severe SCD group, only processing speed and fine motor dexterity were significantly impaired after adjusting for multiple comparisons (Table 1 &amp; Figure 1). Mild SCD patients exhibited lower scores in processing speed, working memory, and fine motor dexterity compared to the norms. In contrast, after adjustment for multiple comparisons, thalassemia patients and healthy controls only showed significantly lower scores in fine motor dexterity (Table 1). When comparing groups, SCD patients had significantly slower processing speed compared to thalassemia patients and healthy controls. Surprisingly, SCD patients without SCIs exhibited poorer fine motor dexterity than those with SCIs (p=0.03), while no such associations were identified in other groups. Finally, no associations were found between the neurocognitive domains and SCI volumes, CBF, OEF and CMRO 2. Conclusion Our results show slower processing speed in SCD patients compared to thalassemia patients and healthy controls, aligning with previous studies. However, unlike previous research, we did not find additional neurocognitive deficits in SCD patients. This could be due to variations in patient selection, environmental factors, socioeconomic status, or recent enhancements in SCD treatment approaches, such as the early administration of hydroxyurea and/or blood transfusion. Interestingly, all groups showed diminished fine motor dexterity, potentially due to the ongoing digital transition. A key observation from this study was the lack of association between neurocognitive performance and SCIs, hemodynamics, and oxygen metabolism, suggesting that SCIs and oxygenation might not be the only factors contributing to impaired processing speed. Our results suggest that recent developments in medical treatments could have improved the neurocognitive function of SCD patients residing in Western countries. However, concerning the domain of processing speed, further studies are required to investigate other SCD-related factors that might influence this particular area.

Automatic Rejection based on Tissue Signal (ARTS) for motion-corrected quantification of cerebral venous oxygenation in neonates and older adults

ObjectiveCerebral venous oxygenation (Yv) is a key parameter for the brain's oxygen utilization and has been suggested to be a valuable biomarker in various brain diseases including hypoxic ischemic encephalopathy in neonates and Alzheimer's disease in older adults. T2-Relaxation-Under-Spin-Tagging (TRUST) MRI is a widely used technique to measure global Yv level and has been validated against gold-standard PET. However, subject motion during TRUST MRI scan can introduce considerable errors in Yv quantification, especially for noncompliant subjects. The aim of this study was to develop an Automatic Rejection based on Tissue Signal (ARTS) algorithm for automatic detection and exclusion of motion-contaminated images to improve the precision of Yv quantification. MethodsTRUST MRI data were collected from a neonatal cohort (N = 37, 16 females, gestational age = 39.12 ± 1.11 weeks, postnatal age = 1.89 ± 0.74 days) and an older adult cohort (N = 223, 134 females, age = 68.02 ± 9.01 years). Manual identification of motion-corrupted images was conducted for both cohorts to serve as a gold-standard. 9.3% of the images in the neonatal datasets and 0.4% of the images in the older adult datasets were manually identified as motion-contaminated. The ARTS algorithm was trained using the neonatal datasets. TRUST Yv values, as well as the estimation uncertainty (ΔR2) and test-retest coefficient-of-variation (CoV) of Yv, were calculated with and without ARTS motion exclusion. The ARTS algorithm was tested on datasets of older adults: first on the original adult datasets with little motion, and then on simulated adult datasets where the percentage of motion-corrupted images matched that of the neonatal datasets. ResultsIn the neonatal datasets, the ARTS algorithm exhibited a sensitivity of 0.95 and a specificity of 0.97 in detecting motion-contaminated images. Compared to no motion exclusion, ARTS significantly reduced the ΔR2 (median = 3.68 Hz vs. 4.89 Hz, P = 0.0002) and CoV (median = 2.57% vs. 6.87%, P = 0.0005) of Yv measurements. In the original older adult datasets, the sensitivity and specificity of ARTS were 0.70 and 1.00, respectively. In the simulated adult datasets, ARTS demonstrated a sensitivity of 0.91 and a specificity of 1.00. Additionally, ARTS significantly reduced the ΔR2 compared to no motion exclusion (median = 2.15 Hz vs. 3.54 Hz, P < 0.0001). ConclusionARTS can improve the reliability of Yv estimation in noncompliant subjects, which may enhance the utility of Yv as a biomarker for brain diseases.

Toward vendor-independent measurement of cerebral venous oxygenation: Comparison of TRUST MRI across three major MRI manufacturers and association with end-tidal CO2.

Cerebral venous oxygenation (Yv ) is a valuable biomarker for a variety of brain diseases. T2 relaxation under spin tagging (TRUST) MRI is a widely used method for Yv quantification. In this work, there were two main objectives. The first was to evaluate the reproducibility of TRUST Yv measurements across MRI scanners from different vendors. The second was to examine the correlation between Yv and end-tidal CO2 (EtCO2 ) in a multisite, multivendor setting and determine the usefulness of this correlation to account for variations in Yv caused by normal variations and physiological fluctuations. Standardized TRUST pulse sequences were implemented on three scanners from major MRI vendors (GE, Siemens, Philips). These scanners were located at two research institutions. Ten healthy subjects were scanned. On each scanner, the subject underwent two scan sessions, each of which included three TRUST scans, to evaluate the intrasession and intersession reproducibility of Yv . Each scanner was also equipped with a capnograph device to record the EtCO2 of the subject during the MRI scan. We found no significant bias in Yv measurements across the three scanners (P = 0.18). The measured Yv values on the three scanners were also strongly correlated with each other (intraclass correlation coefficients > 0.85, P < 0.001). The intrasession and intersession coefficients of variation of Yv were less than 4% and showed no significant difference among the scanners. In addition, our results revealed that (1) within the same subject, Yv increased with EtCO2 at a rate of 1.24 ± 0.17%/mmHg (P < 0.0001), and (2) across different subjects, individuals with a higher EtCO2 had a higher Yv , at a rate of 0.94 ± 0.36%/mmHg (P = 0.01). These results suggest that (1) the standardized TRUST sequences had similar accuracies and reproducibilities for the quantification of Yv across the scanners, and (2) recording of EtCO2 may be a useful complement to Yv measurement to account for CO2 -related physiological fluctuations in Yv in multisite, multivendor studies.

Venous Blood Oxygenation Measurements Using TRUST and T2-TRIR MRI During Hypoxic and Hypercapnic Gas Challenges.

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. To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. Prospective. Twelve healthy volunteers (four female, age 36 ± 10 years). A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). 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 ). 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. 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). 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. 2 TECHNICAL EFFICACY: Stage 2.

Vascular space occupancy asymmetric spin echo (VASO-ASE) for non-invasive quantification of cerebral oxygen extraction fraction.

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 15 O positron emission tomography (PET)-validated T2 -relaxation-under-spin-tagging (TRUST) OEF measures. Healthy adults (n= 14; age=27.7 ± 5.2y; 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=0.5ms). TRUST was acquired twice sequentially for independent global OEF assessment (τCPMG = 10ms; 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). 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). VASO-ASE and TRUST provide similar OEF values; however, VASO-ASE spatial coverage and repeatability improvements are required.

MRI assessment of cerebral oxygen extraction fraction in the medial temporal lobe

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<0.0001) than the OEF of 33.3±2.9% measured in superior sagittal sinus (SSS). After caffeine ingestion, there was an absolute percentage increase of 9.1±4.0% in MTL-OEF. Additionally, OEF in SSS measured with AS-aTRUPC showed a strong correlation with TRUST OEF (intra-class correlation coefficient=0.94 with 95% confidence interval [0.91, 0.96]), with no significant bias (P=0.12). MTL-OEF was found to increase with age (MTL-OEF=20.997+0.100 × age; P=0.02). In conclusion, AS-aTRUPC MRI provides non-invasive assessments of MTL-OEF and may facilitate future clinical applications of MTL-OEF as a disease biomarker.

Cerebral Oxygen Metabolism in Patients with Mild and Severe Sickle Cell Disease and Thalassemia

Introduction Studies in patients with severe (HbSS and HbSβ0) sickle cell disease (SCD) have reported reduced oxygen metabolism compared to controls despite the preserved oxygen delivery (OD). Whereas previous studies have found similar lesion load in mild SCD patients (HbSC and HbSβ+), oxygen metabolism has not been studied in this group. Interestingly, we previously showed that CBF values in mild SCD patients were lower compared to severe SCD, and comparable with healthy controls. Here, we assessed the OD, oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and lesion volumes in adult patients with severe and mild SCD and compared our results with thalassemia patients as anemic controls and healthy controls. In addition, the effect of a vasodilatory stimulus on the cerebral parameters was studied to test if increased CBF influences oxygen consumption. Methods In this study, 75 patients with severe SCD (64 HbSS and 11 HbSβ0), 26 patients with mild SCD (16 HbSC and 10 HbSβ+), 17 patients with thalassemia (7 NTDT and 10 TDT) and 30 healthy controls were included. Venous blood T2 was measured using T2-Relaxation-Under-Spin-Tagging (TRUST). Whole brain (WB) CBF was measured using time-encoded pseudo-continuous ASL (te-ASL). TRUST and te-ASL scans were performed before and after acetazolamide (ACZ) administration as a vasodilatory stimulus. Fluid-Attenuated Inversion Recovery (FLAIR) scans were acquired for the assessment and segmentation of lesions. OEF was calculated from arterial saturation measured by pulse oximetry and venous saturation calculated from blood T2 using a sickle cell-specific calibration model and a healthy control model. CMRO2 was calculated from the WB CBF, OEF and oxygen content (calculated from hemoglobin and arterial saturation). To test the effect of ACZ-induced vasodilation, ∆CBF, ∆OD, ∆OEF and ∆CMRO2 were calculated. A one-way analysis of covariance (ANCOVA) was conducted (or a nonparametric alternative) with posthoc Bonferroni correction to test for statistically significant differences in cerebral parameters between the participating groups controlling for age and sex. For ∆CBF, ∆OD, ∆OEF and ∆CMRO2, baseline values were added as additional covariates. Results CBF was significantly higher in severe SCD compared to other groups and significantly higher in thalassemia patients compared to mild SCD and healthy controls (Table 1). No significant differences were found in OD between the groups. OEF was significantly lower in severe SCD patients compared to other groups and significantly lower in thalassemia patients compared to mild SCD patients and healthy controls (Table 1). CMRO2 was significantly lower in severe SCD and thalassemia patients compared to mild SCD patients and healthy controls (Table 1). ∆CBF upon ACZ administration was not significantly different between the groups. ∆OD was significantly higher in controls compared to severe SCD and thalassemia patients (Table 1). Infusion of ACZ impaired the OEF and CMRO2 more in severe SCD compared to the other groups (Table 1: ∆OEF and ∆CMRO2). Lesion volume was significantly larger in the severe SCD group compared to the healthy controls but no significant differences were found between the other groups (Fig. 1). Conclusion Our results show that OEF and CMRO2 were significantly higher in mild SCD patients, and no different from healthy controls, compared to severe SCD and thalassemia patients, illustrating a more balanced oxygen supply versus demand in these less anemic patients. Furthermore, the finding that ACZ-induced elevated CBF significantly reduced the CMRO2 in severe SCD, but not in the other groups, suggests that functional shunting may play a role in severely affected SCD patients. Despite the large differences in cerebral oxygen metabolism between severe and mild SCD, no difference in lesion volume could be observed between these groups. One possible mechanism that might be responsible for the lesion load in mild SCD patients could be the higher blood viscosity in this group that has been hypothesized to cause other complications such as retinopathy, particularly in patients with HbSC. Another explanation could be that lesion volume is more related to deep brain hypoxia than whole brain oxygen metabolism which could be confirmed by further studies investigating deep brain oxygenation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Comparison of MRI Quantitative Susceptibility Mapping and TRUST-Based Measures of Brain Venous Oxygen Saturation in Sickle Cell Anaemia.

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Yv) to improve neurological risk prediction. T2-relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Yv in patients with sickle cell anemia (SCA). However, prior studies comparing Yv in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T2 to Yv, is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Yv in SCA as blood magnetic susceptibility is linearly dependent upon Yv, and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Yv using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Yv was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T2, within a similar but much smaller region, were converted to Yv using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Yv between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Yv, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Yv varied with method. The TRUST-HbBV and QSM methods suggested decreased Yv in SCA relative to healthy controls, while the TRUST-HbS (p < 0.01) and TRUST-HbA models suggested increased Yv in SCA as in previous studies. Further validation of all MRI measures of Yv, relative to ground truth measures such as O15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction.

Longitudinal changes in brain oxygen extraction fraction (OEF) in older adults: Relationship to markers of vascular and Alzheimer's pathology.

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. 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. 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. Longitudinal OEF change in older adults is primarily related to vascular pathology.

Anemia Increases Oxygen Extraction Fraction in Deep Brain Structures but Not in the Cerebral Cortex.

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.

Metabolism of oxygen via T2 and interleaved velocity encoding: A rapid method to quantify whole-brain cerebral metabolic rate of oxygen.

Cerebral metabolic rate of oxygen (CMRO2 ) is an important biomarker of brain function. Key physiological parameters required to quantify CMRO2 include blood flow rate in the feeding arteries and venous oxygen saturation (SvO2 ) in the draining vein. Here, a pulse sequence, metabolism of oxygen via T2 and interleaved velocity encoding (MOTIVE), was developed to measure both parameters simultaneously and enable CMRO2 quantification in a single pass. The MOTIVE sequence interleaves a phase-contrast module between a nonselective saturation and a background-suppressed T2 -prepared EPI readout (BGS-EPI) to measure T2 of blood water protons and cerebral blood flow in 20 s or less. The MOTIVE and standalone BGS-EPI sequences were compared against TRUST ("T2 relaxation under spin tagging") in the brain in healthy subjects (N= 24). Variants of MOTIVE to enhance resolution or shorten scan time were explored. Intrasession and intersession reproducibility studies were performed. MOTIVE experiments yielded an average SvO2 of 61 ± 6% in the superior sagittal sinus of the brain and an average cerebral blood flow of 56 ± 10ml/min/100 g. The bias in SvO2 of MOTIVE and BGS-EPI to TRUST was +2 ± 4% and +1 ± 3%, respectively. The bias in cerebral blood flow of MOTIVE to Cartesian phase-contrast reference was +1 ± 6ml/min/100 g. The MOTIVE sequence is an advance over existing T2 -based oximetric methods. It does not require a control image and simultaneously measures SvO2 and flow velocity. The measurements agree well with TRUST and reference phase-contrast sequences. This noninvasive technique enables CMRO2 quantification in under 20 s and is reproducible for in vivo applications.

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

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

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

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

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

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

Chronic Anemia Is Associated with Lower Cerebral and Peripheral Arterio-Venous Oxygen Gradients

▪Introduction: Patients with chronic anemia syndromes, such as thalassemia major and sickle cell disease, have premature white matter volume loss in characteristic watershed areas, suggesting ischemic damage. We have previously demonstrated that resting brain blood flow is increased in these patients, suggesting adequate oxygen delivery at rest. However, we postulate that increased blood flow velocity in the microvascular beds might not provide adequate time for oxygen exchange, leading to decreased arterio-venous oxygen gradients. To test this hypothesis, we evaluated peripheral (brachial) and cerebral arteriovenous oxygen gradients in 24 patients with chronic anemia syndromes and 45 control subjects.Methods: All patients were part of a larger study evaluating cerebral blood flow and oxygen delivery in chronic anemia syndromes. For the present comparison, we excluded patients with sickle cell anemia because sickle cells have abnormal magnetic properties. Anemic subjects included 15 patients with thalassemia major, three patients with E-beta thalassemia, three patients with hemoglobin H-constant spring, two patients with hereditary spherocytosis, and one patient with dyserythropoetic anemia. 45 age matched healthy subjects were recruited from friends and family of the patient cohort. Peripheral oxygen saturation was measured by fingertip pulse oximetry. Brachial venous oxygen saturation was assessed by cooximetry (blood gas was drawn after tourniquet release). Sagittal sinus oxygen saturation was estimated using T2 Relaxation Under Spin Tagging (TRUST), a validated MRI technique for noninvasive oximetry in the brain.Results: Table 1 summarizes the oxygen saturation and arteriovenous oxygen gradients (AVO2 differences) between the two populations. No difference was observed in arterial oxygen saturation, however both brachial and sagittal sinus saturations were significantly higher in anemic patients. AVO2 gradients were markedly lower in anemic subjects, indicating lower oxygen extraction in the periphery as well as the brain. AVO2 gradients were correlated with hemoglobin (r2 = 0.17, p=0.002) in both the brain and periphery. AVO2 gradient in the brain was correlated with AVO2 gradient in the forearm (Figure 1).Discussion: We demonstrate that arteriovenous oxygen gradients are decreased in anemic subjects, relative to controls, in both peripheral and cerebral vascular beds. Cardiac output and cerebral blood flow are increased in anemic subjects to preserve oxygen delivery. However, increased blood flow potentially shortens microvascular transit time, decreasing the oxygen exchange time. It is not yet clear whether the lower AVO2 gradients are inherently pathologic, but clearly represent an abnormal physiology with potential impact on the white matter disease observed in these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.