Repeatability of diffusion-weighted arterial spin labeling MRI for mapping blood-brain barrier water exchange rate at different postlabel delays.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Simultaneous Measurement of Cerebral Blood Flow and Arterial Transit Time for Sickle Cell Disease

Purpose:Arterial spin labeling (ASL) is an MRI perfusion imaging method from which quantitative cerebral blood flow (CBF) maps can be calculated. Acquisition with variable post‐labeling delays (PLD) and variable TRs allows for arterial transit time (ATT) mapping and leads to more accurate CBF quantification with a scan time saving of 48%. In addition, T1 and M0 maps can be obtained without a separate scan. In order to accurately estimate ATT and T1 of brain tissue from the ASL data, variable labeling durations were invented, entitled variable‐bolus ASL.Methods:All images were collected on a healthy subject with a 3T Siemens Skyra scanner. Variable‐bolus Psuedo‐continuous ASL (PCASL) images were collected with 7 TI times ranging 100‐4300ms in increments of 700ms with TR ranging 1000‐5200ms. All boluses were 1600ms when the TI allowed, otherwise the bolus duration was 100ms shorter than the TI. All TI times were interleaved to reduce sensitivity to motion. Voxel‐wise T1 and M0 maps were estimated using a linear least squares fitting routine from the average singal from each TI time. Then pairwise subtraction of each label/control pair and averaging for each TI time was performed. CBF and ATT maps were created using the standard model by Buxton et al. with a nonlinear fitting routine using the T1 tissue map.Results:CBF maps insensitive to ATT were produced along with ATT maps. Both maps show patterns and averages consistent with literature. The T1 map also shows typical T1 contrast.Conclusion:It has been demonstrated that variablebolus ASL produces CBF maps free from the errors due to ATT and tissue T1 variations and provides M0, T1, and ATT maps which have potential utility. This is accomplished with a single scan in a feasible scan time (under 6 minutes) with low sensivity to motion.

BackgroundArterial spin labeling perfusion MRI is increasingly proving to be a promising tool for exploring neurovascular changes in neurodegenerative conditions. Using an advanced 3D pseudo‐continuous arterial spin labeling sequence with Hadamard‐encoded multiple post‐labeling delays (eASL), this study evaluated both cerebral blood flow (CBF) and arterial transit time (ATT) alterations in mild cognitive impairment (MCI) phenotypes.MethodMCI patients (N = 19;Mage = 74.63±5.65) and controls (N = 20;Mage = 70.04±7.06) underwent a 3T MR scan with the eASL sequence. ATT and CBF were simultaneously measured. Voxel‐wise group comparisons of CBF and ATT were performed. Results were thresholded at a cluster‐size corrected p<0.001 (a<0.05). A region of interest (ROI) was defined as the overlap of clusters showing a significant difference in CBF and ATT between MCI and controls. Independent t‐tests between MCI phenotypes (amnestic, non‐amnestic) and controls on CBF and ATT ROIs were conducted. Pearson correlations of ROIs with measures of cognition, including executive functioning, were calculated. Correlations informed regression analysis.ResultsVoxelwise analyses (Figure1) demonstrated decreased CBF in MCI compared to controls in the default mode network, middle and superior frontal gyri, inferior parietal lobule, and temporal lobe. Increased ATT was seen in similar regions, with clusters centered in inferior and middle temporal lobe and visual cortex. T‐tests using created ROIs (as described above) revealed group differences between controls and MCI phenotypes in both CBF and ATT (ps≤.01); there was a non‐significant trend for higher ATT in naMCI versus aMCI. The highest correlational values emerged between CBF and ATT ROIs with a measure of executive functioning (TrailsB). IVs in regression analysis were age (step 1) and ATT and CBF overlapping ROI values (step 2, stepwise); TrailsB = DV . Across the entire cohort, CBF (R2 change = .239, p<.001), not ATT, was included in the model.ConclusionAdvanced 3D pCASL with Hadamard encoded multiple PLDs (eASL) can be used to simultaneously measure CBF and ATT in MCI and controls. MCI patients showed different patterns of reduced CBF and prolonged ATT. While CBF and ATT values were significantly correlated with TrailsB, regression analysis revealed that CBF was a more robust predictor of TrailsB. Future research should examine eASL as a biomarker for MCI phenotypes.

Nitrous oxide, in a concentration of 50% or more, is a known cerebral vasodilator. This study investigated whether a lower dose (30%) of nitrous oxide would also increase cerebral blood flow. In addition, the authors wished to study whether the increase in cerebral blood flow was accompanied by an increase in cerebral metabolism. Multimodal Magnetic Resonance Imaging at 3T was performed, and data were obtained in 17 healthy volunteers during three inhalation conditions: medical air, oxygen-enriched medical air (40% oxygen), and 30% nitrous oxide with oxygen-enriched medical air (40% oxygen). Arterial spin labeling was used to derive the primary tissue specific hemodynamic outcomes: cerebral blood flow, arterial blood volume and arterial transit times. Magnetic Resonance Susceptometry and proton Magnetic Resonance Spectroscopy were used for secondary metabolic outcomes: venous oxygenation, oxygen extraction fraction, cerebral metabolic oxygen rate and prefrontal metabolites. Nitrous oxide in 40% oxygen, but not 40% oxygen alone, significantly increased gray matter cerebral blood flow (22%; P < 0.05) and arterial blood volume (41%; P < 0.05). Venous oxygenation increased in both oxygen and nitrous oxide conditions. Compared with medical air inhalation, nitrous oxide condition caused a significantly larger decrease in oxygen extraction fraction than 40% oxygen alone (mean [SD] 11.3 [5.6]% vs. 8.3 [5.9]% P < 0.05), while global cerebral metabolic rate and prefrontal metabolites remained unchanged. This study demonstrates that 30% nitrous oxide in oxygen-enriched air (40% oxygen) significantly increases cerebral perfusion, and reduces oxygen extraction fraction, reflecting a strong arterial vasodilatory effect without associated increases in metabolism.

Purpose: To demonstrate the feasibility of a novel Arterial Spin Labeling (ASL) method for simultaneously measuring cerebral blood flow (CBF), arterial transit time (ATT), and arterial cerebral blood volume (aCBV) without the use of a contrast agent. Methods: A series of multi-TI ASL images were acquired from one healthy subject on a 3T Siemens Skyra, with the following parameters: PCASL labeling with variable TI [300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000] ms, labeling bolus 1400 ms when TI allows, otherwise 100 ms less than TI, TR was minimized for each TI, two sinc shaped pre-saturation pulses were applied in the imaging plane immediately before 2D EPI acquisition. 64×64×24 voxels, 5 mm slice thickness, 1 mm gap, full brain coverage, 6 averages per TI, no crusher gradients, 11 ms TE, scan time of 4:56. The perfusion weighted time-series was created for each voxel and fit to a novel model. The model has two components: 1) the traditional model developed by Buxton et al., accounting for CBF and ATT, and 2) a box car function characterizing the width of the labeling bolus, with variable timing and height in proportion to the aCBV. All three parameters were fit using a nonlinear fitting routine that constrained all parameters to be positive. The main purpose of the high-temporal resolution TI sampling for the first second of data acquisition was to precisely estimate the blood volume component for better detection of arrival time and magnitude of signal. Results: Whole brain maps of CBF, ATT, and aCBV were produced, and all three parameters maps are consistent with similar maps described in the literature. Conclusion: Simultaneous mapping of CBF, ATT, and aCBV is feasible with a clinically tractable scan time (under 5 minutes).

Changes in cerebral hemodynamics with aging are important for understanding age-related variation in neuronal health. While many prior studies have focused on gray matter, less is known regarding white matter due in part to measurement challenges related to the lower vascular density in white matter. To investigate the impact of age and sex on white matter hemodynamics in a Human Connectome Project in Aging (HCP-A) cohort using tract-based spatial statistics (TBSS). Retrospective cross-sectional. Six hundred seventy-eight typically aging individuals (381 female), aged 36-100 years. Multi-delay pseudo-continuous arterial spin labeling (ASL) and diffusion-weighted pulsed-gradient spin-echo echo planar imaging sequences at 3.0 T. A skeleton of mean fractional anisotropy (FA) was produced using TBSS. This skeleton was used to project ASL-derived cerebral blood flow (CBF) and arterial transit time (ATT) measures onto white matter tracts. General linear models were applied to white matter FA, CBF, and ATT maps, while covarying for age and sex. Threshold-free cluster enhancement multiple comparisons correction was performed for the effects of age and sex, thresholded at PFWE < 0.05. CBF, ATT, and FA were compared between sex for each tract using analysis of covariance, with multiple comparisons correction for the number of tracts at PFDR < 0.05. Significantly lower white matter CBF and significantly prolonged white matter ATTs were associated with older age. These effects were widespread across tracts for ATT. Significant (PFDR < 0.05) sex differences in ATT were observed across all tracts, and significant sex differences in CBF were observed in all tracts except the bilateral uncinate fasciculus. Females demonstrated significantly higher CBF compared to males across the lifespan. Few tracts demonstrated significant sex differences in FA. This study identified significant sex- and age-associated differences in white matter hemodynamics across tracts. 3 TECHNICAL EFFICACY: Stage 3.

Spatially selective arterial spin labeling (ASL) perfusion MRI is sensitive to arterial transit times (ATT) that can result in inaccurate perfusion quantification when ATTs are long. Velocity-selective ASL is robust to this effect because blood is labeled within the imaging region, allowing immediate label delivery. However, velocity-selective ASL cannot characterize ATTs, which can provide important clinical information. Here, we introduce a novel pulse sequence, called VESPA ASL, that combines velocity-selective and pseudo-continuous ASL to simultaneously label different pools of arterial blood for robust cerebral blood flow (CBF) and ATT measurement. The VESPA ASL sequence is similar to velocity-selective ASL, but the velocity-selective labeling is made spatially selective, and pseudo-continuous ASL is added to fill the inflow time. The choice of inflow time and other sequence settings were explored. VESPA ASL was compared to multi-delay pseudo-continuous ASL and velocity-selective ASL through simulations and test-retest experiments in healthy volunteers. VESPA ASL is shown to accurately measure CBF in the presence of long ATTs, and ATTs < TI can also be measured. Measurements were similar to established ASL techniques when ATT was short. When ATT was long, VESPA ASL measured CBF more accurately than multi-delay pseudo-continuous ASL, which tended to underestimate CBF. VESPA ASL is a novel and robust approach to simultaneously measure CBF and ATT and offers important advantages over existing methods. It fills an important clinical need for noninvasive perfusion and transit time imaging in vascular diseases with delayed arterial transit.

Multi-phase 3D arterial spin labeling brain MRI in assessing cerebral blood perfusion and arterial transit times in children at 3T

Arterial spin labeling (ASL) is an MRI perfusion imaging method from which quantitative cerebral blood flow (CBF) can be calculated. We present a multi-TI ASL method (multi-TI integrated ASL) in which variable post-labeling delays and variable TRs are used to improve the estimation of arterial transit time (ATT) and CBF while shortening the scan time by 41% compared to the conventional methods. Variable bolus widths allow for T1 and M0 estimation from raw ASL data. Multi-TI integrated pseudo-continuous ASL images were collected at 7 TI times ranging 100-4300 ms. Voxel-wise T1 and M0 maps were estimated, then CBF and ATT maps were created using the estimated T1 tissue map. All maps were consistent with physiological values reported in the literature. Based on simulations and in vivo comparisons, this method demonstrates higher CBF and ATT estimation efficiency than other ATT acquisition methods and better fit to the perfusion model. It produces CBF maps with reduced sensitivity to errors from ATT and tissue T1 variations. The estimated M0, T1, and ATT maps also have potential clinical utility. The method requires a single scan acquired within a clinically acceptable scan time (under 6 minutes) and with low sensitivity to motion.

APOE ε4 ALLELE EFFECT ON WHITE AND GRAY MATTER PERFUSION IN COGNITIVELY NORMAL AND MCI GROUPS

To improve the quantification of existing multi-timepoint arterial spin labeling (ASL) methods in estimating cerebral blood flow (CBF) and arterial transit time (ATT) for a wider range of ATTs. MULti-TImepoint VElocity-selective Reconciled with Spatially-sElective (MULTIVERSE) ASL utilizes multi-delay pseudo-continuous (PC) ASL and velocity-selective (VS) ASL with spatially defined bolus, and joint fitting to estimate CBF and ATT. Numerical simulations were performed to evaluate the accuracy and precision of single-delay and multi-delay PCASL and VSASL, as well as the proposed MULTIVERSE ASL, in quantifying CBF and ATT across an extended range of ATTs. The CBF and ATT estimates between multi-delay PCASL, VSASL, and MULTIVERSE ASL were compared across healthy volunteers. Numerical simulations showed that the utility of MULTIVERSE ASL improved the accuracy and precision over an extended ATT range of up to 4000 ms. In vivo scans from healthy subjects demonstrated that MULTIVERSE ASL led to reduced uncertainty in CBF and ATT quantification compared to multi-post-labeling delay PCASL while maintaining comparable repeatability. This novel and straightforward approach improves the accuracy and precision of the fitted CBF and ATT over an extended range of ATT, which is not possible with existing ASL methods. Brain scans from healthy subjects demonstrated the feasibility and reliability of the technique, highlighting the clinical potential of ASL-based perfusion mapping in various altered physiological and pathological conditions.

BackgroundChanges in blood‐brain barrier (BBB) integrity are associated with cognitive decline in aging. Inflammatory processes are thought to contribute to BBB dysfunction but this link has been difficult to measure in humans using non‐invasive, in‐vivo methods. Recently, a novel magnetic resonance imaging (MRI) technique, diffusion‐prepared arterial spin labeling (DP‐ASL), has been shown to provide a means to test the water exchange rate across the BBB (kw) as well as arterial transit time (ATT) and cerebral blood flow (CBF). Here, we tested the association between these DP‐ASL measures and a specific plasma marker of inflammation, IL‐6, in older adults without dementia.MethodWe tested the association between kw, ATT, and CBF and a marker of peripheral inflammation in a sample of 58 older adults without dementia. Regions of interest (ROIs) included the putamen, caudate, and pallidum. Plasma IL‐6 levels were assessed using Simoa assays. IL‐6 was natural log transformed and data collected ≤ 1 year from the MRI visit were used for subsequent analyses. Multiple linear regression models, controlling for age, sex, and ROI size, tested the impact of plasma IL‐6 on kw, ATT, and CBF metrics. Both linear and quadratic effects of IL‐6 on the outcomes of interest were examined.ResultThere was a negative linear association between IL‐6 and kw in the putamen. As plasma IL‐6 levels increased, kw values decreased. In contrast, no relationships were observed between plasma IL‐6 and ATT or CBF in any of the ROIs tested.ConclusionOur results suggest that the water exchange rate across the BBB in the putamen was most uniquely associated with the peripheral proinflammatory cytokine, IL‐6. These findings could be indicative of the involvement of peripheral inflammation in reducing glymphatic clearance which would manifest as reduced water exchange rate across the BBB. The lack of association with ATT and CBF suggest that peripheral cytokines could act on a mechanism more closely related to water channel function rather than overall brain perfusion.

Arterial transit time (ATT) prolongation causes an error of cerebral blood flow (CBF) measurement during arterial spin labeling (ASL). To improve the accuracy of ATT and CBF in patients with prolonged ATT, we propose a robust ATT and CBF estimation method for clinical practice. The proposed method consists of a three-delay Hadamard-encoded pseudo-continuous ASL (H-pCASL) with an additional-encoding and single-delay with long-labeled long-delay (1dLLLD) acquisition. The additional-encoding allows for the reconstruction of a single-delay image with long-labeled short-delay (1dLLSD) in addition to the normal Hadamard sub-bolus images. Five different images (normal Hadamard 3 delay, 1dLLSD, 1dLLLD) were reconstructed to calculate ATT and CBF. A Monte Carlo simulation and an in vivo study were performed to access the accuracy of the proposed method in comparison to normal 7-delay (7d) H-pCASL with equally divided sub-bolus labeling duration (LD). The simulation showed that the accuracy of CBF is strongly affected by ATT. It was also demonstrated that underestimation of ATT and CBF by 7d H-pCASL was higher with longer ATT than with the proposed method. Consistent with the simulation, the 7d H-pCASL significantly underestimated the ATT compared to that of the proposed method. This underestimation was evident in the distal anterior cerebral artery (ACA; P = 0.0394) and the distal posterior cerebral artery (PCA; 2 P = 0.0255). Similar to the ATT, the CBF was underestimated with 7d H-pCASL in the distal ACA (P = 0.0099), distal middle cerebral artery (P = 0.0109), and distal PCA (P = 0.0319) compared to the proposed method. Improving the SNR of each delay image (even though the number of delays is small) is crucial for ATT estimation. This is opposed to acquiring many delays with short LD. The proposed method confers accurate ATT and CBF estimation within a practical acquisition time in a clinical setting.

To investigate whether measurement of arterial transit time (ATT) can improve the accuracy of arterial spin labeling (ASL) cerebral blood flow (CBF) quantification in an elderly cohort due to the potentially prolonged ATT in the cohort. We employed a 1-minute, low-resolution (12 mm in-plane), sequential multidelay ATT measurement (both with and without vessel suppression) approach to characterize and correct ATT errors in CBF imaging of an elderly, clinical cohort. In all, 140 nondemented subjects greater than 70 years old were imaged at 3T with a single delay, volumetric continuous ASL sequence and also with the fast ATT measurement method. Nine healthy young subjects (28 ± 6 years old) were also imaged. ATTs measured without vessel suppression (superior frontal: 1.51 ± 0.27 sec) in the elderly were significantly shorter than those with suppression (P < 0.0001). Correction of CBF for ATT significantly increased average CBF in multiple brain regions where ATT was longer than the postlabeling delay (P < 0.01) and decreased intersubject variability of CBF in frontal, parietal, and occipital regions (P < 10-8 ). Measured ATT with vessel suppression was significantly longer in the elderly subjects (eg, superior frontal: 1.76 ± 0.25 sec) compared to the younger adults (superior frontal: 1.59 ± 0.19 sec) in basal ganglia and frontal cortical regions (P < 0.05). The ATT measurement is beneficial for imaging of elderly clinical populations. If ATT mapping is not feasible or available, postlabeling delays of 2-2.3 seconds should be used for elderly populations based on longest measured regional ATTs. 1 J. Magn. Reson. Imaging 2017;45:472-481.