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Purpose Dynamic angiography using arterial spin labeling (ASL) can provide detailed hemodynamic information. However, the long time-resolved readouts require small flip angles to preserve ASL signal for later timepoints, limiting SNR. By using time-encoded ASL to generate temporal information, the readout can be shortened. Here, the SNR improvements from using larger flip angles, made possible by the shorter readout, are quantitatively investigated. Methods The SNR of a conventional protocol with nine Look-Locker readouts and a 4 3 time-encoded protocol with three Look-Locker readouts (giving nine matched timepoints) were compared using simulations and in vivo data. Both protocols were compared using readouts with constant flip angles (CFAs) and variable flip angles (VFAs), where the VFA scheme was designed to produce a consistent ASL signal across readouts. Optimization of the background suppression to minimize physiological noise across readouts was also explored. Results The time-encoded protocol increased in vivo SNR by 103% and 96% when using CFAs or VFAs, respectively. Use of VFAs improved SNR compared with CFAs by 25% and 21% for the conventional and time-encoded protocols, respectively. The VFA scheme also removed signal discontinuities in the time-encoded data. Preliminary data suggest that optimizing the background suppression could improve in vivo SNR by a further 16%. Conclusions Time encoding can be used to generate additional temporal information in ASL angiography. This enables the use of larger flip angles, which can double the SNR compared with a non-time-encoded protocol. The shortened time-encoded readout can also lead to improved background suppression, reducing physiological noise and further improving SNR.

This review article provides an overview of a range of recent technical developments in advanced arterial spin labeling (ASL) methods that have been developed or adopted by the community since the publication of a previous ASL consensus paper by Alsop et al. 1 . It is part of a series of review/recommendation papers from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. Here, we focus on advancements in readouts and trajectories, image reconstruction, noise reduction, partial volume correction, quantification of non-perfusion parameters, fMRI, fingerprinting, vessel selective ASL, angiography, deep learning, and ultra-high field ASL. We aim to provide a high level understanding of these new approaches and some guidance for their implementation, with the goal of facilitating the adoption of such advances by research groups and by MRI vendors. Topics that are outside the scope of this article, and are reviewed at length in separate articles, include velocity selective ASL, multiple-timepoint ASL, body ASL, and clinical ASL recommendations.

Purpose In chemical exchange saturation transfer imaging, saturation effects between − 2 to − 5 ppm (nuclear Overhauser effects, NOEs) have been shown to exhibit contrast in preclinical stroke models. Our previous work on NOEs in human stroke used an analysis model that combined NOEs and semisolid MT; however their combination might feasibly have reduced sensitivity to changes in NOEs. The aim of this study was to explore the information a 4-pool Bloch–McConnell model provides about the NOE contribution in ischemic stroke, contrasting that with an intentionally approximate 3-pool model. Methods MRI data from 12 patients presenting with ischemic stroke were retrospectively analyzed, as well as from six animals induced with an ischemic lesion. Two Bloch–McConnell models (4 pools, and a 3-pool approximation) were compared for their ability to distinguish pathological tissue in acute stroke. The association of NOEs with pH was also explored, using pH phantoms that mimic the intracellular environment of naïve mouse brain. Results The 4-pool measure of NOEs exhibited a different association with tissue outcome compared to 3-pool approximation in the ischemic core and in tissue that underwent delayed infarction. In the ischemic core, the 4-pool measure was elevated in patient white matter ( 1.20±0.20 ) and in animals ( 1.27±0.20 ). In the naïve brain pH phantoms, significant positive correlation between the NOE and pH was observed. Conclusion Associations of NOEs with tissue pathology were found using the 4-pool metric that were not observed using the 3-pool approximation. The 4-pool model more adequately captured in vivo changes in NOEs and revealed trends depending on tissue pathology in stroke.

Purpose: To improve the labeling efficiency of pseudo‐continuous arterial spin labeling (PCASL) at 7T using parallel transmission (pTx). Methods: Five healthy subjects were scanned on an 8‐channel‐transmit 7T human MRI scanner. Time‐of‐flight (TOF) angiography was acquired to identify regions of interest (ROIs) around the 4 major feeding arteries to the brain, and urn:x-wiley:07403194:media:mrm28173:mrm28173-math-0001 and B0 maps were acquired in the labeling plane for tagging pulse design. Complex weights of the labeling pulses for each of the 8 transmit channels were calculated to produce a homogenous radiofrequency (RF) ‐shimmed labeling across the ROIs. Variable‐Rate Selective Excitation (VERSE) pulses were also implemented as a part of the labeling pulse train. Whole‐brain perfusion‐weighted images were acquired under conditions of RF shimming, VERSE with RF shimming, and standard circularly polarized (CP) mode. The same subjects were scanned on a 3T scanner for comparison. Results: In simulation, VERSE with RF shimming improved the flip‐angles across the ROIs in the labeling plane by 90% compared with CP mode. VERSE with RF shimming improved the temporal signal‐to‐noise ratio by 375% compared with CP mode, but did not outperform a matched 3T sequence with a matched flip‐angle. Conclusion: We have demonstrated improved PCASL tagging at 7T using VERSE with RF shimming on a commercial head coil under conservative SAR limits at 7T. However, improvements of 7T over 3T may require strategies with less conservative SAR restrictions.

Purpose Multi-phase PCASL has been proposed as a means to achieve accurate perfusion quantification that is robust to imperfect shim in the labelling plane. However, there exists a bias in the estimation process that is a function of noise in the data. In this work, this bias is characterised and then addressed in animal and human data. Methods The proposed algorithm to overcome bias uses the initial biased voxel-wise estimate of phase tracking error to cluster regions with different off-resonance phase shifts, from which a high-SNR estimate of regional phase offset is derived. Simulations were used to predict the bias expected at typical SNR. Multi-phase PCASL in three rat strains (n = 21) at 9.4 T was considered, along with 20 human subjects previously imaged using ASL at 3 T. The algorithm was extended to include estimation of arterial blood flow velocity. Results Based on simulations, a perfusion estimation bias of 6–8% was expected using 8-phase data at typical SNR. This bias was eliminated when a high-precision estimate of phase error was available. In the preclinical data, the bias-corrected measure of perfusion (107±14 mL/100g/min) was lower than the standard analysis (116±14 mL/100g/min), corresponding to a mean observed bias across strains of 8.0%. In the human data, bias correction resulted in a 15% decrease in the estimate of perfusion. Conclusion Using a retrospective algorithmic approach, it was possible to exploit common information found in multiple voxels within a whole region of the brain, offering superior SNR and thus overcoming the bias in perfusion quantification from multi-phase PCASL.

PURPOSE:T2 -relaxation-under-spin-tagging (TRUST) is an MR technique for the non-invasive assessment of whole-brain cerebral oxygen extraction fraction (OEF), through measurement of the venous blood T2 relaxation time in the sagittal sinus. A key limitation of TRUST, however, is the lack of spatial specificity of the measurement. We sought to develop a modified TRUST sequence, selective localized TRUST (SL-TRUST), having sensitivity to venous blood T2 within a targeted brain region, and therefore achieving spatially localized measurements of cerebral tissue OEF, while still retaining acquisition in the sagittal sinus. METHODS:A method for selective localization of TRUST sequence was developed, and the reproducibility of the technique was evaluated in healthy participants. Regional measurements were achieved for a single hemisphere and for a 3D-localized 70 × 70 × 80 mm3 tissue region using SL-TRUST and compared to a global TRUST measure. An additional measure of venous blood T1 in the sagittal sinus was used to estimate subject-specific hematocrit. Six subjects were scanned over 4 sessions, including intra-session repeat measurements. RESULTS:The average T2 in the sagittal sinus was found to be 60.8 ± 8.9, 62.7 ± 7.9, 64.6 ± 8.4, and 66.3 ± 10.3 ms (mean ± SD) for conventional TRUST, global SL-TRUST, hemispheric SL-TRUST, and 3D-localized SL-TRUST, respectively. Intra-, inter-session, and inter-subject coefficients of variation for OEF using SL-TRUST were found to be comparable and in some cases superior to those obtained using TRUST. CONCLUSION:OEF comparison of 2 contralateral regions was achievable in under 5 min suggesting SL-TRUST offers potential for quantifying regional OEF differences in both healthy and clinical populations.

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study.The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 minutes. The automated imaging pipeline derives 1575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, these quantitative measures were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed that recovered COVID-19 patients had a decrease in frontal grey matter volumes, an increased burden of white matter hyperintensities, and reduced mean diffusivity in the total and normal appearing white matter in the posterior thalamic radiation and sagittal stratum, relative to controls. These differences were generally more prominent in patients who received organ support. Increased T2* in the thalamus was also observed in recovered COVID-19 patients, with a more prominent increase for non-critical patients.This initial evidence of brain changes in COVID-19 survivors prompts the need for further investigations. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in large-scale studies. The pipeline is widely applicable and will contribute to new analyses to hopefully clarify the medium to long-term effects of COVID-19.HighlightsUK Biobank brain MRI protocol and pipeline was adapted for multiorgan MRI of COVID-19High-quality brain MRI data from 5 modalities are acquired in 17 minutesAnalysis pipeline derives 1575 IDPs of brain anatomy, perfusion, and microstructureEvidence of brain changes in COVID-19 survivors was found in the C-MORE studyThis MRI protocol is now being used in multiple large-scale studies on COVID-19

The objective of the current study was to combine a time‐encoded pseudocontinuous arterial spin labeling (te‐pCASL) scheme with a golden angle radial readout for simultaneous acquisition of angiography and perfusion images from one single dataset, both in a highly flexible single‐slice approach as well as within a multislice setting. A te‐pCASL preparation and the golden angle radial readout were both used as a temporal resolution tool to retrospectively choose the temporal window for the reconstruction of both angiography and perfusion images from a single‐slice dataset. The temporal window could be chosen retrospectively and adjusted to the hemodynamics of the volunteer on the scanner for the single‐slice dataset. Angiographic images were reconstructed at a minimum temporal resolution of 69 ms. For the perfusion phase, only the densely sampled center of k‐space was included in the reconstruction. For a multislice acquisition, the golden angle radial readout allowed reconstruction of images with different spatial resolutions to provide angiographic and perfusion information over 10 slices. The te‐pCASL preparation was used as the only source for dynamic information. The multislice acquisition shows the ability of the golden angle radial readout to display the inflow of the labeled blood into the arteries as well as the perfusion in the tissue with full brain coverage. By combining a te‐pCASL preparation with a golden angle radial readout, single‐slice high temporal resolution angiography and good quality perfusion images were reconstructed in a flexible manner from a single dataset. Optimizing the golden angle radial readout for reconstructions at multiple spatial resolutions allows for multislice acquisition., A time‐encoded pseudocontinuous arterial spin labeling scheme was combined with a golden angle radial readout for simultaneous acquisition of angiography and perfusion images from one single dataset. This allows for retrospectively changing the temporal window, because the golden angle readout was optimized as a temporal resolution tool. Optimizing this readout for different spatial resolutions shows the ability to display the inflow of labeled blood into the arteries as well as the perfusion in the tissue with full brain coverage.

Background Psychiatric medication that has a soothing effect on the limbic responses to affective stimuli could improve affective instability symptoms as observed in Borderline Personality Disorder (BPD). The objective of this study was to investigate whether Citalopram vs. Placebo reduces the response of the affective neural circuitry during emotional challenge. Methods N=30 femaie individuals with BPD diagnosis participated in a Placebo-controlled, double-blind crossover trial design. Three hours after oral drug intake, individuals with BPD viewed affective pictures while undergoing functional Magnetic Resonance Imaging. Blood Oxygenation Level Dependent responses to images of negative affective scenes and faces showing negative emotional expressions were assessed in regions-of-interest (amygdala, anterior cingulate cortex, anterior insula, dorsolateral prefrontal cortex). Blood perfusion at rest was assessed with arterial spin labeling. Results The neural response to pictures showing negative affective scenes was not significantly affected by Citalopram (N=23). Citalopram significantly reduced the amygdala response to pictures of faces with negative affective expressions (N=25, treatment difference left hemisphere: -0.06 ±0.16, P Conclusions Citalopram can alter the amygdala response to affective stimuli in BPD, which is characterized by overly responsive affective neural circuitry.

Background The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Methods Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. Findings At 2–3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p Interpretation A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. Funding NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

Arterial Spin Labeling (ASL) is a non-invasive, non-contrast, perfusion imaging technique which is inherently SNR limited. It is, therefore, important to carefully design scan protocols to ensure accurate measurements. Many pseudo-continuous ASL (PCASL) protocol designs have been proposed for measuring cerebral blood flow (CBF), but it has not yet been demonstrated which design offers the most accurate and repeatable CBF measurements. In this study, a wide range of literature PCASL protocols were first optimized for CBF accuracy and then compared using Monte Carlo simulations and in vivo experiments. The protocols included single-delay, sequential and time-encoded multi-timepoint protocols, and several novel protocol designs, which are hybrids of time-encoded and sequential multi-timepoint protocols. It was found that several multi-timepoint protocols produced more confident, accurate, and repeatable CBF estimates than the single-delay protocol, while also generating maps of arterial transit time. Of the literature protocols, the time-encoded protocol with T1-adjusted label durations gave the most confident and accurate CBF estimates in vivo (16% and 40% better than single-delay), while the sequential multi-timepoint protocol was the most repeatable (20% more repeatable than single-delay). One of the novel hybrid protocols, HybridT1-adj was found to produce the most confident, accurate and repeatable CBF estimates out of all the protocols tested in both simulations and in vivo (24%, 47%, and 28% more confident, accurate, and repeatable than single-delay in vivo). The HybridT1-adj protocol makes use of the best aspects of both time-encoded and sequential multi-timepoint protocols and should be a useful tool for accurately and efficiently measuring CBF.

BackgroundThe medium-term effects of Coronavirus disease (COVID-19) on multiple organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.MethodsFifty-eight COVID-19 patients post-hospital discharge and 30 comorbidity-matched controls were prospectively enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.FindingsAt 2-3 months from disease-onset, 64% of patients experienced persistent breathlessness and 55% complained of significant fatigue. On MRI, tissue signal abnormalities were seen in the lungs (60%), heart (26%), liver (10%) and kidneys (29%) of patients. COVID-19 patients also exhibited tissue changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domain relative to controls. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance (405±118m vs 517±106m in controls, pInterpretationA significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of breathlessness, fatigue, anxiety, depression and exercise limitation at 2-3 months from disease-onset. Persistent lung and extra-pulmonary organ MRI findings are common. In COVID-19 survivors, chronic inflammation may underlie multiorgan abnormalities and contribute to impaired quality of life.FundingNIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

PurposeTo present and assess a method for choosing a fixed increment between spokes in radially sampled MRI that results in higher SNR than other radial sampling increments.Theory and MethodsSampling uniformity contributes to image SNR when reconstructed using linear methods. Thus, for a radial trajectory, uniformly spaced sampling is ideal. However, uniform sampling lacks post-acquisition reconstruction flexibility, which is often needed in dynamic imaging. Golden ratio-based increments are often used for this purpose. The method presented here, Set Increment with Limited Views Encoding Ratio (SILVER), optimizes sampling uniformity when a limited number of temporal resolutions are required. With SILVER, an optimization algorithm finds the angular increment that provides the highest uniformity for a pre-defined set of reconstruction window sizes. SILVER was tested over multiple sets and assessed in terms of uniformity, noise amplification, and SNR both in simulations and in acquisitions of a phantom and healthy volunteers.ResultsThe proposed algorithm produced trajectories that, for the optimized window sizes, had higher uniformity and lower image noise than golden ratio sampling both in a simulated single-coil system and in a multi-coil system, assessed using simulation, phantom, and in vivo experiments. The noise in SILVER optimized trajectories was comparable to uniformly distributed spokes whilst retaining flexibility in reconstruction at multiple temporal resolutions. In a resting state fMRI experiment, tSNR increases at different spatial and temporal resolutions ranged from 21-72%.ConclusionSILVER is a simple addition to any sequence currently using golden ratio sampling and significantly increases sampling efficiency and SNR.

Purpose: To establish the feasibility of using vessel-encoded pseudocontinuous arterial spin labeling (VEPCASL) for non-invasive vascular territory imaging (VTI) and artery-specific dynamic angiography of a large number of arterial branches above the circle of Willis within a clinically feasible scan time. Methods: 3D time-of-flight angiography was used to select a labeling plane and establish seven pairs of encoding cycles. These were used for VEPCASL VTI and dynamic 2D angiography (8 min and 3 min acquisition times, respectively) in healthy volunteers, allowing the separation of signals arising from 13 arterial branches (including extracranial arteries) in post-processing. To demonstrate the clinical potential of this approach, VEPCASL angiography was also applied in five patients with brain arteriovenous malformation (AVM). Results: In healthy volunteers, the artery-specific filling of the vascular tree and resulting perfusion territories were well depicted. Signal-to-noise ratios were approximately five times higher than those achievable with single-artery selective methods. Blood supply to the AVMs was well visualized in all cases, showing the main feeding arteries and venous drainage. Conclusions: VEPCASL is a highly efficient method for both VTI and dynamic angiography of a large number of arterial branches, providing a comprehensive picture of vascular flow patterns and the effect on downstream tissue perfusion within an acceptable scan time. Automation of labeling plane and vessel-encoding selection would improve robustness and efficiency, and further refinement could allow quantitative blood flow measurements to be obtained. This technique shows promise for visualizing the blood supply to lesions and collateral flow patterns.

Purpose: To demonstrate the feasibility of a novel non-invasive MRI technique for the comprehensive evaluation of blood flow to the brain: combined angiography and perfusion using radial imaging and arterial spin labeling (CAPRIA). Methods: In the CAPRIA pulse sequence, blood labeled with a pseudocontinuous arterial spin labeling (PCASL) pulse train is continuously imaged as it flows through the arterial tree and into the brain tissue using a golden ratio radial readout. From a single raw data set, this flexible imaging approach allows the reconstruction of both high spatial/temporal resolution angiographic images with a high undersampling factor and low spatial/temporal resolution perfusion images with a low undersampling factor. The sparse and high SNR nature of angiographic images ensures that radial undersampling artifacts are relatively benign, even when using a simple regridding image reconstruction. Pulse sequence parameters were optimized through sampling efficiency calculations and the numerical evaluation of modified PCASL signal models. Comparison was made against conventional PCASL angiographic and perfusion acquisitions. Results: 2D CAPRIA data in healthy volunteers demonstrated the feasibility of this approach, with good vessel visualization in the angiographic images and clear tissue perfusion signal when reconstructed at 108 ms and 252 ms temporal resolution, respectively. Images were qualitatively similar to those from conventional acquisitions, but CAPRIA had significantly higher SNR-efficiency (48% improvement on average, p = 0.02). Conclusion: The CAPRIA technique shows potential for the efficient evaluation of both macrovascular blood flow and tissue perfusion within a single scan, with potential applications in a range of cerebrovascular diseases.

Arterial spin labeling (ASL) is an MRI technique that was first proposed a quarter of a century ago. It offers the prospect of non-invasive quantitative measurement of cerebral perfusion, making it potentially very useful for research and clinical studies, particularly where multiple longitudinal measurements are required. However, it has suffered from a number of challenges, including a relatively low signal-to-noise ratio, and a confusing number of sequence variants, thus hindering its clinical uptake. Recently, however, there has been a consensus adoption of an accepted acquisition and analysis framework for ASL, and thus a better penetration onto clinical MRI scanners. Here, we review the basic concepts in ASL and describe the current state-of-the-art acquisition and analysis approaches, and the versatility of the method to perform both quantitative cerebral perfusion measurement, along with quantitative cerebral angiographic measurement.

Purpose: To assess the impact of the different post‐processing options in the calibration of arterial spin labeling (ASL) data on perfusion quantification and its reproducibility.Theory and Methods: Absolute quantification of perfusion measurements is one of the promises of ASL techniques. However, it is highly dependent on a calibration procedure that involves a complex processing pipeline for which no standardized procedure has been fully established. In this work, we systematically compare the main ASL calibration methods as well as various post‐processing calibration options, using 2 data sets acquired with the most common sequences, pulsed ASL and pseudo‐continuous ASL.Results: Significant and sometimes large discrepancies in ASL perfusion quantification were obtained when using different post‐processing calibration options. Nevertheless, when using a set of theoretically based and carefully chosen options, only small differences were observed for both reference tissue and voxelwise methods. The voxelwise and white matter reference tissue methods were less sensitive to post‐processing options than the cerebrospinal fluid reference tissue method. However, white matter reference tissue calibration also produced poorer reproducibility results. Moreover, it may also not be an appropriate reference in case of white matter pathology.Conclusion: Poor post‐processing calibration options can lead to large errors in perfusion quantification, and a complete description of the calibration procedure should therefore be reported in ASL studies. Overall, our results further support the voxelwise calibration method proposed by the ASL white paper, particularly given the advantage of being relatively simple to implement and intrinsically correcting for the coil sensitivity profile.

Purpose Contributions of cerebrospinal fluid (CSF) have not been previously taken into account in the quantification of APT CEST effects, and correction for the dilution of CEST effects by CSF may allow for more robust measurement of CEST signals. The objective of this study was to compare the robustness of a partial volume (PV) correction model against a standard (4-pool) multi-pool model as far as their ability to quantify CEST effects in healthy, normal, and pathological tissue. Methods MRI data from 12 patients presenting with ischemic stroke, and 6 healthy subjects, were retrospectively analyzed. CEST signals derived from a 4-pool model and a PV correction model were compared for repeatability and pathological tissue contrast. The effect of PV correction (PVC) was assessed within 3 ranges of tissue PV estimate (PVE): high PVE voxels, low PVE voxels, and the whole slice. Results In voxels with a high tissue PVE, PV correction did not make a significant difference to absolute A P T R * . In low PVE voxels, the PVC model exhibited a significantly decreased ischemic core signal. The PVC measures exhibited higher repeatability between healthy subjects (4 pools: 3.4%, PVC: 2.4%) while maintaining a similar ischemic core CNR (0.7) to the 4-pool model. In whole slice analysis it was found that both models exhibited similar results. Conclusions PV correction yielded a measure of APT effects that was more repeatable than standard 4-pool analysis while achieving a similar CNR in pathological tissue, suggesting that PV-corrected analysis was more robust at low values of tissue PVE.

Four-dimensional arterial spin labeling magnetic resonance angiography (4D ASL MRA) is a non-invasive medical imaging modality that can be used for anatomical and hemodynamic analysis of the cerebrovascular system. However, it generates a considerable amount of data, which is tedious to analyze visually. As an alternative, medical image processing methods can be used to process the data and present measurements of the geometry and blood flow in the cerebrovascular system to the user, such as vessel radius, tortuosity, blood flow volume, and transit time. Nevertheless, evaluating medical image processing methods developed for this modality requires annotated data, which can be time-consuming and expensive to obtain. Alternatively, virtual simulations are a faster and less expensive option that can be used for initial evaluation of image processing methods. The present work proposes a methodology for generating annotated 4D ASL MRA virtual phantoms, in different scenarios with different acquisition parameter settings. In each scenario, the phantoms are generated using real cerebrovascular geometries of healthy volunteers, where blood flow is simulated according to a mathematical model specifically designed to describe the signal observed in 4D ASL MRA images. Realistic noise is added using an homomorphic approach, designed to replicate noise characteristic of multi-coil acquisitions. In order to exemplify the utility of the phantoms, they are used to evaluate the accuracy of a method to estimate blood flow parameter values, such as relative blood volume and transit time, in different scenarios. The estimated values are then compared to its corresponding virtual ground-truth values. The accuracy of the results is ranked according to the average absolute error. The results of the experiments show that blood flow parameters can be more accurately estimated when blood is magnetically labeled for longer periods of time and when the datasets are acquired with higher temporal resolution. In summary, the present work describes a methodology to create annotated virtual phantoms, which represent a useful alternative for initial evaluation of medical image processing methods for 4D ASL MRA images.

Collateral perfusion is important for sustaining tissue viability in acute ischemic stroke. Conventional techniques for its visualization are invasive, require contrast agents and demonstrate collateral vessels, rather than measuring perfusion directly. In this study we utilize a non-invasive, non-contrast magnetic resonance imaging (MRI)-based method to directly quantify collateral perfusion in acute stroke patients. Vessel-encoded multi-postlabeling delay arterial spin labeling (ASL) was used to separately quantify the blood flow and blood arrival time from four arteries supplying the brain in patients presenting within 18 hours of stroke onset. Twenty-nine acute ischemic stroke patients were scanned with a median time of onset to first MRI of 3 hours. Collateral perfusion at presentation was associated with tissue fate at 1-week. It sustained tissue prior to reperfusion, but was less effective than direct blood flow at maintaining tissue viability in patients who did not reperfuse. Delay in the blood arrival around the ischemic region was found at presentation and reduced over time but was not consistently associated with collateral perfusion. Vessel-encoded multi-postlabeling delay ASL provides a non-invasive tool for direct measurement of collateral perfusion and delayed blood arrival in acute stroke patients.

Key Points Question Is midlife cardiovascular risk associated with cerebral blood flow in older age, and does this association vary with age? Findings In this longitudinal cohort study of 116 older adults without dementia, higher cardiovascular risk scores during a 20-year period were significantly associated with lower cerebral blood flow to the medial temporal, parietal, and occipital cortices. The association varied during the life span such that cardiovascular risk in midlife but not in later life was significantly associated with cerebral hypoperfusion in older age. Meaning Because cerebral hypoperfusion is an early mechanism in Alzheimer disease and vascular dementia, these findings may inform the development of dementia prevention strategies aimed at managing cardiovascular health., This longitudinal cohort study examines the association of midlife cardiovascular risk factors with cerebral perfusion at older ages among adults without dementia., Importance Poor cardiovascular health is an established risk factor for dementia, but little is known about its association with brain physiology in older adults. Objective To examine the association of cardiovascular risk factors, measured repeatedly during a 20-year period, with cerebral perfusion at older ages. Design, Setting, and Participants In this longitudinal cohort study, individuals were selected from the Whitehall II Imaging Substudy. Participants were included if they had no clinical diagnosis of dementia, had no gross brain structural abnormalities on magnetic resonance imaging scans, and had received pseudocontinuous arterial spin labeling magnetic resonance imaging. Cardiovascular risk was measured at 5-year intervals across 5 phases from September 1991 to October 2013. Arterial spin labeling scans were acquired between April 2014 and December 2014. Data analysis was performed from June 2016 to September 2018. Exposures Framingham Risk Score (FRS) for cardiovascular disease, comprising age, sex, high-density lipoprotein cholesterol level, total cholesterol level, systolic blood pressure, use of antihypertensive medications, cigarette smoking, and diabetes, was assessed at 5 visits. Main Outcomes and Measures Cerebral blood flow (CBF; in milliliters per 100 g of tissue per minute) was quantified with pseudocontinuous arterial spin labeling magnetic resonance imaging. Results Of 116 adult participants, 99 (85.3%) were men. At the first examination, mean (SD) age was 47.1 (5.0) years; at the last examination, mean (SD) age was 67.4 (4.9) years. Mean (SD) age at MRI scan was 69.3 (5.0) years. Log-FRS increased with time (B = 0.058; 95% CI, 0.044 to 0.072; P

Medical imaging has enormous potential for early disease prediction, but is impeded by the difficulty and expense of acquiring data sets before symptom onset. UK Biobank aims to address this problem directly by acquiring high-quality, consistently acquired imaging data from 100,000 predominantly healthy participants, with health outcomes being tracked over the coming decades. The brain imaging includes structural, diffusion and functional modalities. Along with body and cardiac imaging, genetics, lifestyle measures, biological phenotyping and health records, this imaging is expected to enable discovery of imaging markers of a broad range of diseases at their earliest stages, as well as provide unique insight into disease mechanisms. We describe UK Biobank brain imaging and present results derived from the first 5,000 participants' data release. Although this covers just 5% of the ultimate cohort, it has already yielded a rich range of associations between brain imaging and other measures collected by UK Biobank.

Vessel‐selective dynamic angiograms provide a wealth of useful information about the anatomical and functional status of arteries, including information about collateral flow and blood supply to lesions. Conventional x‐ray techniques are invasive and carry some risks to the patient, so non‐invasive alternatives are desirable. Previously, non‐contrast dynamic MRI angiograms based on arterial spin labeling (ASL) have been demonstrated using both spoiled gradient echo (SPGR) and balanced steady‐state free precession (bSSFP) readout modules, but no direct comparison has been made, and bSSFP optimization over a long readout period has not been fully explored. In this study bSSFP and SPGR are theoretically and experimentally compared for dynamic ASL angiography. Unlike SPGR, bSSFP was found to have a very low ASL signal attenuation rate, even when a relatively large flip angle and short repetition time were used, leading to a threefold improvement in the measured signal‐to‐noise ratio (SNR) efficiency compared with SPGR. For vessel‐selective applications, SNR efficiency can be further improved over single‐artery labeling methods by using a vessel‐encoded pseudo‐continuous ASL (VEPCASL) approach. The combination of a VEPCASL preparation with a time‐resolved bSSFP readout allowed the generation of four‐dimensional (4D; time‐resolved three‐dimensional, 3D) vessel‐selective cerebral angiograms in healthy volunteers with 59 ms temporal resolution. Good quality 4D angiograms were obtained in all subjects, providing comparable structural information to 3D time‐of‐flight images, as well as dynamic information and vessel selectivity, which was shown to be high. A rapid 1.5 min dynamic two‐dimensional version of the sequence yielded similar image features and would be suitable for a busy clinical protocol. Preliminary experiments with bSSFP that included the extracranial vessels showed signal loss in regions of poor magnetic field homogeneity. However, for intracranial vessel‐selective angiography, the proposed bSSFP VEPCASL sequence is highly SNR efficient and could provide useful information in a range of cerebrovascular diseases. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Purpose In vessel-encoded pseudo-continuous arterial spin labeling (ve-pCASL), vessel-selective labeling is achieved by modulation of the inversion efficiency across space. However, the spatial transition between the labeling and control conditions is rather gradual, which can cause partial labeling of vessels, reducing SNR-efficiency and necessitating complex postprocessing to decode the vessel-selective signals. The purpose of this study is to optimize the pCASL labeling parameters to obtain a sharper spatial inversion profile of the labeling and thereby minimizing the risk of partial labeling of untargeted arteries. Methods Bloch simulations were performed to investigate how the inversion profile was influenced by the pCASL labeling parameters: the maximum (Gmax ) and mean (Gmean ) labeling gradient were varied for ve-pCASL with unipolar and bipolar gradients. The findings in the simulation study were subsequently confirmed in an in vivo volunteer study. Moreover, conventional and optimized settings were compared for 4D-MRA using four-cycle Hadamard ve-pCASL; the visualization of arteries and the presence of the partial labeling were assessed by an expert observer. Results When using unipolar gradient, lower Gmean resulted in a steeper spatial transition, whereas the width of the control region was broader for higher Gmax . The in vivo study confirmed these findings. When using bipolar gradients, the control region was always very narrow. Qualitative comparison of the 4D-MRA demonstrated lower occurrence of partial labeling when using the optimized gradient parameters. Conclusion The shape of the ve-pCASL inversion profile can be optimized by changing Gmean and Gmax to reduce partial labeling of untargeted arteries.

Background: Amide proton transfer (APT) imaging may help identify the ischaemic penumbra in stroke patients, the classical definition of which is a region of tissue around the ischaemic core that is hypoperfused and metabolically stressed. Given the potential of APT imaging to complement existing imaging techniques to provide clinically-relevant information, there is a need to develop analysis techniques that deliver a robust and repeatable APT metric. The challenge to accurate quantification of an APT metric has been the heterogeneous in-vivo environment of human tissue, which exhibits several confounding magnetisation transfer effects including spectrally-asymmetric nuclear Overhauser effects (NOEs). The recent literature has introduced various model-free and model-based approaches to analysis that seek to overcome these limitations. Objectives: The objective of this work was to compare quantification techniques for CEST imaging that specifically separate APT and NOE effects for application in the clinical setting. Towards this end a methodological comparison of different CEST quantification techniques was undertaken in healthy subjects, and around clinical endpoints in a cohort of acute stroke patients. Methods: MRI data from 12 patients presenting with ischaemic stroke were retrospectively analysed. Six APT quantification techniques, comprising model-based and model-free techniques, were compared for repeatability and ability for APT to distinguish pathological tissue in acute stroke. Results: Robustness analysis of six quantification techniques indicated that the multi-pool model-based technique had the smallest contrast between grey and white matter (2%), whereas model-free techniques exhibited the highest contrast (>30%). Model-based techniques also exhibited the lowest spatial variability, of which 4-pool APTR∗ was by far the most uniform (10% coefficient of variation, CoV), followed by 3-pool analysis (20%). Four-pool analysis yielded the highest ischaemic core contrast-to-noise ratio (0.74). Four-pool modelling of APT effects was more repeatable (3.2% CoV) than 3-pool modelling (4.6% CoV), but this appears to come at the cost of reduced contrast between infarct growth tissue and normal tissue. Conclusion: The multi-pool measures performed best across the analyses of repeatability, spatial variability, contrast-to-noise ratio, and grey matter-white matter contrast, and might therefore be more suitable for use in clinical imaging of acute stroke. Addition of a fourth pool that separates NOEs and semisolid effects appeared to be more biophysically accurate and provided better separation of the APT signal compared to the 3-pool equivalent, but this improvement appeared be accompanied by reduced contrast between infarct growth tissue and normal tissue. Keywords: Chemical exchange saturation transfer, Amide proton transfer, Nuclear Overhauser effects, Acute ischaemic stroke

Purpose The recently introduced “Acquisition of ConTRol and labEled imaging in the Same Shot” (ACTRESS) approach was designed to halve the scan time of arterial spin labeling (ASL) ‐based 4D‐MRA by obtaining both labeled and control images in a single Look‐Locker readout. However, application for vessel‐selective labeling remains difficult. The aim of this study was to achieve a combination of ACTRESS and vessel‐selective labeling to halve the scan time of vessel‐selective 4D‐MRA. Methods By Bloch equation simulations, Look‐Locker pseudocontinuous‐ASL (pCASL) was optimized to achieve constant static tissue signal across the multidelay readout, which is essential for the ACTRESS approach. Additionally, a new subtraction scheme was proposed to achieve visualization of the inflow phase even when labeled blood will have already arrived in the distal arteries during the first phase acquisition due to the long duration of the pCASL labeling module. In vivo studies were performed to investigate the signal variation of the static tissue, as well as to assess image quality of vessel‐selective 4D‐MRA with ACTRESS. Results In in vivo studies, the mean signal variation of the static tissue was 8.98% over the Look‐Locker phases, thereby minimizing the elevation of background signal. This allowed visualization of peripheral arteries and slowly arriving arterial blood with image quality as good as conventional pCASL within half the acquisition time. Vessel‐selective pCASL‐ACTRESS enabled the separated visualization of vessels arising from internal and external carotid arteries within this shortened acquisition time. Conclusion By combining vessel‐selective pCASL and ACTRESS approach, 4D‐MRA of a single targeted arterial tree was achieved in a few minutes.

Collateral blood flow plays a pivotal role in steno-occlusive internal carotid artery (ICA) disease to prevent irreversible ischaemic damage. Our aim was to investigate the effect of carotid artery disease upon cerebral perfusion and cerebrovascular reactivity and whether haemodynamic impairment is influenced at brain tissue level by the existence of primary and/or secondary collateral. Eighty-eight patients with steno-occlusive ICA disease and 29 healthy controls underwent MR examination. The presence of collaterals was determined with time-of-flight, two-dimensional phase contrast MRA and territorial arterial spin labeling (ASL) imaging. Cerebral blood flow and cerebrovascular reactivity were assessed with ASL before and after acetazolamide. Cerebral haemodynamics were normal in asymptomatic ICA stenosis patients, as opposed to patients with ICA occlusion, in whom the haemodynamics in both hemispheres were compromised. Haemodynamic impairment in the affected brain region was always present in symptomatic patients. The degree of collateral blood flow was inversely correlated with haemodynamic impairment. Recruitment of secondary collaterals only occurred in symptomatic ICA occlusion patients. In conclusion, both CBF and cerebrovascular reactivity were found to be reduced in symptomatic patients with steno-occlusive ICA disease. The presence of collateral flow is associated with further haemodynamic impairment. Recruitment of secondary collaterals is associated with severe haemodynamic impairment.

Purpose: When employing simultaneous multi-slice (SMS-) EPI for background suppressed (BGS-) arterial spin labeling (ASL), correction of through-plane motion could introduce artefacts, since the slices with most effective BGS are adjacent to slices with the least BGS. In this study, a new framework is presented to correct for such artefacts. Methods: The proposed framework consists of three steps: (i) homogenization of the static tissue signal over the different slices to eliminate most inter-slice differences due to different levels of BGS, (ii) motion correction is applied, (iii) extraction of perfusion-weighted signal using a general linear model. The proposed framework was evaluated by simulations and a functional ASL-study with intentional head-motion. Results: Simulation studies demonstrated that the strong signal differences between slices with the most and least effective BGS caused sub-optimal estimation of motion parameters when through-plane motion was present. Although use of the M0-image as the reference for registration allowed 82% improvement of motion estimation for through-plane motion, it still led to residual subtraction errors caused by different static tissue signal between control and label due to different BGS-levels. By using our proposed framework, those problems were minimized and the accuracy of CBF-estimation was improved. Moreover, the functional ASL-study showed improved detection of visual and motor activation when applying the framework as compared to conventional motion correction, as well as when motion correction was completely omitted. Conclusion: When combining BGS-ASL with SMS-EPI, particular attention is needed to avoid artefacts introduced by motion correction. With the proposed framework these issues are minimized.

Importance: Risk of stroke and brain atrophy in later life relate to levels of cardiovascular risk in early adulthood. However, it is unknown whether cerebrovascular changes are present in young adults. Objective: To examine relationships between modifiable cardiovascular risk factors and cerebrovascular structure, function, and white matter integrity in young adults. Design, Setting, and Participants: A cross-sectional observational study of 125 young adults (aged 18-40 years) without clinical evidence of cerebrovascular disease. Data collection was completed between August 2014 and May 2016 at the University of Oxford, United Kingdom. Final data collection was completed on May 31, 2016. Exposures: The number of modifiable cardiovascular risk factors at recommended levels, based on the following criteria: body mass index (BMI) 6 months; blood pressure on awake ambulatory monitoring Main Outcomes and Measures: Cerebral vessel density, caliber and tortuosity, brain white matter hyperintensity lesion count. In a subgroup (n = 52), brain blood arrival time and cerebral blood flow assessed by brain magnetic resonance imaging (MRI). Results: A total of 125 participants, mean (SD) age 25 (5) years, 49% women, with a mean (SD) score of 6.0 (1.4) modifiable cardiovascular risk factors at recommended levels, completed the cardiovascular risk assessment and brain MRI protocol. Cardiovascular risk factors were correlated with cerebrovascular morphology and white matter hyperintensity count in multivariable models. For each additional modifiable risk factor categorized as healthy, vessel density was greater by 0.3 vessels/cm3 (95% CI, 0.1-0.5; P = .003), vessel caliber was greater by 8 μm (95% CI, 3-13; P = .01), and white matter hyperintensity lesions were fewer by 1.6 lesions (95% CI, −3.0 to −0.5; P = .006). Among the 52 participants with available data, cerebral blood flow varied with vessel density and was 2.5 mL/100 g/min higher for each healthier category of a modifiable risk factor (95% CI, 0.16-4.89; P = .03). Conclusions and Relevance: In this preliminary study involving young adults without clinical evidence of cerebrovascular disease, a greater number of modifiable cardiovascular risk factors at recommended levels was associated with higher cerebral vessel density and caliber, higher cerebral blood flow, and fewer white matter hyperintensities. Further research is needed to verify these findings and determine their clinical importance.