Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates.

OBJECTIVE: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors. DESIGN: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic PBGD gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue. RESULTS: Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP. CONCLUSION: This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.

ASL lexicon and reporting recommendations: A consensus report from the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

The 2015 consensus statement published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group and the European Cooperation in Science and Technology ( COST) Action ASL in Dementia aimed to encourage the implementation of robust arterial spin labeling (ASL) perfusion MRI for clinical applications and promote consistency across scanner types, sites, and studies. Subsequently, the recommended 3D pseudo-continuous ASL sequence has been implemented by most major MRI manufacturers. However, ASL remains a rapidly and widely developing field, leading inevitably to further divergence of the technique and its associated terminology, which could cause confusion and hamper research reproducibility. On behalf of the ISMRM Perfusion Study Group, and as part of the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI), the ASL Lexicon Task Force has been working on the development of an ASL Lexicon and Reporting Recommendations for perfusion imaging and analysis, aiming to (1) develop standardized, consensus nomenclature and terminology for the broad range of ASL imaging techniques and parameters, as well as for the physiological constants required for quantitative analysis; and (2) provide a community-endorsed recommendation of the imaging parameters that we encourage authors to include when describing ASL methods in scientific reports/papers. In this paper, the sequences and parameters in (pseudo-)continuous ASL, pulsed ASL, velocity-selective ASL, and multi-timepoint ASL for brain perfusion imaging are included. However, the content of the lexicon is not intended to be limited to these techniques, and this paper provides the foundation for a growing online inventory that will be extended by the community as further methods and improvements are developed and established.

Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.

Comparison of Myocardial Blood Flow Quantification Models for Double ECG Gating Arterial Spin Labeling MRI: Reproducibility Assessment.

BACKGROUND: Arterial spin labeling (ASL) allows non-invasive quantification of myocardial blood flow (MBF). Double-ECG gating (DG) ASL is more robust to heart rate variability than single-ECG gating (SG), but its reproducibility requires further investigation. Moreover, the existence of multiple quantification models hinders its application. Frequency-offset-corrected-inversion (FOCI) pulses provide sharper edge profiles than hyperbolic-secant (HS), which could benefit myocardial ASL. PURPOSE: To assess the performance of MBF quantification models for DG compared to SG ASL, to evaluate their reproducibility and to compare the effects of HS and FOCI pulses. STUDY TYPE: Prospective. SUBJECTS: Sixteen subjects (27 ± 8 years). FIELD STRENGTH/SEQUENCE: 1.5 T/DG and SG flow-sensitive alternating inversion recovery ASL. ASSESSMENT: Three models for DG MBF quantification were compared using Monte Carlo simulations and in vivo experiments. Two models used a fitting approach (one using only a single label and control image pair per fit, the other using all available image pairs), while the third model used a T1 correction approach. Slice profile simulations were conducted for HS and FOCI pulses with varying B0 and B1. Temporal signal-to-noise ratio (tSNR) was computed for different acquisition/quantification strategies and inversion pulses. The number of images that minimized MBF error was investigated in the model with highest tSNR. Intra and intersession reproducibility were assessed in 10 subjects. STATISTICAL TESTS: Within-subject coefficient of variation, analysis of variance. P-value <0.05 was considered significant. RESULTS: MBF was not different across acquisition/quantification strategies (P = 0.27) nor pulses (P = 0.9). DG MBF quantification models exhibited significantly higher tSNR and superior reproducibility, particularly for the fitting model using multiple images (tSNR was 3.46 ± 2.18 in vivo and 3.32 ± 1.16 in simulations, respectively; wsCV = 16%). Reducing the number of ASL pairs to 13/15 did not increase MBF error (minimum = 0.22 mL/g/min). DATA CONCLUSION: Reproducibility of MBF was better for DG than SG acquisitions, especially when employing a fitting model. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Diagnostic and Prognostic Potential of Multiparametric Renal MRI in Kidney Transplant Patients.

BACKGROUND: Multiparametric MRI provides assessment of functional and structural parameters in kidney allografts. It offers a non-invasive alternative to the current reference standard of kidney biopsy. PURPOSE: To evaluate the diagnostic and prognostic utility of MRI parameters in the assessment of allograft function in the first 3-months post-transplantation. STUDY TYPE: Prospective. SUBJECTS: 32 transplant recipients (54 ± 17 years, 20 females), divided into two groups according to estimated glomerular filtration rate (eGFR) at 3-months post-transplantation: inferior graft function (IGF; eGFR<45 mL/min/1.73 m2 , n = 10) and superior graft function (SGF; eGFR ≥ 45 mL/min/1.73 m2 , n = 22). Further categorization was based on the need for hemodialysis (C1) and decrease in s-creatinine (C2) at 1-week post-transplantation: delayed-graft-function (DGF: n = 4 C1, n = 10 C2) and early graft-function (EGF: n = 28 C1, n = 22 C2). FIELD STRENGTH/SEQUENCE: 3-T, pseudo-continuous arterial spin labeling, T1-mapping, and diffusion-weighted imaging. ASSESSMENT: Multiparametric MRI was evaluated at 1-week in all patients and 3-months after transplantation in 28 patients. Renal blood flow (RBF), diffusion coefficients (ADC, ΔADC, D, ∆ $$ \Delta $$ D, D*, flowing fraction f), T1 and ∆ $$ \Delta $$ T1 were calculated in cortex and medulla. The diagnostic and prognostic value of these parameters, obtained at 3-months and 1-week post-transplantation, respectively, was evaluated in the cortex to discriminate between DGF and EGF, and between SGF and IGF. STATISTICAL TESTS: Logistic regression, receiver-operating-characteristics, area-under-the-curve (AUC), confidence intervals (CIs), analysis-of-variance, t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Pearson's correlation. P-value<0.05 was considered significant. RESULTS: DGF patients exhibited significantly lower cortical RBF and f and higher D*. The diagnostic value of MRI for detecting DGF was excellent (AUC = 100%). Significant differences between patients with IGF and SGF were found in RBF, ∆T1 , and ∆D. Multiparametric MRI showed higher diagnostic (AUC = 95.32%; CI: 88%-100%) and prognostic (AUC = 97.47%, CI: 92%-100%) values for detecting IGF than eGFR (AUC = 89.50%, CI: 79%-100%). DATA CONCLUSION: Multiparametric MRI may show high diagnostic and prognostic value in transplanted patients, yielding better results compared to eGFR measurements. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Update on state-of-the-art for arterial spin labeling (ASL) human perfusion imaging outside of the brain.

This review article provides an overview of developments for arterial spin labeling (ASL) perfusion imaging in the body (i.e., outside of the brain). It is part of a series of review/recommendation papers from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. In this review, we focus on specific challenges and developments tailored for ASL in a variety of body locations. After presenting common challenges, organ-specific reviews of challenges and developments are presented, including kidneys, lungs, heart (myocardium), placenta, eye (retina), liver, pancreas, and muscle, which are regions that have seen the most developments outside of the brain. Summaries and recommendations of acquisition parameters (when appropriate) are provided for each organ. We then explore the possibilities for wider adoption of body ASL based on large standardization efforts, as well as the potential opportunities based on recent advances in high/low-field systems and machine-learning. This review seeks to provide an overview of the current state-of-the-art of ASL for applications in the body, highlighting ongoing challenges and solutions that aim to enable more widespread use of the technique in clinical practice.

Clinical utility of intraoperative arterial spin labeling for resection control in brain tumor surgery at 3 T.

Resection control in brain tumor surgery can be achieved in real time with intraoperative MRI (iMRI). Arterial spin labeling (ASL), a technique that measures cerebral blood flow (CBF) non-invasively without the use of intravenous contrast agents, can be performed intraoperatively, providing morpho-physiological information. This study aimed to evaluate the feasibility, image quality and potential to depict residual tumor of a pseudo-continuous ASL (PCASL) sequence at 3 T. Seventeen patients with brain tumors, primary (16) or metastatic (1), undergoing resection surgery with iMRI monitoring, were prospectively recruited (nine men, age 56 ± 16.6 years). A PCASL sequence with long labeling duration (3000 ms) and postlabeling delay (2000 ms) was added to the conventional protocol, which consisted of pre- and postcontrast 3D T1 -weighted (T1w) images, optional 3D-FLAIR, and diffusion. Three observers independently assessed the image quality (four-point scale) of PCASL-derived CBF maps. In those with diagnostic quality (Scores 2-4) they evaluated the presence of residual tumor using the conventional sequences first, and the CBF maps afterwards (three-point scale). Inter-observer agreement for image quality and the presence of residual tumor was assessed using Fleiss kappa statistics. The intraoperative CBF ratio of the surgical margins (i.e., perilesional CBF values normalized to contralateral gray matter CBF) was compared with preoperative CBF ratio within the tumor (Wilcoxon's test). Diagnostic ASL image quality was observed in 94.1% of patients (interobserver Fleiss κ = 0.76). PCASL showed additional foci suggestive of high-grade residual component in three patients, and a hyperperfused area extending outside the enhancing component in one patient. Interobserver agreement was almost perfect in the evaluation of residual tumor with the conventional sequences (Fleiss κ = 0.92) and substantial for PCASL (Fleiss κ = 0.80). No significant differences were found between pre and intraoperative CBF ratios (p = 0.578) in patients with residual tumor (n = 7). iMRI-PCASL perfusion is feasible at 3 T and is useful for the intraoperative assessment of residual tumor, providing in some cases additional information to the conventional sequences.

Multiparametric renal magnetic resonance imaging: A reproducibility study in renal allografts with stable function.

Monitoring renal allograft function after transplantation is key for the early detection of allograft impairment, which in turn can contribute to preventing the loss of the allograft. Multiparametric renal MRI (mpMRI) is a promising noninvasive technique to assess and characterize renal physiopathology; however, few studies have employed mpMRI in renal allografts with stable function (maintained function over a long time period). The purposes of the current study were to evaluate the reproducibility of mpMRI in transplant patients and to characterize normal values of the measured parameters, and to estimate the labeling efficiency of Pseudo-Continuous Arterial Spin Labeling (PCASL) in the infrarenal aorta using numerical simulations considering experimental measurements of aortic blood flow profiles. The subjects were 20 transplant patients with stable kidney function, maintained over 1 year. The MRI protocol consisted of PCASL, intravoxel incoherent motion, and T1 inversion recovery. Phase contrast was used to measure aortic blood flow. Renal blood flow (RBF), diffusion coefficient (D), pseudo-diffusion coefficient (D*), flowing fraction ( f ), and T1 maps were calculated and mean values were measured in the cortex and medulla. The labeling efficiency of PCASL was estimated from simulation of Bloch equations. Reproducibility was assessed with the within-subject coefficient of variation, intraclass correlation coefficient, and Bland-Altman analysis. Correlations were evaluated using the Pearson correlation coefficient. The significance level was p less than 0.05. Cortical reproducibility was very good for T1, D, and RBF, moderate for f , and low for D*, while medullary reproducibility was good for T1 and D. Significant correlations in the cortex between RBF and f (r = 0.66), RBF and eGFR (r = 0.64), and D* and eGFR (r = -0.57) were found. Normal values of the measured parameters employing the mpMRI protocol in kidney transplant patients with stable function were characterized and the results showed good reproducibility of the techniques.

Automatic Segmentation and Quantification of Nigrosome-1 Neuromelanin and Iron in MRI: A Candidate Biomarker for Parkinson's Disease.

BACKGROUND: There is a lack of automated tools for the segmentation and quantification of neuromelanin (NM) and iron in the nigrosome-1 (N1). Existing tools evaluate the N1 sign, i.e., the presence or absence of the "swallow-tail" in iron-sensitive MRI, or globally analyze the MRI signal in an area containing the N1, without providing a volumetric delineation. PURPOSE: Present an automated method to segment the N1 and quantify differences in N1's NM and iron content between Parkinson's disease (PD) patients and healthy controls (HCs). Study whether N1 degeneration is clinically related to PD and could be used as a biomarker of the disease. STUDY TYPE: Prospective. SUBJECTS: Seventy-one PD (65.3 ± 10.3 years old, 34 female/37 male); 30 HC (62.7 ± 7.8 years old, 17 female/13 male). FIELD STRENGTH/SEQUENCE: 3 T Anatomical T1-weighted MPRAGE, NM-MRI T1-weighted gradient with magnetization transfer, susceptibility-weighted imaging (SWI). ASSESSMENT: N1 was automatically segmented in SWI images using a multi-image atlas, populated with healthy N1 structures manually annotated by a neurologist. Relative NM and iron content were quantified and their diagnostic performance assessed and compared with the substantia nigra pars compacta (SNc). The association between image parameters and clinically relevant variables was studied. STATISTICAL TESTS: Nonparametric tests were used (Mann-Whitney's U, chi-square, and Friedman tests) at P = 0.05. RESULTS: N1's relative NM content decreased and relative iron content increased in PD patients compared with HCs (NM-CRHC = 22.55 ± 1.49; NM-CRPD = 19.79 ± 1.92; NM-nVolHC = 2.69 × 10-5 ± 1.02 × 10-5 ; NM-nVolPD = 1.18 × 10-5 ± 0.96 × 10-5 ; Iron-CRHC = 10.51 ± 2.64; Iron-CRPD = 19.35 ± 7.88; Iron-nVolHC = 0.72 × 10-5 ± 0.81 × 10-5 ; Iron-nVolPD = 2.82 × 10-5 ± 2.04 × 10-5 ). Binary logistic regression analyses combining N1 and SNc image parameters yielded a top AUC = 0.955. Significant correlation was found between most N1 parameters and both disease duration (ρNM-CR = -0.31; ρiron-CR = 0.43; ρiron-nVol = 0.46) and the motor status (ρNM-nVol = -0.27; ρiron-CR = 0.33; ρiron-nVol = 0.28), suggesting NM reduction along with iron accumulation in N1 as the disease progresses. DATA CONCLUSION: This method provides a fully automatic N1 segmentation, and the analyses performed reveal that N1 relative NM and iron quantification improves diagnostic performance and suggest a relative NM reduction along with a relative iron accumulation in N1 as the disease progresses. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Assessment of Splenic Switch-Off With Arterial Spin Labeling in Adenosine Perfusion Cardiac MRI.

BACKGROUND: In patients with suspected coronary artery disease (CAD), myocardial perfusion is assessed under rest and pharmacological stress to identify ischemia. Splenic switch-off, defined as the stress to rest splenic perfusion attenuation in response to adenosine, has been proposed as an indicator of stress adequacy. Its occurrence has been previously assessed in first-pass perfusion images, but the use of noncontrast techniques would be highly beneficial. PURPOSE: To explore the ability of pseudo-continuous arterial spin labeling (PCASL) to identify splenic switch-off in patients with suspected CAD. STUDY TYPE: Prospective. POPULATION: Five healthy volunteers (age 24.8 ± 3.8 years) and 32 patients (age 66.4 ± 8.2 years) with suspected CAD. FIELD STRENGTH/SEQUENCE: A 1.5-T/PCASL (spin-echo) and first-pass imaging (gradient-echo). ASSESSMENT: In healthy subjects, multi-delay PCASL data (500-2000 msec) were acquired to quantify splenic blood flow (SBF) and determine the adequate postlabeling delay (PLD) for single-delay acquisitions (PLD > arterial transit time). In patients, single-delay PCASL (1200 msec) and first-pass perfusion images were acquired under rest and adenosine conditions. PCASL data were used to compute SBF maps and SBF stress-to-rest ratios. Three observers classified patients into "switch-off" and "failed switch-off" groups by visually comparing rest-stress perfusion data acquired with PCASL and first-pass, independently. First-pass categories were used as reference to evaluate the accuracy of quantitative classification. STATISTICAL TESTS: Wilcoxon signed-rank, Pearson correlation, kappa, percentage agreement, Generalized Linear Mixed Model, Mann-Whitney, Pearson Chi-squared, receiver operating characteristic, area-under-the-curve (AUC) and confusion matrix. SIGNIFICANCE: P value < 0.05. RESULTS: A total of 27 patients (84.4%) experienced splenic switch-off according to first-pass categories. Comparison of PCASL-derived SBF maps during stress and rest allowed assessment of splenic switch-off, reflected in a reduction of SBF values during stress. SBF stress-to-rest ratios showed a 97% accuracy (sensitivity = 80%, specificity = 100%, AUC = 85.2%). DATA CONCLUSION: This study could demonstrate the feasibility of PCASL to identify splenic switch-off during adenosine perfusion MRI, both by qualitative and quantitative assessments. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2.

Advanced MR Techniques for Preoperative Glioma Characterization: Part 2.

Preoperative clinical MRI protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this second part, we review magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), susceptibility-weighted imaging (SWI), MRI-PET, MR elastography (MRE), and MR-based radiomics applications. The first part of this review addresses dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI, arterial spin labeling (ASL), diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting (MRF). EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Advanced MR Techniques for Preoperative Glioma Characterization: Part 1.

Preoperative clinical magnetic resonance imaging (MRI) protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation or lack thereof. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this first part, we discuss dynamic susceptibility contrast and dynamic contrast-enhanced MRI, arterial spin labeling, diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting. The second part of this review addresses magnetic resonance spectroscopy, chemical exchange saturation transfer, susceptibility-weighted imaging, MRI-PET, MR elastography, and MR-based radiomics applications. Evidence Level: 3 Technical Efficacy: Stage 2.

Brain ventricular enlargement in human and murine acute intermittent porphyria.

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

Reduction of motion effects in myocardial arterial spin labeling.

PURPOSE: To evaluate the accuracy and reproducibility of myocardial blood flow measurements obtained under different breathing strategies and motion correction techniques with arterial spin labeling. METHODS: A prospective cardiac arterial spin labeling study was performed in 12 volunteers at 3 Tesla. Perfusion images were acquired twice under breath-hold, synchronized-breathing, and free-breathing. Motion detection based on the temporal intensity variation of a myocardial voxel, as well as image registration based on pairwise and groupwise approaches, were applied and evaluated in synthetic and in vivo data. A region of interest was drawn over the mean perfusion-weighted image for quantification. Original breath-hold datasets, analyzed with individual regions of interest for each perfusion-weighted image, were considered as reference values. RESULTS: Perfusion measurements in the reference breath-hold datasets were in line with those reported in literature. In original datasets, prior to motion correction, myocardial blood flow quantification was significantly overestimated due to contamination of the myocardial perfusion with the high intensity signal of blood pool. These effects were minimized with motion detection or registration. Synthetic data showed that accuracy of the perfusion measurements was higher with the use of registration, in particular after the pairwise approach, which probed to be more robust to motion. CONCLUSION: Satisfactory results were obtained for the free-breathing strategy after pairwise registration, with higher accuracy and robustness (in synthetic datasets) and higher intrasession reproducibility together with lower myocardial blood flow variability across subjects (in in vivo datasets). Breath-hold and synchronized-breathing after motion correction provided similar results, but these breathing strategies can be difficult to perform by patients.

Recent Technical Developments in ASL: A Review of the State of the Art.

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. It is part of a series of review/recommendation papers from the International Society for Magnetic Resonance in Medicine Perfusion Study Group. Here, we focus on advancements in readouts and trajectories, image reconstruction, noise reduction, partial volume correction, quantification of nonperfusion parameters, fMRI, fingerprinting, vessel selective ASL, angiography, deep learning, and ultrahigh field ASL. We aim to provide a high level of 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 outside the scope of this article that are reviewed at length in separate articles include velocity selective ASL, multiple-timepoint ASL, body ASL, and clinical ASL recommendations.

Consensus-Based Technical Recommendations for Clinical Translation of Renal Phase Contrast MRI.

BACKGROUND: Phase-contrast (PC) MRI is a feasible and valid noninvasive technique to measure renal artery blood flow, showing potential to support diagnosis and monitoring of renal diseases. However, the variability in measured renal blood flow values across studies is large, most likely due to differences in PC-MRI acquisition and processing. Standardized acquisition and processing protocols are therefore needed to minimize this variability and maximize the potential of renal PC-MRI as a clinically useful tool. PURPOSE: To build technical recommendations for the acquisition, processing, and analysis of renal 2D PC-MRI data in human subjects to promote standardization of renal blood flow measurements and facilitate the comparability of results across scanners and in multicenter clinical studies. STUDY TYPE: Systematic consensus process using a modified Delphi method. POPULATION: Not applicable. SEQUENCE FIELD/STRENGTH: Renal fast gradient echo-based 2D PC-MRI. ASSESSMENT: An international panel of 27 experts from Europe, the USA, Australia, and Japan with 6 (interquartile range 4-10) years of experience in 2D PC-MRI formulated consensus statements on renal 2D PC-MRI in two rounds of surveys. Starting from a recently published systematic review article, literature-based and data-driven statements regarding patient preparation, hardware, acquisition protocol, analysis steps, and data reporting were formulated. STATISTICAL TESTS: Consensus was defined as ≥75% unanimity in response, and a clear preference was defined as 60-74% agreement among the experts. RESULTS: Among 60 statements, 57 (95%) achieved consensus after the second-round survey, while the remaining three showed a clear preference. Consensus statements resulted in specific recommendations for subject preparation, 2D renal PC-MRI data acquisition, processing, and reporting. DATA CONCLUSION: These recommendations might promote a widespread adoption of renal PC-MRI, and may help foster the set-up of multicenter studies aimed at defining reference values and building larger and more definitive evidence, and will facilitate clinical translation of PC-MRI. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Optimization of pseudo-continuous arterial spin labeling for renal perfusion imaging.

PURPOSE: To evaluate labeling efficiency of pseudo-continuous arterial spin labeling (PCASL) and to find the gradient parameters that increase PCASL robustness for renal perfusion measurements. METHODS: Aortic blood flow was characterized in 3 groups: young healthy volunteers (YHV1), chronic kidney disease (CKD) patients (CKDP), and healthy controls (HCO). PCASL inversion efficiency was evaluated through numeric simulations considering the measured pulsatile flow velocity profiles and off-resonance effects for a wide range of gradient parameters, and the results were assessed in vivo. The most robust PCASL implementation was used to measure renal blood flow (RBF) in CKDP and HCO. RESULTS: Aortic blood velocities reached peak values of 120 cm/s in YHV1, whereas for elderly subjects values were lower by approximately a factor of 2. Simulations and experiments showed that by reducing the gradient average (Gave ) and the selective to average gradient ratio (Gmax /Gave ), labeling efficiency was maximized and PCASL robustness to off-resonance was improved. The study in CKDP and HCO showed significant differences in RBF between groups. CONCLUSION: An efficient and robust PCASL scheme for renal applications requires a Gmax /Gave ratio of 6-7 and a Gave value that depends on the aortic blood flow velocities (0.5 mT/m being appropriate for CKDP and HCO).

Quantification of Myocardial Perfusion With Vasodilation Using Arterial Spin Labeling at 1.5T.

BACKGROUND: Myocardial perfusion is evaluated in first-pass MRI using a gadolinium-based contrast agent, which limits its repeatability and restricts its use in patients with abnormal kidney function. Arterial spin labeling (ASL) is a promising technique for measuring myocardial perfusion without contrast injection. The ratio of stress to rest perfusion, termed myocardial perfusion reserve (MPR), is an indicator of the severity of stenosis in patients with coronary artery disease (CAD). PURPOSE: To quantify perfusion increases with pharmacological vasodilation, explore MPR differences between segments with and without perfusion defects, and examine the correlations between quantitative ASL and semiquantitative first-pass measurements. STUDY TYPE: Prospective. SUBJECTS: Sixteen patients with suspected CAD: 10 classified as "healthy," having normal perfusion on first-pass and no enhancement on late gadolinium enhancement (LGE), and six as "nonhealthy," having hypoperfused segments including ischemic and infarcted. FIELD STRENGTH/SEQUENCE: Flow-sensitive alternating inversion recovery (FAIR) rest-stress cardiac ASL with balanced steady-state free precession (bSSFP), rest-stress first-pass imaging using gradient-echo and LGE using a phase-sensitive inversion-recovery bSSFP at 1.5T. ASSESSMENT: For healthy subjects, rest-stress perfusion data were compared in global, coronary artery territory, and segment regions of interest (ROIs). A segmental MPR comparison was performed between normal segments from healthy subjects and abnormal segments from nonhealthy subjects. Correlations between ASL and first-pass parameters were explored. STATISTICAL TESTS: Wilcoxon-signed-rank test, nonparametric factorial analysis of variance (ANOVA), and Pearson's/Spearman's correlations. RESULTS: Perfusion increases were significant globally (P = 0.005), per coronary artery territory (P = 0.015), and per segment (P = 0.03 for all segments in ASL and first-pass, except anteroseptal in ASL P = 0.04). MPR differences between normal and abnormal segments were significant (P = 0.0028: ASL, P = 0.033: first-pass). ASL and first-pass measurements were correlated (MPR: r = 0.64, P = 0.008 and perfusion: rho = 0.47, P = 0.007). DATA CONCLUSION: This study demonstrates the feasibility of ASL to detect hyperemia, the potential to differentiate segments with and without perfusion defects, and significant correlations between ASL and semiquantitative first-pass. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Consensus-based technical recommendations for clinical translation of renal ASL MRI.

OBJECTIVES: This study aimed at developing technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5 T and 3 T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-centre clinical studies. METHODS: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting. RESULTS: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labelling with a single-slice spin-echo EPI readout with background suppression and a simple but robust quantification model. DISCUSSION: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data become available, since the renal ASL literature is rapidly expanding.

Optimal repetition time for free breathing myocardial arterial spin labeling.

The aim of this study was to improve the scan efficiency of ASL in the myocardium. Free breathing FAIR-ASL scans with different TRs were compared, while keeping the acquisition time constant. Scans were named by the trigger pulse that started each acquisition: every two (TP1), four (TP2) and six (TP3) cardiac cycles. TP2 offered the best alternative with a coefficient of variation of 17.15% intrasession and 36.85% intersession. Mean MBF increased by 0.22 ± 0.41 ml/g/min with mild stress.

Arterial spin labeling (ASL) offers a noninvasive and repeatable measurement of tissue blood flow, but its application in the human heart is still challenging. The aim of this study was to improve the scan efficiency of flow-sensitive alternating inversion recovery (FAIR) ASL using a single inversion time. First, by evaluating a free breathing acquisition without navigators. Second, by shortening TR to acquire more ASL pairs. A FAIR ASL with balanced steady state free precession (bSSFP) readout was implemented at 3 T and tested in 14 healthy volunteers. Three cardiac-triggered ASL scans with different TRs were compared while maintaining a constant acquisition time. These scans were named by the trigger pulse (TP) that started each acquisition: every two (TP1), four (TP2) and six (TP3) cardiac cycles. Two studies were performed on different days to assess the reproducibility of TP2 and TP3 scans. Perfusion response during passive leg raising was also evaluated. Student t-test and nonparametric equivalent were computed for perfusion differences. Bland-Altman and coefficient of variation (CV) were calculated for the reproducibility assessment. Mean myocardial blood flow (MBF) values measured at rest were: 1.47 ± 0.91 ml/g/min (TP1), 1.95 ± 0.93 ml/g/min (TP2) and 1.94 ± 1.41 ml/g/min (TP3). Intrasession CV was 17.15% (TP2) and 24.17% (TP3) and intersession CV was 36.86% (TP2) and 18.38% (TP3). Mean MBF was found to increase with passive stress by 0.22 ± 0.41 ml/g/min for TP2 (P = 0.037). Mean MBF values were consistent with the literature, although in the high end of the normal range. The lower MBF values measured in TP1 scans are attributable to saturation of blood outside the slice because of shorter TR. Free breathing FAIR cardiac ASL without navigators is feasible. A TR of approximately four seconds (TP2) offers the best alternative with similar mean ASL and tSNR than longer TR acquisitions.