Multidelay ASL of the pediatric brain

Arterial spin labeling (ASL) is a powerful noncontrast MRI technique for evaluation of cerebral blood flow (CBF). A key parameter in single-delay ASL is the choice of postlabel delay (PLD), which refers to the timing between the labeling of arterial free water and measurement of flow into the brain. Multidelay ASL (MDASL) utilizes several PLDs to improve the accuracy of CBF calculations using arterial transit time (ATT) correction. This approach is particularly helpful in situations where ATT is unknown, including young subjects and slow-flow conditions. In this article, we discuss the technical considerations for MDASL, including labeling techniques, quantitative metrics, and technical artefacts. We then provide a practical summary of key clinical applications with real-life imaging examples in the pediatric brain, including stroke, vasculopathy, hypoxic-ischemic injury, epilepsy, migraine, tumor, infection, and metabolic disease

Arterial Spin Labeling Perfusion of the Brain: Emerging Clinical Applications

Arterial spin labeling (ASL) is a magnetic resonance (MR) imaging technique used to assess cerebral blood flow noninvasively by magnetically labeling inflowing blood. In this article, the main labeling techniques, notably pulsed and pseudocontinuous ASL, as well as emerging clinical applications will be reviewed. In dementia, the pattern of hypoperfusion on ASL images closely matches the established patterns of hypometabolism on fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images due to the close coupling of perfusion and metabolism in the brain. This suggests that ASL might be considered as an alternative for FDG, reserving PET to be used for the molecular disease-specific amyloid and tau tracers. In stroke, ASL can be used to assess perfusion alterations both in the acute and the chronic phase. In arteriovenous malformations and dural arteriovenous fistulas, ASL is very sensitive to detect even small degrees of shunting. In epilepsy, ASL can be used to assess the epileptogenic focus, both in peri- and interictal period. In neoplasms, ASL is of particular interest in cases in which gadolinium-based perfusion is contraindicated (eg, allergy, renal impairment) and holds promise in differentiating tumor progression from benign causes of enhancement. Finally, various neurologic and psychiatric diseases including mild traumatic brain injury or posttraumatic stress disorder display alterations on ASL images in the absence of visualized structural changes. In the final part, current limitations and future developments of ASL techniques to improve clinical applicability, such as multiple inversion time ASL sequences to assess alterations of transit time, reproducibility and quantification of cerebral blood flow, and to measure cerebrovascular reserve, will be reviewed

Motion-corrected multiparametric renal arterial spin labelling at 3T: Reproducibility and effect of vasodilator challenge

Objectives We investigated the feasibility and reproducibility of free-breathing motion-corrected multiple inversion time (multi-TI) pulsed renal arterial spin labelling (PASL), with general kinetic model parametric mapping, to simultaneously quantify renal perfusion (RBF), bolus arrival time (BAT) and tissue T1. Methods In a study approved by the Health Research Authority, 12 healthy volunteers (mean age, 27.6 ± 18.5 years; 5 male) gave informed consent for renal imaging at 3 T using multi-TI ASL and conventional single-TI ASL. Glyceryl trinitrate (GTN) was used as a vasodilator challenge in six subjects. Flow-sensitive alternating inversion recovery (FAIR) preparation was used with background suppression and 3D-GRASE (gradient and spin echo) read-out, and images were motion-corrected. Parametric maps of RBF, BAT and T1 were derived for both kidneys. Agreement was assessed using Pearson correlation and Bland-Altman plots. Results Inter-study correlation of whole-kidney RBF was good for both single-TI (r2 = 0.90), and multi-TI ASL (r2 = 0.92). Single-TI ASL gave a higher estimate of whole-kidney RBF compared to multi-TI ASL (mean bias, 29.3 ml/min/100 g; p <0.001). Using multi-TI ASL, the median T1 of renal cortex was shorter than that of medulla (799.6 ms vs 807.1 ms, p = 0.01), and mean whole-kidney BAT was 269.7 ± 56.5 ms. GTN had an effect on systolic blood pressure (p < 0.05) but the change in RBF was not significant. Conclusions Free-breathing multi-TI renal ASL is feasible and reproducible at 3 T, providing simultaneous measurement of renal perfusion, haemodynamic parameters and tissue characteristics at baseline and during pharmacological challenge

Development and Application of MRI Techniques for Non-Invasive Assessment of Blood-Cerebrospinal Fluid Barrier Function

The choroid plexus (CP) tissue forms the blood-cerebrospinal fluid barrier (BCSFB) - a unique interface which plays a critical role in effective homeostasis of the central nervous system. To date, exploration of the BCSFB’s role in health and disease has been hindered by a lack of non-invasive, translatable methodologies. The recent development of BCSFB-ASL MRI by Evans et al. has permitted the non-invasive, surrogate measurement of BCSFB function. The work presented herein develops and applies the BCSFB-ASL method to investigate BCSFB function in rodent models of ageing and disease. Chapter 2 describes a novel platform for simultaneous recording of BCSFB function and brain tissue perfusion using interleaved echo-time ASL, which provided insight into alterations of vessel tone at the BBB and BCSFB under the influence of pharmacological agents, as well as how reactivity towards a vasopressin challenge is impaired in the aged mouse brain. In Chapter 3, I reproduce, optimise, and characterise the BCSFB-ASL MRI approach on a Bruker 9.4T system, that was heretofore applied only on an Agilent 9.4T MRI system. This work seeks to utilise the improved hardware and software on the Bruker system to increase measurement precision with minimised scan times. Chapter 4 describes efforts to further characterise the contributing sources and kinetics of ultra-long echo-time ASL signals arising from brain-wide CSF regions. These experiments seek to determine the reliability of the estimated labelled blood water delivery rates, alongside potential factors which may contribute to the appearance of these signals, in regions distal to the caudal lateral ventricles. In Chapter 5, BCSFB function was then investigated in the context of systemic hypertension. Spontaneously hypertensive rats displayed a reduction in BCSFB function, which highlights the potential for such measures to serve as a sensitive early biomarker for hypertension-driven neurodegeneration. Overall, we demonstrate the scope of BCSFB-ASL to capture changes to BCSFB function, which not only has value in providing a useful biomarker for downstream neurodegeneration, but also provides an insight into mechanisms which may increase the brain’s susceptibility towards neurodegenerative outcomes

Designing and comparing optimized pseudo-continuous Arterial Spin Labeling protocols for measurement of cerebral blood flow

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

Impact of the inversion time on regional brain perfusion estimation with clinical arterial spin labeling protocols

Objective: Evaluating the impact of the Inversion Time (TI) on regional perfusion estimation in a pediatric cohort using Arterial Spin Labeling (ASL). Materials and methods: Pulsed ASL (PASL) was acquired at 3 T both at TI 1500 ms and 2020 ms from twelve MRI-negative patients (age range 9–17 years). A volume of interest (VOIs) and a voxel-wise approach were employed to evaluate subject-specific TI-dependent Cerebral Blood Flow (CBF) differences, and grey matter CBF Z-score differences. A visual evaluation was also performed. Results: CBF was higher for TI 1500 ms in the proximal territories of the arteries (PTAs) (e.g. insular cortex and basal ganglia — P < 0.01 and P < 0.05 from the VOI analysis, respectively), and for TI 2020 ms in the distal territories of the arteries (DTAs), including the watershed areas (e.g. posterior parietal and occipital cortex — P < 0.001 and P < 0.01 from the VOI analysis, respectively). Similar differences were also evident when analyzing patient-specific CBF Z-scores and at a visual inspection. Conclusions: TI influences ASL perfusion estimates with a region-dependent effect. The presence of intraluminal arterial signal in PTAs and the longer arterial transit time in the DTAs (including watershed areas) may account for the TI-dependent differences. Watershed areas exhibiting a lower perfusion signal at short TIs (~ 1500 ms) should not be misinterpreted as focal hypoperfused areas

Arterial spin labelling magnetic resonance imaging of the brain: techniques and development

This thesis centres on the development of arterial spin labelling (ASL) MRI, a non-invasive technique to image cerebral perfusion. In the first chapter I explain the principles of cerebral blood flow (CBF) quantification using ASL beginning with the original implementation through to the most recent advances. I proceed to describe the established theory behind the key additional MRI contrast mechanisms and techniques that underpin the novel experiments described in this thesis (T2 and T1 relaxation, diffusion imaging and half-Fourier acquisition and reconstruction). In Chapter 2 I describe work undertaken to sample the transverse relaxation of the ASL perfusion-weighted and control images acquired with and without vascular crusher gradients at a range of post-labelling delay times and tagging durations, to estimate the intra-vascular, intra-cellular and extra-cellular distribution of labelled water in the rat cortex. The results provide evidence for rapid exchange of labelled water into the intra-cellular space relative to the transit-time through the vascular bed, and provide a more solid foundation for CBF quantification using ASL techniques. In Chapter 3 the performance of image de-noising techniques for reducing errors in ASL CBF and arterial transit time estimates is investigated. I show that noise reduction methods can suppress random and systematic errors, improving both the precision and accuracy of CBF measurements and the precision of transit time maps. In Chapter 4 I present the first in-vivo demonstration of Hadamard-encoded continuous ASL (H-CASL); an efficient method of imaging small volumes of labelled blood water in the brain at multiple post labelling delay times. I present evidence that H-CASL is viable for in-vivo application and can improve the precision of δa estimation in 2/3 of the imaging time required for standard multi post labelling delay continuous ASL

Optimized cervical spinal cord perfusion MRI after traumatic injury in the rat

Despite the potential to guide clinical management of spinal cord injury and disease, noninvasive methods of monitoring perfusion status of the spinal cord clinically remain an unmet need. In this study, we optimized pseudo-continuous arterial spin labeling (pCASL) for the rodent cervical spinal cord and demonstrate its utility in identifying perfusion deficits in an acute contusion injury model. High-resolution perfusion sagittal images with reduced imaging artifacts were obtained with optimized background suppression and imaging readout. Following moderate contusion injury, perfusion was clearly and reliably decreased at the site of injury. Implementation of time-encoded pCASL confirmed injury site perfusion deficits with blood flow measurements corrected for variability in arterial transit times. The noninvasive protocol of pCASL in the spinal cord can be utilized in future applications to examine perfusion changes after therapeutic interventions in the rat and translation to patients may offer critical implications for patient management.Neuro Imaging Researc

Diffusion and perfusion MRI and applications in cerebral ischaemia

Two MRI techniques, namely diffusion and perfusion imaging, are becoming increasingly used for evaluation of the pathophysiology of stroke. This work describes the use of these techniques, together with more conventional MRI modalities (such as T1, and T2 imaging) in the investigation of cerebral ischaemia. The work was performed both in a paediatric population in a whole-body clinical MR system (1.5 T) and in an animal model of focal ischaemia at high magnetic field strength (8.5 T). For the paediatric studies, a single shot echo planar imaging (EPI) sequence was developed to enable the on-line calculation of maps of the trace of the diffusion tensor. In the process of this development, it was necessary to address two different imaging artefacts in these maps: eddy current induced image shifts, and residual Nyquist ghost artefacts. Perfusion imaging was implemented using an EPI sequence to follow the passage through the brain of a bolus of a paramagnetic contrast agent. Computer simulations were performed to evaluate the limitations of this technique in the quantification of cerebral blood flow when delay in the arrival and dispersion of the bolus of contrast agent are not accounted for. These MRI techniques were applied to paediatric patients to identify acute ischaemic events, as well as to differentiate between multiple acute events, or between acute and chronic events. Furthermore, the diffusion and perfusion findings were shown to contribute significantly to the management of patients with high risk of stroke, and in the evaluation of treatment outcome. In the animal experiments, permanent middle cerebral artery occlusion was performed in rats to investigate longitudinally the acute MRI changes (first 4-6 hours) following an ischaemic event. This longitudinal analysis contributed to the understanding of the evolution of the ischaemic lesion. Furthermore, the findings allowed the acute identification of tissue 'at risk' of infarction