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

Improved quantification of perfusion in patients with cerebrovascular disease.

In recent years measurements of cerebral perfusion using bolus-tracking MRI have become common clinical practice in the diagnosis and management of patients with stroke and cerebrovascular disease. An active area of research is the development of methods to identify brain tissue that is at risk of irreversible damage, but amenable to salvage using reperfusion treatments, such as thrombolysis. However, the specificity and sensitivity of these methods are limited by the inaccuracies in the perfusion data. Accurate measurements of perfusion are difficult to obtain, especially in patients with cerebrovascular diseases. In particular, if the bolus of MR contrast is delayed and/or dispersed due to cerebral arterial abnormalities, perfusion is likely to be underestimated using the standard analysis techniques. The potential for such underestimation is often overlooked when using the perfusion maps to assess stroke patients. Since thrombolysis can increase the risk of haemorrhage, a misidentification of 'at-risk' tissue has potentially dangerous clinical implications. This thesis presents several methodologies which aim to improve the accuracy and interpretation of the analysed bolus-tracking data. Two novel data analysis techniques are proposed, which enable the identification of brain regions where delay and dispersion of the bolus are likely to bias the perfusion measurements. In this way true hypoperfusion can be distinguished from erroneously low perfusion estimates. The size of the perfusion measurement errors are investigated in vivo, and a parameterised characterisation of the bolus delay and dispersion is obtained. Such information is valuable for the interpretation of in vivo data, and for further investigation into the effects of abnormal vasculature on perfusion estimates. Finally, methodology is presented to minimise the perfusion measurement errors prevalent in patients with cerebrovascular diseases. The in vivo application of this method highlights the dangers of interpreting perfusion values independently of the bolus delay and dispersion

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

Measurement of vascular water transport in human subjects using time-resolved pulsed arterial spin labelling.

Most approaches to arterial spin labelling (ASL) data analysis aim to provide a quantitative measure of the cerebral blood flow (CBF). This study, however, focuses on the measurement of the transfer time of blood water through the capillaries to the parenchyma (referred to as the capillary transfer time, CTT) as an alternative parameter to characterise the haemodynamics of the system. The method employed is based on a non-compartmental model, and no measurements need to be added to a common time-resolved ASL experiment. Brownian motion of labelled spins in a potential was described by a one-dimensional general Langevin equation as the starting point, and as a Fokker-Planck differential equation for the averaged distribution of labelled spins at the end point, which takes into account the effects of flow and dispersion of labelled water by the pseudorandom nature of the microvasculature and the transcapillary permeability. Multi-inversion time (multi-TI) ASL data were acquired in 14 healthy subjects on two occasions in a test-retest design, using a pulsed ASL sequence and three-dimensional gradient and spin echo (3D-GRASE) readout. Based on an error analysis to predict the size of a region of interest (ROI) required to obtain reasonably precise parameter estimates, data were analysed in two relatively large ROIs, i.e. the occipital lobe (OC) and the insular cortex (IC). The average values of CTT in OC were 260 ± 60 ms in the first experiment and 270 ± 60 ms in the second experiment. The corresponding IC values were 460 ± 130 ms and 420 ± 139 ms, respectively. Information related to the water transfer time may be important for diagnostics and follow-up of cerebral conditions or diseases characterised by a disrupted blood-brain barrier or disturbed capillary blood flow. Copyright © 2015 John Wiley & Sons, Ltd

Arterial cerebral blood volume–weighted functional MRI using pseudocontinuous arterial spin tagging (AVAST)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110725/1/mrm25220.pd

Arterial spin labelling MRI for assessment of cerebral perfusion in children with moyamoya disease: comparison with dynamic susceptibility contrast MRI

Introduction: This study seeks to evaluate the diagnostic accuracy of cerebral perfusion imaging with arterial spin labelling (ASL) MR imaging in children with moyamoya disease compared to dynamic susceptibility contrast (DSC) imaging. Methods: Ten children (7 females; age, 9.2 ± 5.4years) with moyamoya disease underwent cerebral perfusion imaging with ASL and DSC on a 3-T MRI scanner in the same session. Cerebral perfusion images were acquired with ASL (pulsed continuous 3D ASL sequence, 32 axial slices, TR = 5.5s, TE = 25ms, FOV = 24cm, matrix = 128 × 128) and DSC (gradient echo EPI sequence, 35 volumes of 28 axial slices, TR = 2,000ms, TE = 36ms, FOV = 24cm, matrix = 96 × 96, 0.2ml/kg Gd-DOTA). Cerebral blood flow maps were generated. ASL and DSC images were qualitatively assessed regarding perfusion of left and right ACA, MCA, and PCA territories by two independent readers using a 3-point-Likert scale and quantitative relative cerebral blood flow (rCBF) was calculated. Correlation between ASL and DSC for qualitative and quantitative assessment and the accuracy of ASL for the detection of reduced perfusion per territory with DSC serving as the standard of reference were calculated. Results: With a good interreader agreement (κ = 0.62) qualitative perfusion assessment with ASL and DSC showed a strong and significant correlation (ρ = 0.77; p < 0.001), as did quantitative rCBF (r = 0.79; p < 0.001). ASL showed a sensitivity, specificity and accuracy of 94%, 93%, and 93% for the detection of reduced perfusion per territory. Conclusion: In children with moyamoya disease, unenhanced ASL enables the detection of reduced perfusion per vascular territory with a good accuracy compared to contrast-enhanced DS

Functional brain perfusion evaluation with Arterial Spin Labeling at 3 Tesla

Dissertation submitted in Faculdade de Ciências e Tecnologia of Universidade Nova de Lisboa for the degree of Master of Biomedical EngineeringBackground: The new clinically available arterial spin labelling (ASL) sequences present some advantages relatively to the commonly used blood oxygenation level dependent (BOLD) method for functional brain studies using magnetic resonance imaging (MRI), namely the fact of being potentially quantitative and more reproducible. Purpose: The main aim of this work was to evaluate the functional use of a commercial ASL sequence implemented on a 3 Tesla MRI system (Siemens, Verio) in the Imaging Department of Hospital da Luz. The first aim was to obtain a functional validation of this technique by comparison with the BOLD contrast, using a number of different approaches. The second aim was to accomplish perfusion quantification, by resolving some important quantification issues. Materials and Methods: Fifteen adult volunteers participated in a single functional imaging session using three different protocols: one using BOLD and two using ASL. The subjects performed a motor finger tapping task and the data analysis was performed using Siemens Neuro3D and FSL (FMRIB’s Software Library). The location and variability of the activated areas were analysed in MNI (Montereal Neurological Institute) standard space. Results: Topographic agreement between the activated regions obtained by BOLD and ASL was found. However, the results show that inter-subject variability and distance to the hand motor cortex were smaller when measured with ASL as compared with BOLD fMRI. Quantitative studies revealed that ASL allows the calculation of cerebral blood flow (CBF), both at baseline and upon functional activation. Conclusion: The results suggest that the functional imaging protocols using ASL produce comparable results to a conventional BOLD protocol, with the additional advantages of reduced inter-subject variability, better spatial specificity and quantification possibilities

Supporting measurements or more averages? How to quantify cerebral blood flow most reliably in 5 minutes by arterial spin labeling

Purpose To determine whether sacrificing part of the scan time of pseudo-continuous arterial spin labeling (PCASL) for measurement of the labeling efficiency and blood T1 is beneficial in terms of CBF quantification reliability. Methods In a simulation framework, 5-minute scan protocols with different scan time divisions between PCASL data acquisition and supporting measurements were evaluated in terms of CBF estimation variability across both noise and ground truth parameter realizations taken from the general population distribution. The entire simulation experiment was repeated for a single-post-labeling delay (PLD), multi-PLD, and free-lunch time-encoded (te-FL) PCASL acquisition strategy. Furthermore, a real data study was designed for preliminary validation. Results For the considered population statistics, measuring the labeling efficiency and the blood T1 proved beneficial in terms of CBF estimation variability for any distribution of the 5-minute scan time compared to only acquiring ASL data. Compared to single-PLD PCASL without support measurements as recommended in the consensus statement, a 26%, 33%, and 42% reduction in relative CBF estimation variability was found for optimal combinations of supporting measurements with single-PLD, free-lunch, and multi-PLD PCASL data acquisition, respectively. The benefit of taking the individual variation of blood T1 into account was also demonstrated in the real data experiment. Conclusions Spending time to measure the labeling efficiency and the blood T1 instead of acquiring more averages of the PCASL data proves to be advisable for robust CBF quantification in the general population

The Role of Arterial Spin Labelling (ASL) in Classification of Primary Adult Gliomas

Currently, the histological biopsy is the gold standard for classifying gliomas using the most recent histomolecular features. However, this process is both invasive and challenging, mainly when the lesion is in eloquent brain regions. Considering the complex interaction between the presence of the isocitrate dehydrogenase (IDH)-mutation, the upregulation of the hypoxia-induced factor (HIF), the neo-angiogenesis and the increased cellularity, perfusion MRI may be used indirectly for gliomas staging and further to predict the presence of key mutations, such as IDH. Recently, several studies have reported the subsidiary role of perfusion MRI in the prediction of gliomas histomolecular class. The three most common perfusion MRI methods are dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labelling (ASL). Both DSC and DCE use exogenous contrast agent (CA) while ASL uses magnetically labelled blood water as an inherently diffusible tracer. ASL has begun to feature more prominently in clinical settings, as this method eliminates the need for CA and facilitates quantification of absolute cerebral blood flow (CBF). As a non-invasive, CA-free test, it can also be performed repeatedly where necessary. This makes it ideal for vulnerable patients, e.g. post-treatment oncological patients, who have reduced tolerance for high rate contrast injections and those suffering from renal insufficiency. This thesis performed a systematic review and critical appraisal of the existing ASL techniques for brain perfusion estimation, followed by a further systematic review and meta-analysis of the published studies, which have quantitatively assessed the diagnostic performance of ASL for grading preoperative adult gliomas. The repeatability of absolute tumour blood flow (aTBF) and relative TBF (rTBF) ASL-derived measurements were estimated to investigate the reliability of these ASL biomarkers in the clinical routine. Finally, utilising the radiomics pipeline analysis, the added diagnostic performance of ASL compared with CA-based MRI perfusion techniques, including DSC and DCE, and diffusion-weighted imaging (DWI) was investigated for glioma class prediction according to the WHO-2016 classification