Diffusion tensor imaging and arterial tissue: establishing the influence of arterial tissue microstructure on fractional anisotropy, mean diffusivity and tractography

This study investigates diffusion tensor imaging (DTI) for providing microstructural insight into changes in arterial tissue by exploring how cell, collagen and elastin content effect fractional anisotropy (FA), mean diffusivity (MD) and tractography. Five ex vivo porcine carotid artery models (n = 6 each) were compared-native, fixed native, collagen degraded, elastin degraded and decellularised. Vessels were imaged at 7 T using a DTI protocol with b = 0 and 800 s/mm2 and 10 isotopically distributed directions. FA and MD were evaluated in the vessel media and compared across models. FA values measured in native (p < 0.0001), fixed native (p < 0.0001) and collagen degraded (p = 0.0018, p = 0.0016, respectively) were significantly higher than those in elastin degraded and decellularised arteries. Native and fixed native had significantly lower MD values than elastin degraded (p < 0.0001) and decellularised tissue (p = 0.0032, p = 0.0003, respectively). Significantly lower MD was measured in collagen degraded compared with the elastin degraded model (p = 0.0001). Tractography yielded helically arranged tracts for native and collagen degraded vessels only. FA, MD and tractography were found to be highly sensitive to changes in the microstructural composition of arterial tissue, specifically pointing to cell, not collagen, content as the dominant source of the measured anisotropy in the vessel wall

Advances in neuroimaging in frontotemporal dementia

Frontotemporal dementia (FTD) is a clinically and neuroanatomically heterogeneous neurodegenerative disorder with multiple underlying genetic and pathological causes. Whilst initial neuroimaging studies highlighted the presence of frontal and temporal lobe atrophy or hypometabolism as the unifying feature in patients with FTD, more detailed studies have revealed diverse patterns across individuals, with variable frontal or temporal predominance, differing degrees of asymmetry, and the involvement of other cortical areas including the insula and cingulate, as well as subcortical structures such as the basal ganglia and thalamus. Recent advances in novel imaging modalities including diffusion tensor imaging, resting-state functional magnetic resonance imaging and molecular positron emission tomography imaging allow the possibility of investigating alterations in structural and functional connectivity and the visualisation of pathological protein deposition. This review will cover the major imaging modalities currently used in research and clinical practice, focusing on the key insights they have provided into FTD, including the onset and evolution of pathological changes and also importantly their utility as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. Validating neuroimaging biomarkers that are able to accomplish these tasks will be crucial for the ultimate goal of powering upcoming clinical trials by correctly stratifying patient enrolment and providing sensitive markers for evaluating the effects and efficacy of disease-modifying therapies

Diffusion and Perfusion MRI in Paediatric Posterior Fossa Tumours

Brain tumours in children frequently occur in the posterior fossa. Most undergo surgical resection, after which up to 25% develop cerebellar mutism syndrome (CMS), characterised by mutism, emotional lability and cerebellar motor signs; these typically improve over several months. This thesis examines the application of diffusion (dMRI) and arterial spin labelling (ASL) perfusion MRI in children with posterior fossa tumours. dMRI enables non-invasive in vivo investigation of brain microstructure and connectivity by a computational process known as tractography. The results of a unique survey of British neurosurgeons’ attitudes towards tractography are presented, demonstrating its widespread adoption and numerous limitations. State-of-the-art modelling of dMRI data combined with tractography is used to probe the anatomy of cerebellofrontal tracts in healthy children, revealing the first evidence of a topographic organization of projections to the frontal cortex at the superior cerebellar peduncle. Retrospective review of a large institutional series shows that CMS remains the most common complication of posterior fossa tumour resection, and that surgical approach does not influence surgical morbidity in this cohort. A prospective case-control study of children with posterior fossa tumours treated at Great Ormond Street Hospital is reported, in which children underwent longitudinal MR imaging at three timepoints. A region-of-interest based approach did not reveal any differences in dMRI metrics with respect to CMS status. However, the candidate also conducted an analysis of a separate retrospective cohort of medulloblastoma patients at Stanford University using an automated tractography pipeline. This demonstrated, in unprecedented spatiotemporal detail, a fine-grained evolution of changes in cerebellar white matter tracts in children with CMS. ASL studies in the prospective cohort showed that following tumour resection, increases in cortical cerebral blood flow were seen alongside reductions in blood arrival time, and these effects were modulated by clinical features of hydrocephalus and CMS. The results contained in this thesis are discussed in the context of the current understanding of CMS, and the novel anatomical insights presented provide a foundation for future research into the condition

Review of Journal of Cardiovascular Magnetic Resonance 2014

There were 102 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2014, which is a 6 % decrease on the 109 articles published in 2013. The quality of the submissions continues to increase. The 2013 JCMR Impact Factor (which is published in June 2014) fell to 4.72 from 5.11 for 2012 (as published in June 2013). The 2013 impact factor means that the JCMR papers that were published in 2011 and 2012 were cited on average 4.72 times in 2013. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal’s impact over the last 5 years has been impressive. Our acceptance rate is <25 % and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication

SHEEP AS ANIMAL MODEL IN MINIMALLY INVASIVE NEUROSURGERY IN EDEN2020

Glioblastomas (GBMs) is a malignant type of central nervous system tumours and its presentation is almost 80% of all malignant primary brain neoplasia. This kind of tumour is highly invasive infiltrating the white matter area and is confined to the central nervous with a very poor patient outcome survival around 10 months. Of the existing treatment approaches, Convection Enhanced drug Delivery (CED) offers several advantages for the patient but still suffers from significant shortcomings. Enhanced Delivery Ecosystem for Neurosurgery in 2020 (EDEN2020) is a European project supported with a new catheter development as the key project point in an integrated technology platform for minimally invasive neurosurgery. Due to the particular anatomy and size, sheep (Ovis aries) have been selected as experimental large animal model and a new Head Frame system MRI/CT compatible has been made and validated ad hoc for the project. In order to understand experimentally the best target point for the catheter introduction a sheep brain DTI atlas has been created. Corticospinal tract (CST), corpus callosum (CC), fornix (FX), visual pathway (VP) and occipitofrontal fascicle (OF), have been identified bilaterally for all the animals. Three of these white matter tracts, the corpus callosum, the fornix and the corona radiata, have been selected to understand the drugs diffusion properties and create a computational model of diffusivity inside the white matter substance. The analysis have been conducted via Focused Ion Beam using scanning Electron Microscopy combined with focused ion beam milling and a 2D analysis and 3D reconstruction made. The results showed homogeneous myelination via detection of ~40% content of lipids in all the different fibre tracts and the fibrous organisation of the tissue described as composite material presenting elliptical tubular fibres with an average cross-sectional area of circa 0.52\u3bcm2 and an estimated mean diameter of 1.15\u3bcm. Finally, as the project is currently ongoing, we provided an overview on the future experimental steps focalised on the brain tissue damage after the rigid catheter introduction

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response

MECHANICAL CHARACTERIZATION OF PORCINE AORTA USING MAGNETIC RESONANCE IMAGING

Determination of aortic mechanical properties in a non-invasive way would be an important step in predicting the onset and development of one of the most fatal degenerative cardiovascular diseases: abdominal aortic aneurysm(AAA). The approach presented in this work to achieve this goal couples Magnetic Resonance Imaging (MRI) with Finite Element (FE) analysis to define a model of aortic mechanical behaviour. In particular, the aortic fibrous structure was analysed using Diffusion Tensor MRI, the results of which showed that fibres could be tracked in the aortic tissue, and that their angles measured ( 15◦) are in accordance with the angles reported in literature. DTI was also applied to a frozen aorta, where the structural parameters obtained were different from those for fresh tissue thus indicating the potential of DTI to measure damage in aortic tissue. MRI was also used for characterization of aortic tissue deformation, using Phase Contrast MRI (PC MRI). With this technique circumferential strains were measured in an aorta, which on average ranged between 0.95-4.7%, in accordance with the range found in vivo from literature. A mechanical constitutive model was implemented, initially based on the structural information from DTI and uniaxial test data, in a finite element (FE) model. Strains estimated in the model under applied physiological pressure were compared with the strains measured using PC MRI. Material parameters of the constitutive model were changed iteratively until the strains matched, thus obtaining the material constants necessary to characterize the behaviour of the aorta non-invasively. This thesis clearly demonstrates the feasibility of a novel approach to mechanical characterization of aortas, based on the use of innovative MRI techniques. Moreover, the application of DTI to both fresh and frozen tissue, which clearly identified differences in the tissues at the fibre level, demonstrates the potential of DTI as a diagnostic tool for degenerative arterial diseases such as AAAs

Image-based predictive modelling frameworks for personalised drug delivery in cancer therapy

Peer reviewe

Cervical weakness and preterm birth: The structure and function of the internal cervical os

The cervix is integral to the maintenance of pregnancy and timely delivery of the baby. Mechanical failure of the cervix resulting in spontaneous preterm birth presents with collapse of the internal os, yet little is known about why the cervix behaves in this way. This may in part be due to research being technically limited and/or limited to punch biopsies of the distal cervix that did not include tissue from the internal os. The aim of this thesis was to re-evaluate cervical anatomy using novel laboratory and imaging methods to gain further insight into the structure of the cervix and how this may influence function during pregnancy. To achieve this, whole cervical samples were obtained from women undergoing hysterectomy for benign pathology. Uterine tissue was subsequently fixed and analysed using 2D and 3D histological methods. Cervical anatomy was characterised using markers for smooth muscle and collagen and analysed using computer-assisted quantification methods. Sequential tissue slices were then reconstructed to produce 3D models of the proximal, middle and distal cervix. High-resolution diffusion-tensor imaging was used to determine whether complex cervical anatomy could be visualised using radiological methods. Tissue was assessed using quantitative and qualitative diffusion methods, and directly compared to immunohistochemically stained tissue. The results obtained demonstrated that diffusion-tensor imaging accurately assessed cervical anatomy and provided further detail in terms of fibre volume, density and organisation. Ex vivo endoscopic ultrasound was used to assess whether current, established medical imaging technology could discern cervical smooth muscle and collagen fibres. Although this method could be used to identify gross anatomical structures, it was not an appropriate method to identify cervical microanatomy. The results described in this thesis provide further insight into how the cervix resists intrauterine forces throughout pregnancy, and then dilates and effaces to allow for delivery of a fetus. Diffusion-tensor imaging accurately assessed cervical anatomy, which may have implications for in vivo characterisation of cervical remodelling during pregnancy and identifying those at risk of delivering early. Finally, observations in this thesis encourage continued re-examination of the cervix using high-resolution imaging to provide insight into function and to develop strategies to discern cervical insufficiency from other known causes of preterm birth