published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

Background: An association between cartilaginous endplate (CEP) defects and intervertebral disc (IVD) degeneration has been previously suggested in animal and cadaveric studies. CEP defects may also be involved in Schmorl’s nodes (SN). There have been no previous reports in the literature that describe the use of ultrashort time-to-echo (UTE) MRI to assess the CEP in humans in vivo. In chapter 5 of this thesis, a retrospective study of paediatric spines and the neurocentral synchondrosis (NCS) was singled out to report the incidence of NCS and to raise the hypothesis of NCS as a precursor of SN. Purpose: To assess the feasibility of detecting CEP defects in live humans using UTE MRI, and to assess their relationship with IVD degeneration and SN. Subjects and Methods: A total number of 22 subjects underwent T2-weighted (T2W) and UTE MRI to assess for the presence and severity of IVD degeneration, the presence of SN and for the presence of CEP defects. SN and IVD degeneration were confirmed by assessing T2W images and IVD degeneration was graded according to the Schneiderman classification. CEP defects were defined as discontinuity of high signal over 4 consecutive images and were independently assessed by two raters. Results: Analyses of CEP defects between IVD degeneration and SN were performed separately. For the study of CEP defects and IVD degeneration, subjects with SN were excluded. 37 out of 108 (34.3%) CEPs had defects, which mainly occurred at T12/L1, L1/L2 and L4/L5 (p=0.008). Inter-rater reliability was substantial (Kappa statistic= 0.67, p<0.001). Multivariate logistic regression revealed that lower BMI (p=0.009) and younger (p=0.034) individuals had a decreased likelihood of having CEP defects. A statistically significant association was found to exist between the presence of cartilaginous endplate defects and intervertebral disc degeneration (p=0.036). Degenerated discs with CEP defects were found in L4/5 and L5/S1, while degenerated discs with no CEP defects were found throughout the whole lumbar region. Mean degeneration scores of L4/5 and L5/S1 levels with CEP defects were higher than that of L4/5 and L5/S1 levels without. For the study of CEP defects and SN, with all 22 subjects assessed, 125 out of 264 (47.3%) CEPs had defects. 40 SN were found, and among those, 35 SN had CEP defects (87.5%). 125 CEPs had the presence of CEP defects; among them, a large number of CEP defects did not have SN underneath (92 out of 125, 73.2%). Conclusion: The studies demonstrate the feasibility of using UTE MRI in live humans to assess the integrity of the CEP. Longitudinal studies may reveal the diagnosis of CEP defects to be clinically beneficial for assessment of IVD degeneration and SN. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

In this work, novel Gd(III) complexes endowed with non-steroidal anti-inflammatory drugs (NSAIDs) were synthesised and their targeting properties towards sites of inflammation were studied in U87 xenograft and rheumatoid arthritis animal models. The Tb(III) analogues were also synthesised and their photophysical properties were studied. Six new Gd(III) DO3A-amide complexes bearing different linkers, ethylenediamine (GdL1), hexamethylenediamine (GdL2), 2,2’-oxydiethylamine (GdL3), 4,7,10-trioxa-1,13-tridecanediamine (GdL4), trans-1,4-cyclohexanediamine (GdL5), and 1,4-phenylenediamine (GdL6) were incorporated to mefenamic acid (MA) moiety, a common NSAID. The syntheses, relaxometric properties by NMR techniques, hydration number determinations by luminescence lifetime measurements, lipophilicities by UV-Vis spectrometry, serum albumin binding properties by tryptophan emission-quenching experiments, cytotoxicities by MTT assay, cellular uptake properties; MRI scans on U87 sxenograft and rheumatoid arthritis animal models, and biodistributions of these new complexes were discussed. GdL1-L6 possess one bound water molecule and GdL2-L5 show higher relaxivities than Gd-DOTA (4.21 mM?1s?1, 300 MHz, 25oC), a clinically used MRI contrast agent (CA). The relaxivities at 300 and 400 MHz respectively at 25oC are in the descending order of GdL4 (5.70 and 4.87 mM?1?1) > GdL3 (4.94 and 4.07 mM?1s?1) > GdL2 (4.60 and 4.07 mM?1s?1) > GdL5 (4.41 and 4.12 mM?1s?1) > GdL6 (3.98 and 3.31 mM?1s?1) > GdL1 (3.96 and 3.56 mM?1s?1). GdL1-L5 show low cytotoxicities towards HeLa cells at 1000 μM. The MRI scans of GdL1-L6 on U87 xenograft show strong intensity boost immediately after administration. The intensity enhancements persist for more than 90 mins and complete clearances are found after 24 h post-administration. Their MRI scans on arthritis model also show prolonged retention. It is concluded that the retention is related to the targeting on inflammatory mediators of the complexes. All complexes show superior retention and intensity enhancements in kidney, liver, tumour and arthritis joint than Gd-DOTA. GdL1-L6 are therefore potential candidates as universal MRI CAs. Three new Gd(III) DO3A-amide complexes bearing respectively benzoic acid (GdL7), salicylic acid (GdL8), and methylated salicylic acid (GdL9), one known Gd(III) DTPA-bissalicylic acid (GdL10) complex and one new Gd(III) DTPA-bismethylated salicylic acid (GdL11) were synthesised and investigated. Their syntheses, relaxivities, hydration numbers, pH dependent photophysical properties, cytotoxicities, cellular uptake properties and MRI scans on arthritis rat model were discussed. All GaL7-L11 possess one bound water molecule and show lower relaxivities than Gd-DOTA. The relaxivities at 300 MHz at 25oC are in the descending order of GdL10 (3.64 mM?1s?1) > GdL9 (3.53 mM?1s?1) > GdL11 (2.69 mM?1s?1) > GdL8 (2.10 mM?1s?1) > GdL7 (1.99 mM?1s?1). Their Tb(III) analogue (TbL7-L11) show pH dependent UV-Vis and photoluminescence spectra which are consequences of protonation or deprotonation of the carboxylic acid, hydroxyl and amide groups. It is concluded that the pH change alters energy transfer efficiency and the ligand triplet energy level. GdL7-L11 show low cytotoxicities in MTT assay. Specifically, GdL8 is examined on arthritis rat model to give a comparable intensity at the arthritis joint to Gd-DOTA but having a longer retention time. LnL8 has therefore demonstrated its potential as both a MRI CA to target inflammation sites and a pH dependent luminescence probe. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Functional MRI or Functional Magnetic Resonance Imaging (fMRI) is a type of specialized MRI scan which measures the hemodynamic response related to neural activity in the brain or spinal cord of humans and animals. Due to its relatively low invasiveness, absence of radiation exposure, and relatively wide availability, functional MRI has come to dominate the brain mapping field since the early 1990s. The objective of this thesis work is to develop and apply functional MRI methods at 7 Tesla, for in vivo investigation of rodent visual and auditory system. Firstly, the development of the rat visual pathway was studied by blood oxygenation level–dependent (BOLD) contrast from the time of eyelid opening (P14) to adulthood (P60) in normal rat brain. By studying BOLD-fMRI measurements in the normal brain superior colliculus (SC), we determined that the regional BOLD response undergoes a systematic increase in amplitude especially over the third postnatal week. Secondly, the potential for plasticity of the rodent superior colliculus (SC) was studied using BOLD fMRI. By studying BOLD-fMRI measurements in the SC of three groups of rats (normal, HI-injured with left SC partially damaged and HI-injured with left SC completely damaged), we can evaluate the extent of plastic changes, compensatory and transneuronal plasticity after varying degrees of SC injury. We also applied BOLD-fMRI using very short repetition time (TR) of 0.2s on rats to measure the difference in response temporal dynamics between the SC and LGN, which has not been measured conclusively or with high temporal resolution. The primary finding in this study is that there is an approximately 0.8s difference between the BOLD responses of the rat contralateral SC and LGN to the visual stimuli. In addition, the amplitude of the SC response is larger than that of the LGN. Thirdly, BOLD-fMRI is used to measure the SC hemodynamic responses, in normal adult Sprague-Dawley (SD) rats, during a dynamic visual stimulus similar to those used in long-range apparent motion studies. The stimulation paradigm mimic effective speeds of motion between 7 and 164?/s, the results suggest that the SC is sensitive to slow moving visual stimuli but the hemodynamic response is reduced at higher speeds. Finally, BOLD-fMRI is used to study hemodynamic response temporal dynamics in the superior colliculus (SC) and inferior colliculus (IC) following visual and auditory associated stimulation. Our results show the baselines of SC BOLD signal (in two sides) increase during the ON period of auditory stimulation, which demonstrate that auditory stimulation can increase ROI activation signal intensity in superior colliculus (SC). The previous dominant theory is that individual senses each have separate areas of the brain dedicated to processing each sense, while the individual sense perceptions are integrated together to produce a multi-sensory experience. As a result of new research over the past several years, however, this view has been challenged by studies showing that processing in the visual area of the brain can be directly influenced by hearing and touch. All these discoveries represent a new view of how the brain is actually organized. / published_or_final_version / Electrical and Electronic Engineering / Master / Master of Philosophy

Underling neuronal loss and subsequent hippocampal sclerosis, as reflected by hippocampal atrophy on structural magnetic resonance (MR) imaging, are the dominant findings in the patient with mesial temporal lobe epilepsy (MTLE). Yet, prolongation of T2 relaxation time has also been reported as an early marker for MTLE, but it is a rather insensitive marker. Typical age-related atrophy often constitutes a significant confounding factor, and atrophy often represents a late sign in hippocampal sclerosis. In this connection, there is an urge for a sensitive independent predictor for the early detection of MTLE. T1rho MR imaging provides a distinct contrast mechanism in tissue characteristics. It is sensitive to physio-chemical processes and has been tested successfully in Alzheimer’s disease, Parkinson’s disease and certain brain tumors. Therefore, it is possible to depict early biochemical change in patients with MTLE by means of measuring the changes in T1rho relaxation time. T1rho relaxation time is not affected by age-related atrophic changes and thus can be used as an independent marker. In this preliminary study, we aimed to assess the feasibility of T2 relaxometry and T1rho MR imaging in identification of the atrophied zones in patients with MTLE. Seven patients with unilateral MTLE and fourteen normal subjects were recruited. Three-dimensional T1-weighted imaging, axial T2 relaxometry and T1rho imaging were performed on a 3T MR scanner. Hippocampal head, hippocampal body, hippocampal tail and amygdala were contoured on the axial T2-weighted images and then co-registered onto T2 relaxometry and T1rho images. A combination of visual and quantitative volumetric assessment was used as the primary end outcome. For T2 relaxometry and T1rho imaging, their respective relaxation times together with the corresponding right-left asymmetric ratios were calculated for subsequent analysis. Abnormal right-left asymmetric ratio is defined as a deviation of 2SD from the mean of the Z-score. In the lateralizing epileptogenic zones, T1rho yielded an overall accuracy of 92.9% (sensitivity 100%, specificity 60%), while T2 relaxometry yielded an overall accuracy of 71.4% (sensitivity 65.2%, specificity 100%) only. T1rho imaging is thus superior to T2 relaxometry (P = 0.036, by chi-square test). To conclude, the present study indicated that T1rho is feasible and potentially useful to serve as a non-invasive imaging tool in the detection of lateralization of the epileptogenic zone in patients with MTLE. It can also facilitate prompt diagnosis and longitudinal disease monitoring. In addition, the generation of associated color-coded parametric map can provide an easy mean for direct visual analysis. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Development of non-invasive imaging biomarkers sensitive to microstructural organization is crucial for deepening our understanding of mechanisms underlying neurodegenerative processes such as aging and further improving early diagnosis and monitoring of neurodegenerative disease such as Alzheimer’s disease (AD) and amnestic mild cognitive impairment (MCI). The diffusional kurtosis imaging (DKI) is an extension of conventional diffusion tensor imaging. It is hypothesized that DKI will provide complementary information to conventional diffusivity metrics in a new dimension that will more comprehensively capture microstructural changes in anisotropic white matter tracts and particularly in relatively isotropic tissues such as gray matter during neurodegenerative processing of aging, MCI and AD and probably improve the early diagnosis of the diseases. Firstly, DKI method and a white-matter model that provided metrics of explicit neurobiological interpretations were applied on healthy participants. In white matter tracts, age-related degenerations appeared to be broadly driven by axonal loss. Demyelination may also be a major driving mechanism, although confined to the anterior brain. In terms of deep gray matter, higher mean kurtosis (MK) and fractional anisotropy (FA) in the globus pallidus, substantia nigra, and red nucleus reflected higher microstructural complexity and directionality compared with the putamen, caudate nucleus, and thalamus. In particular, unique age-related positive correlations for FA, MK, and radial kurtosis (KR) in the putamen opposite to those in other regions were observed. Secondly, to verify the speculation that iron deposition could be one probable underlying mechanism driving changes in microstructure, another advance MRI technique of quantitative susceptibility mapping (QSM) was also used in healthy participants. Significant age-related increases of iron were observed in the putamen, red nucleus, substantia nigra, and caudate nucleus. Putamen exhibited the highest rate of iron accumulation with aging, which was nearly twice of the rates in substantia nigra and caudate nucleus. Significant positive correlations between susceptibility value and diffusion measurements were observed for FA and MK in the putamen as well as FA in the red nucleus. Thirdly, whether DKI metrics could serve as imaging biomarkers to indicate the severity of cognitive deficiency for AD and MCI was investigated. In AD, significantly increased diffusivity and decreased kurtosis parameters were observed in both white and gray matter of the parietal and occipital lobes as compared to MCI. Significantly decreased FA was also observed in the white matter of these lobes in AD. With the exception of FA and KR, all the other five DKI metrics exhibited significant correlations with mini-mental state examination score in both white and gray matter. Lastly, DKI metrics were compared against volumetry for diagnosis of AD and MCI. In AD vs. aMCI, although no significant difference of either FA or MD was observed in white matter tracts, it is encouraging to note that MK captured loss of microstructural complexity in the superior longitudinal fasciculus and internal capsule. MK in the putamen showed the highest power that outperformed volume of the hippocampus for discriminating AD from normal. Besides, FA in the putamen showed the second highest power for discriminating aMCI from normal. / published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

Not available / text

Not available / text

Background: Qualitative magnetic resonance imaging methods, such as T2-weighted (T2W) imaging, are commonly used for cardiac tissue characterisation. However, these are sensitive to image artefact, and results are unreliable. Modified Look-Locker inversion recovery (MOLLI) provides robust, quantitative T1 imaging in the myocardium, but it is subject to limitations: its T1 measurement accuracy is dependent on heart rate, it exhibits banding artefacts, and a lengthy breath hold is required. In this thesis, some MOLLI variants were developed with the aim of mitigating these problems. Furthermore, MOLLI was applied to two different patient groups for comparison with a typical T2W method. Methods: MOLLI variants used alternative k-space trajectories, gradient-echo readouts, startup preparations, and sampling schemes, and were tested in silico, in vitro and in vivo—in healthy volunteers. In patients, conventional MOLLI was compared to T2W spectral attenuated inversion recovery (SPAIR) for oedema detection in both acute ST-segment elevation myocardial infarction (STEMI), and Takotsubo cardiomyopathy (TCM). RESULTS: Simulation, phantom and volunteer data showed that a linear sweep up (skipped pulse pair) startup preparation enables improved T1 measurements. A MOLLI variant with a reduced sampling scheme performed similarly to conventional MOLLI, allowing for shorter breath holds. Different k-space trajectories did not significantly affect T1 measurement accuracy, but precision varied: possibly due to artefacts. For oedema identification, MOLLI performed significantly better than T2W-SPAIR in STEMI patients, and the two were comparable in TCM patients. In all patients, remote myocardium showed an elevated T1 relative to healthy volunteers, suggesting remote inflammation. Conclusions: It was shown that MOLLI T1 mapping can delineate oedema in acute STEMI and TCM patients, producing measurements that are more robust and reproducible than those made with T2W SPAIR. A number of improvements were suggested in this work, but there is still substantial scope for developing the MOLLI T1 mapping pulse sequence.

This thesis describes the development of magnetic resonance imaging (MRI) techniques to visualise neurofibrillary tau pathology in transgenic mice. Neurofibrillary pathology is a prominent pathological feature of Alzheimer's disease (AD) and is closely correlated to cognitive impairment and dementia. 19F and 1H MRI methods were developed with a 4.7 T preclinical system. To facilitate these experiments, RF saddle coils were designed and constructed that show good agreement with theoretical SNR calculations and produce uniform B1 fields. A copper wire surface coil, incorporating active decoupling electronics, was built to increase the sensitivity of 19F and 1H mouse brain experiments. A stripline transmission line resonator (TLR) was also developed as a surface coil receiver and because it does not need tuning and matching adjustments, it reduces experimental set up times significantly. An ultra-short echo time (UTE) pulse sequence was developed for imaging 19F compounds, designed to attach to sites of tau pathology in the brain and which were known to exhibit very short T2 relaxation times. Ex vivo, 19F MRI experiments using these compounds indicated low penetration of the blood brain barrier and a tendency for precipitation. An RF spoiled, short TE 3D gradient echo pulse sequence was optimised to produce artefact-free T1-weighted images of the mouse brain. Measurements from a preliminary study using high resolution, T1-weighted MRI showed that the ventricular areas of a control mouse were not appreciably different from those of a transgenic mouse. Software was developed to generate automated T2 brain maps from spin echo MRI data sets and was used to compare T2 relaxation times between a control and a transgenic mouse. This experiment showed that the T2 relaxation times of the tau transgenic mouse brain were prolonged when compared to those of a control mouse.