Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 102-108).

Thesis (Ph. D.)--University of Queensland, 2003. / Includes bibliographical references.

Atherosclerosis is a chronic disease characterized by the formation of plaque in hemodynamically unstable regions of arteries. The disease involves complicated molecular and cellular processes including inflammation, the immune system, low density lipoprotein, cytokines, and many other components. As such, the degree of disease is difficult to determine, and the clinical outcomes that stem from the disease are hard to predict. Current imaging techniques lack specificity for the plaques likely to cause clinical consequences such as heart attack or stroke. Consequently, a new and molecularly selective contrast agent formulation is necessary for accurate imaging of plaque and to aid in the determination of the correct patient-specific treatment. To that end, a stealth biodegradable particle was designed containing a high payload of contrast agent that is targetable to specific states of plaque development. The core material used in creation of the particle was the FDA-approved poly(lactide-co-glycolide) (PLGA), with carboxylic acid termini. The polymer was used in a modified water-in-oil-in-oil double emulsion method to form particles of sizes ranging from approximately 50 nm to 20 [mu]m, of near‐spherical shape, and with smooth surfaces. The PLGA particles were loaded with up to 30% Gd-DTPA, an FDA-approved contrast agent used with magnetic resonance imaging (MRI). As an adjunct, to enable visualization of individual particles in vitro, particles were alternatively loaded with rhodamine 6G, a fluorescent agent. The PLGA particles were surface functionalized with poly(ethylene glycol) (PEG) with a primary amine end group. The acid group of the PLGA and PEG-linked amine were coupled through an amide bond using carbodiimide chemistry. The presence of PEG on the surface of particles was confirmed using electron microscopy, 1H NMR, and zeta potential. The other end of the PEG chain terminated in a carboxylic acid that was subsequently used for coupling to a monoclonal antibody against the cell surface markers of inflammation and atherosclerosis, vascular cell adhesion molecule‐1 (VCAM‐1) and intercellular adhesion molecule-1 (ICAM-1). Particles with conjugated antibodies successfully attached to, entered, and distributed throughout cells in vitro. / text

published_or_final_version / Linguistics / Master / Master of Philosophy

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer ranked as the 5th most common in Hong Kong. We aimed to study the role of dynamic contrast-enhanced MRI (DCE-MRI) and dynamic 2-deoxy-2-[fluorine-18]fluoro -D-glucose positron emission tomography (FDG-PET) for characterizing NPC tumors in newly-diagnosed patients, and to quantitatively evaluate the intratumoral heterogeneity of NPC. In Chapter 2 we employed semi-quantitative analysis of DCE-MRI to study the dynamic enhancement pattern by analyzing the time-intensity curves in 25 NPC patients. Our findings suggested that high blood flow caused a high initial intensity enhancement rate (ER), and that neovasculature due to tumor angiogenesis in tumors of larger volume or higher T-stage caused more accumulation of contrast agent which can be detected by DCE-MRI. PET and semi-quantitative DCE-MRI parameters were not correlated and may reflect different physiological/molecular processes in the microenvironment of NPC tumor. However the major limitation of semi-quantitative analysis was that the physiological correlates of these parameters were unclear. In Chapter 3 we applied quantitative analysis of DCE-MRI to study the permeability and perfusion characteristics in the same cohort as in Chapter 2. Our findings implied that the permeability may be high compared to blood flow in NPC tumor. We also observed significant correlations between iAUC (the initial area under the time-intensity curve) by semi-quantitative analysis and ve (the volume fraction of extravascular extracellular space) by quantitative analysis, and between the two rate constants (kep’s) from these two methods, which showed that semi-quantitative analysis was a feasible alternative in reflecting the physiological characteristics of NPC. However, we did not observe any significant correlation between PET and DCE-MRI quantitative parameters, also suggesting that PET and DCE-MRI reflected different physiological information in NPC. In Chapter 4 we applied dynamic PET scan to study the glucose metabolism in 18 NPC tumors (16 included in DCE-MRI cohort). Our findings showed that the overall FDG uptake was mainly composed of the FDG in tissue compartment (Ki), which was governed by the phosphorylation (k3) but not the transport of FDG (K1). This finding may further indicate a potential role of the phosphorylation rate k3 in NPC. Dynamic PET parameters did not correlate with DCE-MRI, indicating that the two modalities reflect different molecular information in NPC. In Chapter 5, intratumoral heterogeneity in NPC tumors of 40 patients was studied using 18F-FDG PET scan. Our findings showed that as tumors grew to a larger volume and higher T-stage, they showed more heterogeneous glucose metabolism. It was found that more heterogeneous tumor was associated with worse disease-free survival, indicating that tumor metabolic heterogeneity may play an important role for NPC patient prognosis. To summarize, these results showed that DCE-MRI and dynamic PET improved our understanding about the physiological/molecular process of NPC, and, these two modalities reflected different physiological information in the microenvironment of NPC tumors. This indicated that the relationship between supply of nutrients such as glucose and blood flow/permeability is complex and not directly related. Moreover, intratumoral heterogeneity by PET scan was also of importance in prognostication. / published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

Benefiting from higher SNR as well as better spatial, temporal and spectral resolution, magnetic resonance imaging (MRI) at high field has proved to be a valuable neuroimaging modality which provides comprehensive evaluation of the central nervous system non-invasively. The objectives of this doctoral work were to develop MRI methodologies and to assess the functional, metabolic and structural alterations in rodent brains under normal and manipulated conditions. Firstly, to improve the functional sensitivity and spatial precision, a novel functional MRI (fMRI) method using balanced steady state free precession with intravascular susceptibility contrast agent was proposed and its feasibility was evaluated in rat visual system. This new approach was sensitized to cerebral blood volume (CBV) changes. It provided comparable sensitivity to conventional CBVweighted fMRI using echo planar imaging but with no severe image distortion and signal dropout. Robust negative responses during visual stimulation were observed and activation patterns were in excellent agreement with known neuroanatomy. As a promising alternative to conventional CBV-weighted fMRI, it was particularly suited for fMRI investigation of animal models at high field. Secondly, the relationship between anatomical connections and resting-state fMRI connectivity was explored using a well-controlled animal model of corpus callosotomy. Both complete and partial callosotomy resulted in significant loss of interhemispheric connectivity in the cortical areas whose primary interhemispheric connections via corpus callosum (CC) were severed. Partial restoration of interhemispheric connectivity and increased intrahemispheric connectivity were also observed. The experimental findings directly supported that anatomical connections via CC play a primary and indispensable role in resting-state connectivity, and that resting-state networks could be dynamically reorganized or acquired directly or indirectly through the remaining anatomical connections. Thirdly, proton magnetic resonance spectroscopy (1H MRS) was employed to monitor the longitudinal metabolic alterations elicited by exogenous stimulation and endogenous modification, respectively. Significantly lower hippocampal N-acetylaspartate (NAA) was observed in fear conditioning animals, indicating reduced neuronal dysfunction and/or integrity, which contributed to the trauma-related symptoms. Meanwhile, pregnant animals exhibited prominently higher hippocampal NAA level, reflecting the increased density of neurons in this region, which might facilitate supporting behaviors that involving learning and memory. The 1H MRS detection of ongoing neurochemical changes induced by fear conditioning and pregnancy, especially in the hippocampus, can shed light on the mechanisms of learning and memory and the neurochemical underpinnings of behavioral improvement in pregnant animals. Lastly, manganese-enhanced MRI (MEMRI) was employed to investigate the hypoxic-ischemic (HI) injury in the late phase and the neural response to conditioned fear. Significantly higher enhancement in T1-weighted images was found in the peri-lesional region 24 hours after manganese administration and it colocalized with the increase in glial cell density in histological staining, demonstrating the existence of reactive gliosis in the late phase after HI injury. In fear conditioned animals, higher manganese uptake was observed in amygdala, hippocampus, paraventricular nucleus of hypothalamus and cingulate cortex, which were all highly-involved in the process of fear. These findings suggested MEMRI approach were useful in investigation of post-injury cellular events and functional reorganization as well as for in vivo mapping of neuronal activity. / published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

Magnetic Resonance Spectroscopy (MRS) was used to study the relationship between brain regional concentrations of metabolites and normal aging in Chinese. Our goal in this study is to create a database of normal aging and hence enhance further understanding on the degenerative process leading to dementia and related neurodegenerative diseases. Thirty cognitively normal healthy volunteers of age 22-82 years were recruited and the bias on gender effect in data sampling was minimized by recruiting 15 females and 15 males. In the first part of the study, 1H MRS was obtained using single-voxel-spectroscopy (SVS). Offline software java-based version of Magnetic Resonance User Interface (jMRUI) was employed for data analysis. Cerebrospinal fluid was normalized using software voxel based morphormetry (VBM). Brain morphometry data was also analyzed. Brain metabolites choline (Cho), creatine (Cr) and N-acetyl aspartate (NAA) were quantified using internal water as reference. It was found that brain metabolite concentrations of Cr, Cho and NAA increase significantly with age. Gender effect on metabolite concentrations were also discovered, being higher in the female group. For brain morphometry, white matter and grey matter volumes and fractions all reveal a siginificant negative correlation with age, whereas CSF volume and fraction show a significant positive correlation with age. Gender effect was found on grey matter, white matter and intracranial volume, being higher in the male group. In the second part of the study, 31P SVS MRS was performed on the same population of volunteers. jMRUI was also employed for data analysis. Metabolic ratios were obtained. Similar to the 1H MRS study, apart from creating a database in studying normal aging, an additional aim of this 31P MRS study is to correlate with 1H MRS and assist in interpreting the corresponding metabolic activity. Brain metabolite concentrations were found to increase significantly with age. The increase of PCr (phosphocreatine)/Ptot (total phosphorus content) in posterior cingulate suggests lower metabolic activity throughout the course of aging. The strong evidence of PDE (phosphodiester) increase with age in left hippocampus proposes the fact that phospholipid membrane breakdown will be enhanced by aging. In conclusion, MRS can act as a non-invasive tool to study aging at molecular level. Metabolite levels are significant means to investigate the metabolic change in the human brain during the process of aging as the variations in metabolite levels are believed to be footprints of biochemical changes. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Magnetic Resonance Imaging (MRI) is a non-ionizing imaging modality that can provide images with excellent soft tissue contrast at high resolution. In particular, molecular and cellular MRI is a powerful imaging method that could provide a non-invasive way for assessing specific biological processes in vivo in living organisms. The ability to monitor and track biological structures and processes down to molecular and cellular level and the possibility to probe the development, survival, migration, and differentiation of cells in vivo, has opened up new ways for scientists to investigate the fundamental mechanisms of health and diseases. In this dissertation, novel applications of conventional MR contrast agents to study specific biological structures and processes are demonstrated. First, the potential of manganese enhanced MRI (MEMRI) for in vivo tract tracing and assessment of neuroarchitecture was investigated. Manganese was intracortically infused into the visual cortex along the border of the primary and secondary visual cortex and then imaged 8 and 24 hours later. A dynamic migratory path of manganese from the infusion site through the corpus callosum to the contralateral hemisphere was observed. Also, layer specific enhancement on the contralateral cortex and the connection of the visual cortex with other brain structures were shown and the results were consistent with established anatomical data. Secondly, MEMRI was performed to probe in vivo neuronal changes in the rodent brain following 72-hour rapid eye movement sleep deprivation. Significant reduction in manganese uptake was observed in the cortical and hippocampal region in the sleep deprived animals when compared to the normal group. In particular, the dentate gyrus substructure in the hippocampus exhibited the least uptake. This indicated the functional vulnerability of the hippocampus and the cortex to sleep deprivation. Lastly, in vivo tracking of endogenous neural stem and progenitor cell migration during neurogenesis in neonatal rat brain was performed by micron sized iron oxide particles (MPIO) labeling. Susceptibility weighted imaging was used for image processing to highlight the susceptibility contrast induced by the iron oxide particles. MPIO-labeled cells induced contrast was clearly enhanced in the susceptibility weighted images, particularly at day 3 after MPIO injection in which the MPIO-labeled NPCs became more dispersed in the olfactory bulb. The ventral migratory pathway of endogenous neural stem and progenitor cells, which could not be easily observed in conventional T2*W imaging, couldalsobe detected. Overall, various biological systems and processes have been successfully interrogated using MR contrast agents. Through these studies, the versatility and power of molecular and cellular MRI have been demonstrated. Looking ahead, the rapid development and combination of different molecular and cellular imaging techniques would certainly revolutionize the way we study health and diseases. In the end, this could foster our understanding of basic life sciences and hence improve the quality of healthcare. / published_or_final_version / Electrical and Electronic Engineering / Master / Master of Philosophy

Introduction Peritoneal metastasis is advanced disease and is usually widely disseminated at the time of discovery. It is crucial to detect peritoneal metastasis at an early stage and to allow precise patient selection for the right treatments. Both fluorodeoxyglucose positron emission tomography/computed tomography (FDGPET/CT) and magnetic resonance imaging (MRI) are used in peritoneal metastasis detection. Standardized uptake value (SUV), derived from FDGPET/ CT can evaluate glucose metabolism in cells, whilst apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI) is used for quantitative analysis of tumour cellularity. Amide proton transfer (APT) MRI is a novel imaging technique based on exchangeable amide protons as endogenous contrast agent and can measure the increased amide proton signal in malignant tissues indirectly through bulk water proton signals. This thesis aims to: 1) compare the diagnostic performance of FDG-PET/CT and MRI in peritoneal metastasis evaluation; 2) study the relationship between SUV and ADC in peritoneal metastasis; 3) investigate the feasibility of APT in peritoneal metastasis evaluation. Materials and Methods Patients with peritoneal metastasis detected on FDG-PET/CT were prospectively recruited for MRI. FDG-PET/CT and MRI images were reviewed independently by two radiologists in separate sessions. Diagnostic characteristics were calculated for both imaging techniques. SUVmax and SUVmean were obtained by placing ROIs on PET, while ADCmin and ADCmean were calculated by contouring lesions on DWI. APT MRI was performed using a single-slice turbo spin echo sequence, with a block of presaturation pulses at 33 frequency offsets. ROIs were placed on peritoneal metastasis and muscle on APT. Mean of integrated asymmetrical magnetic transfer ratio (MTRasym) over 3-4 ppm with respect to water resonance was calculated for peritoneal metastasis and muscle. Results Eight patients were recruited in this study with 128 anatomical sites evaluated. DWI/MRI had good diagnostic performance (sensitivity = 92%, specificity = 99%, accuracy = 98%) compared to that of FDG-PET/CT (sensitivity = 90%, specificity= 100%, accuracy = 98%). Thirty-four peritoneal metastases were selected for quantitative analysis. Significant inverse correlation was found between ADCmean and SUVmax (r = -0.528, p = 0.001) and between ADCmean and SUVmean (r = -0.548, p = 0.001). ADCmin was significantly and negatively correlated with SUVmax (r = -0.508, p = 0.002) and SUVmean (r = -0.513, p = 0.002). In the above study cohort, 6 patients underwent APT imaging with 8 peritoneal metastases evaluated. Seven lesions showed positive APT signal and one had negative APT signal. The mean APT signal for peritoneal metastasis was 2.28%±1.76%, significantly different from that of muscle (-2.79%±0.95%, p < 0.001). Conclusions In conclusion, both DWI/MRI and FDG-PET/CT had good diagnostic performance in peritoneal metastasis evaluation. The negative correlation between SUV and ADC suggested an inverse relationship between tissue metabolism and cellularity. APT MRI is feasible to generate sufficient contrast signal for peritoneal metastasis and has potential to discriminate peritoneal tumours from its surrounding soft tissue using integrated MTRasym as a quantitative marker. These functional indices allow understanding of the biological behaviours of peritoneal tumours and could act as adjuncts in peritoneal metastasis imaging. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Background Visual hallucinations (VH) are an important non-motor complication of Parkinson’s disease (PD) which carries a negative prognosis, but their biological basis is unclear. Multi-modal magnetic resonance imaging (MRI) can be used to evaluate structural and functional brain mechanisms underpinning VH in PD. Methods To assess cerebral microstructure and resting functional activities in patients with idiopathic PD and VH, I compared PD patients with VH (PDVH) and PD patients without VH (PDnonVH), while healthy controls (HC) were also recruited for comparison. Diffusion tensor imaging was used to calculate mean diffusivity (MD) and fractional anisotropy (FA). Structural MRI was used to calculate voxel-based intensity of grey matter (GM) and white matter (WM) across the entire brain and compared among groups. Furthermore, functional magnetic resonance imaging of the brain, acquired during rest, was processed to calculate the amplitude of low-frequency fluctuations (ALFF) and functional connectivity (FC) to inform a model of VH. In addition, hippocampal volume, shape, mean diffusivity and FC across the whole brain was further examined. Hippocampal dependent visual spatial memory performance was compared between groups, and predicted correlations with hippocampal microstructural indices and VH severity were tested. Results In the first study, PDVH had lower FA than both PDnonVH and HC in the right occipital lobe and left parietal lobe, but increased FA in the right infero-medial fronto-occipital fasciculus and posterior inferior longitudinal fasciculus. Moreover, PDVH patients showed less GM volume compared to PDnonVH in the right lingual gyrus of the occipital lobe. In the second study, PDVH patients compared to non-hallucinators showed lower ALFF in occipital lobes, with greater ALFF in temporo-parietal region, limbic lobe and right cerebellum. The PDVH group also showed alteration in functional connectivity between occipital region and corticostriatal regions. Finally in the third study, although there were no gross hippocampal volume and shape differences across groups, individuals with PDVH had higher diffusivity in hippocampus than PDnonVH and HC. Both PD groups had significantly poorer visuospatial memory compared to HC. Poorer visuospatial memory was correlated with higher hippocampal diffusivity in HC and more severe VH in the PDVH group.FC between hippocampus and primary visual cortex, dorsal/ventral visual pathways was also lower in PDVH than other groups, whereas FC between hippocampus and default mode network regions was greater in PDVH group compared to others. Conclusion Compared to PDnonVH groups, the PDVH group had multiple structural deficits in primary and associative visual cortices. In term of hemodynamic activity, the PDVH group had lower ALFF in occipital lobe, but greater ALFF in regions that comprise the dorsal visual pathway. Moreover, this lower ALFF in the primary visual cortex was accompanied by lower functional connectivity across components of the ventral/dorsal visual pathway in the PDVH group compared to the PDnonVH group. Moreover, evidence supporting a specific role for the hippocampus in PDVH was obtained. In the absence of gross macrostructural anomalies, hippocampal microstructure and functional connectivity was compromised in PDVH. I observed an association between visuospatial memory and hippocampal integrity and suggest that hippocampal pathology and consequent disruption in visuospatial memory plays a key contribution to VH in PD. Thus, in the PDVH group, "bottom-up" primary visual cortex and “top-down” visual association pathways and attentional networks appear to be disrupted. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy