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1
FERRI, FRANCESCA. "Phenotypic and metabolic imaging characterization of posterior cognitive dysfunctions." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/94449.
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In the last decade, the differential diagnosis of dementia has become very challenging. Different clinical syndromes can in fact be associated with the same underlying pathology and different pathologies can be associated with the same clinical phenotype, making it very difficult to distinguish them in vivo.
In the present project we focused on the differential diagnosis of cognitive syndromes affecting, at onset, posterior cerebral networks with particular reference to PCA, CBD and LBD, respectively.
We enrolled 70 consecutive patients, referred to the memory clinic of the Neurology Department of S. Gerardo Hospital, with a cognitive profile characterized primarily by impairment of posterior cognitive functions and a relative spare of language and memory functions. Each patient underwent, an extensive neuropsychological battery, a neurological examination and a [18F]FDG-PET in close proximity to the neuropsychological assessment.
Applying Principal Components Analysis to all the tasks of posterior cognitive functions, we highlighted three cognitive sub-syndromes that we interpret as anatomical-based and label as “left parietal”, “left temporo-occipital” and “right parietal” and we classify patients on the basis of these three components. Cerebral metabolism measured with [18F]FDG-PET confirm this interpretation of the three sub-syndromes. We then compared empirical patients classification and the diagnoses made with the current diagnostic criteria for Posterior Cortical Atrophy (PCA), Corticobasal degeneration (CBD), Lewy body dementia (LBD) and Alzheimer’s disease (AD). One of the most important evidence was that all patients classified as “left temporo-occipital” were diagnosed as AD or PCA (only one of these patients met both criteria of PCA and CBD). Two additional quite interesting associations emerged, although less strong: the first between “left parietal” and CBD diagnosis and the second between “right parietal” and PCA diagnosis. Finally a large group of patients could not be classified only on the basis of their very specific posterior cognitive profile.
In conclusion, this new empirical approach seems to be quite useful in the differential diagnosis of dementia syndromes.
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Zaidi, Syed Anwar Hyder. "Optical Redox Imaging of Metabolic Activity." Wright State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=wright1484672916027993.
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Doyle, Francis James Jr. "Metabolic imaging of the murine brain." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12352.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Alzheimer's disease is the sixth leading cause of death in the United States. While the pathology of the disease is not fully understood, it is becoming increasingly apparent that it involves a complex homeostatic system involving multiple metals, including zinc, copper, and iron. There is also growing evidence that demonstrates developmental lead exposure may also have a role in the pathogenesis of the disease. Understanding the role of these elements in Alzheimer's disease and other metal dyshomeostasis related maladies is key in the development of treatments and possible cures. The development of metallomic imaging using systems like Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) shows great promise in tracking the distribution of individual elements in physiological tissues. However, the process is both time- and resource-consuming. In an effort to alleviate these issues, we developed a method for creating calibration standards for both LA-ICP-MS and LA-ICP-OES (Laser Ablation Inductively Coupled Plasma Optical Emission Spectrometry) and a method for creating 60µm sections for laser ablation. In addition, we also explored the capabilities and sensitivity of a LA-ICP-OES system for metallomic imaging using murine brains. While imaging of the 60µm sections will require additional calibration and fine-tuning, we were able to successfully image and identify physiological areas of interest in the murine brain by elemental distribution. Continued development of this technology will lead to better optical emission spectrometry image resolution, while freeing up the LAICP-MS for ultra-trace elemental and isotopic analysis.
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Azmi, Shazli. "Longitudinal studies in metabolic neuropathies : development of imaging biomarkers." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/longitudinal-studies-in-metabolic-neuropathies-development-of-imaging-biomarkers(6913e957-0e81-4af8-a544-f943f0105b8c).html.
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Corneal Confocal Microscopy (CCM) is a non-invasive imaging technique to quantify small nerve fibre structure in patients with diabetic somatic and autonomic neuropathy and increasingly other metabolic, hereditary, toxic and inflammatory peripheral neuropathies. This thesis establishes that CCM is indeed a powerful imaging technique which can identify early small fibre degeneration and regeneration in relation to the clinical phenotype of subjects with obesity, impaired glucose tolerance and Type1/2 diabetes. We demonstrate a precise relationship between small fibre neuropathy and erectile dysfunction in subjects with Type 1 diabetes. We also demonstrate the utility of CCM in demonstrating relative protection from small fibre damage in Type 1 patients with extreme duration diabetes (medallists) at baseline and over 3 years and repair in patients undergoing simultaneous pancreas and kidney transplantation. This thesis provides further evidence for the utility of CCM as a marker of early small fibre neuropathy by demonstrating nerve damage in subjects with morbid obesity with and without diabetes and explore the mechanisms underlying nerve damage at baseline and repair following bariatric surgery. We also show that CCM can track dynamic changes in small fibre degeneration and regeneration in subjects with impaired glucose tolerance in relation to change in glucose tolerance status and following continuous subcutaneous insulin infusion in subjects with Type 1 diabetes.
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Hung, Yin Pun. "Single Cell Imaging of Metabolism with Fluorescent Biosensors." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10147.
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Cells utilize various signal transduction networks to regulate metabolism. Nevertheless, a quantitative understanding of the relationship between growth factor signaling and metabolic state at the single cell level has been lacking. The signal transduction and metabolic states could vary widely among individual cells. However, such cell-to-cell variation might be masked by the bulk measurements obtained from conventional biochemical methods. To assess the spatiotemporal dynamics of metabolism in individual intact cells, we developed genetically encoded biosensors based on fluorescent proteins. As a key redox cofactor in metabolism, NADH has been implicated in the Warburg effect, the abnormal metabolism of glucose that is a hallmark of cancer cells. To date, however, sensitive and specific detection of NADH in the cytosol of individual live cells has been difficult. We engineered a fluorescent biosensor of NADH by combining a circularly permuted green fluorescent protein variant with a bacterial NADH-binding protein Rex. The optimized biosensor Peredox reports cytosolic \(NADH:NAD^+\) ratios in individual live cells and can be calibrated with exogenous lactate and pyruvate. Notably pH resistant, this biosensor can be used in several cultured and primary cell types and in a high-content imaging format. We then examined the single cell dynamics of glycolysis and energy-sensing signaling pathways using Peredox and other fluorescent biosensors: AMPKAR, a sensor of the AMPK activity; and FOXO3-FP, a fluorescently-tagged protein domain from Forkhead transcription factor FOXO3 to report on the PI3K/Akt pathway activity. With perturbation to growth factor signaling, we observed a transient response in the cytosolic \(NADH:NAD^+\) redox state. In contrast, with partial inhibition of glycolysis by iodoacetate, individual cells varied substantially in their responses, and cytosolic \(NADH:NAD^+\) ratios oscillated between high and low states with a regular, approximately half-hour period, persisting for hours. These glycolytic NADH oscillations appeared to be cell-autonomous and coincided with the activation of the PI3K/Akt pathway but not the AMPK pathway. These results suggest a dynamic coupling between growth factor signaling and metabolic parameters. Overall, this thesis presents novel optical tools to assess metabolic dynamics – and to unravel the elaborate and complex integration of glucose metabolism and signaling pathways at the single cell level.
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Chennell, George. "Imaging of metabolism in 3D culture by FLIM." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/49245.
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The work presented in this thesis is aimed to develop and evaluate methodologies for noninvasive measurements of metabolism using fluorescence microscopy. The use of 3D cell cultures in biomedical research is increasing and these require appropriate tools and techniques to provide quantitative readouts for image-based studies. Fluorescence lifetime imaging microscopy (FLIM) can provide robust readouts in complex optical samples and here I have investigated its application to map changes in the response of genetically expressed biosensors utilising Förster resonance energy transfer (FRET) in spheroids. In particular, I adapted a FRET biosensor for the activity of a key metabolic enzyme, AMP activated protein kinase (AMPK), by substituting the donor fluorescent protein ECFP for mTurquoise2, in order to improve its performance in FLIM-based assays. I developed spheroid cultures expressing FRET biosensors and studied these using quantitative FRET readouts. To take account of possible influences of the microenvironment of 3D culture on the fluorescence lifetime measurements, I generated spheroids expressing simple fluorescent proteins and expressing an inactive mutation of the FRET biosensor. I evaluated the new AMPK FRET biosensor, demonstrating improved performance for fluorescence lifetime readouts, and compared dose responses for a direct activator of AMPK with the biosensor expressed in “2D” monolayer cultures and in spheroids, consistently observing a uniform response. In contrast, the dose response of an indirect activator of AMPK in spheroids presented a spatially varying AMPK activation. I further explored the application of FLIM to map the readout of a genetically expressed FRET biosensor for glucose and again observed a spatially varying response in spheroids. I then explored cell specific AMPK activities using FRET biosensors in prostate cancer cells and bone marrow stromal cells with a spheroid system of tumour stromal interactions. I also used biosensors for ATP and glucose concentration in a similar manner and undertook measurements of oxygen consumption rates using a metabolic flux analyser. I observed changes in metabolism that indicate the prostate cancer cells were metabolically benefitting from the interaction with bone marrow cells.
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Hare, Hannah V. "Quantitative imaging of cerebral oxygen metabolism using MRI." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e2d8d0ac-4425-42d5-81b1-69ea9d59aafd.
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Magnetic resonance imaging (MRI) is a non-invasive medical imaging technique that is sensitive to the level of oxygen in the blood. Calibrated MRI is capable of producing maps of absolute oxygen metabolism by using gas challenges to independently manipulate blood flow and blood oxygen content. In this thesis, several aspects of the signal model are investigated. It is confirmed that the commonly used Davis model is reassuringly insensitive to field strength, provided sufficient signal-to-noise (SNR) can be obtained. The effect in varying the experimental parameter of echo time is explored, and the results are shown to match the theory more closely when intravascular signal contribution is reduced by crusher gradients. A direct comparison was performed between resting oxidative metabolism as measured by calibrated MRI and the gold standard method of positron emission tomography (PET). Good correlation was observed for resting blood flow, but no correlation was found for oxygen extraction fraction (OEF) or absolute cerebral metabolic rate of oxygen consumption (CMRO2). A follow-up study was performed to further investigate some methodological aspects of the calibrated MRI procedure, including the application of background tissue suppression, different gas delivery methods, the effects of using measured respiratory timecourses as part of image analysis, and the impact of physiological noise correction. The limiting factor in the quality of data obtained for calibrated MRI is the SNR of the arterial spin labelling (ASL) method, which is used to quantify blood flow to the brain. The alternative method of intravoxel incoherent motion (IVIM) was investigated, which is hypothesised to be sensitive to cerebral blood volume and perfusion without the signal limitations of ASL. However IVIM was shown to be primarily sensitive to the presence of cerebrospinal fluid within the brain, and thus is not a suitable alternative to ASL when quantification is of interest.
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Germuska, Michael. "Blood oxygen level dependent imaging of cerebral mesostructure." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:1c06d624-6336-4a6d-bdb2-243dc40eb32f.
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In this thesis I investigate blood oxygen level-dependent (BOLD) MRI methods of imaging the cerebral blood volume (CBV), mean vessel radius and oxygen extraction fraction (OEF). Through the investigation of these individual techniques a new framework is proposed for the simultaneous measurement of all three parameters, providing a comprehensive assay of the cerebral mesostructure. A new method for the segmentation of blood filled voxels from the sagittal sinus is presented. The implemented method is completely automated and thus removes user bias in voxel selection. The segmentation method is used in a volunteer study to calculate CBV from a hyperoxic challenge according to an existing technique. CBV measurements from this study are found to be significantly overestimated. However, a new derivation of the hyperoxic CBV equation is presented that reveals significant errors in the original method, corresponding to the observed overestimates in CBV. Modelling studies are presented that investigate the discrepancy in reported BOLD MRI measurement of mean vessel size. A significant degree of the variation in the results is found to arise from the noise sensitivity of the analysis methods. This finding is confirmed with experimental data from healthy volunteers that show good agreement with the modelling studies. Comprehensive modelling of the BOLD response to hyperoxia and hypercapnia is used to develop a new framework for OEF calculation. The new method is based on the calibration of the BOLD signal response against a change in intravascular susceptibility. The OEF calculation is extended by introducing a spin-echo readout into the acquisition scheme. This extension of the acquisition scheme provides a further independent probe of the BOLD signal, enabling the simultaneous calculation of the mean vessel size and CBV. The new framework is shown to provide OEF and vessel size estimates over a wider range of physiological parameters, providing greater scope for the clinical implementation of these techniques.
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Chow, Mei-kwan April, and 周美君. "Cellular, molecular and metabolic magnetic resonance imaging: techniques and applications." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44901148.
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Szula, Ewa. "Metabolic profiling and imaging of CHO cells for fusion protein production." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/metabolic-profiling-and-imaging-of-cho-cells-for-fusion-protein-production(ec83142c-0d97-437e-8d0f-d767887bcde5).html.
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Fc-fusion proteins (e.g. EPO-Fc) are the most often created fusion proteins due to their beneficial biological and pharmacological properties. The economic success of Fc-fusion proteins and other biopharmaceuticals production however, greatly depends on a robust, low-cost and highly effective protein mammalian cell extraction system . Understanding of how cells respond to a protein production environment based on metabolic profiles provides new goals for bioengineering of cell lines for best performance in biomanufacturing. Furthermore, insights on how individual cell metabolism and therefore phenotype, respond to cell microenvironment allows the underlying biological mechanisms to be explored in greater detail. This study focused on the application of mass spectrometry (MS) technologies, combining the analysis of metabolic profiles of cells extracts by GC-MS and MALDI-MS and spatial visualisation and distribution of metabolites within cells producing the fusion protein by MALDI-MSI and SIMS imaging. The analysis of external and internal metabolome profiles of cells producing the protein showed an extended effect of EPO-Fc fusion protein production on cell metabolism. The findings indicate that changes observed in EPO-Fc producing cells are related to enhanced protein and lipid synthesis highlighting that these cells are in a state of increased metabolic activity with the protein exocytosis into growth medium. Moreover, the composition of lipid bilayer of induced cells seemed to be different to non-induced cells. These findings were confirmed with the analysis of EPO-Fc induced cells using MS metabolic imaging. Multivariate analysis highlighted a number of metabolites that were significantly influenced by the protein expression when compared to control cells. The major metabolic changes in induced cells were those related to lipid metabolism. The information about metabolic changes in tetracycline-induced cells obtained from the analysis of cell populations was further supported with the analysis based on single-cell studies. Single-cell based studies also proved that investigations of individual cells provide additional insights about changes in metabolism of induced cells that can be referred to a unique, single cell and its phenotype. The analysis of CHO cells revealed a high level of heterogeneity within a cell population. Different cell phenotype and hence, metabolite content allowed for correlation between cell locations and their metabolite characteristics, specific for each type of cells. This project has successfully shown combination of bio-analytical techniques to investigate external and internal metabolome changes related to a fusion protein production in mammalian cells. Additionally, the significance of single cell approaches in metabolomics has also been highlighted, providing insights into the sub-cellular distribution of metabolites in cells producing EPO-Fc and information on the level of heterogeneity within a cell population. A multidimensional approach for metabolic profiling and future technological improvements of single-cell platforms are required to provide improved data acquisition and data analysis in order to better understand unknown processes involved in cell metabolism.
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Bolar, Divya Sanam. "Magnetic resonance imaging of the cerebral metabolic rate of oxygen (CMRO₂)." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/57542.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student submitted PDF version of thesis.
Includes bibliographical references (p. 120-128).
Oxygen consumption is an essential process of the functioning brain. The rate at which the brain consumes oxygen is known as the cerebral metabolic rate of oxygen (CMRO₂). CMRO₂ is intimately related to brain health and function, and will change in settings of disease and functional activation. Accurate CMRO₂ measurement will enable detailed investigation of neuropathology and facilitate our understanding of the brain's underlying functional architecture. Despite the importance of CMRO₂ in both clinical and basic neuroscience settings, a robust CMRO₂ mapping technique amenable to functional and clinical MRI has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity-selective spin labeling to isolate MR signal exclusively from post-capillary venular blood on a voxel-by-voxel basis. This isolated signal can be related to venular oxygen saturation, oxygen extraction fraction, and ultimately CMRO₂. This thesis first explores fundamental theory behind the QUIXOTIC technique, including design of a novel MRI pulse sequence, explanation of the principal sequence parameters, and results from initial human experiences. A human trial follows, in which QUIXOTIC is used to measure cortical gray matter CMRO₂ in ten healthy volunteers.
(cont.) QUIXOTIC-measured CMRO₂ is found to be within the expected physiological range and is comparable to values reported by other techniques. QUIXOTIC is then applied to evaluate CMRO₂ response to carbon-dioxide-induced hypercapnia in awake humans. In this study, CMRO₂ is observed to decrease in response to mild hypercapnia. Finally, pilot studies that show feasibility of QUIXOTIC-based functional MRI (fMRI) and so-called "turbo" QUIXOTIC are presented and discussed.
by Divya Sanam Bolar.
Ph.D.
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Blacker, T. S. "Monitoring cell metabolism with NAD(P)H fluorescence lifetime imaging." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1401694/.
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In live tissues, alterations in metabolism induce changes in the fluorescence decay of the spectrally identical redox carriers NADH and NADPH. The biochemical pathways and photophysical mechanisms that contribute to these changes are largely unknown. This work combined ultrafast laser spectroscopy and live-cell imaging to investigate these phenomena. Time-resolved spectroscopy of NADH and NADPH was performed using single-photon and two-photon excitation. In solution, the fluorescence lifetimes of the two cofactors were identical. The anisotropy decay dynamics of both molecules indicated that distinct molecular configurations caused the presence of two emitting states, perhaps involving alternate cis/trans geometries of the amide group. Using a range of water/glycerol mixtures as solvents, the viscosity dependence of the non-radiative decay of NAD(P)H was shown to be well described by Kramers and Kramers-Hubbard models of activated barrier crossing. This suggested that variations in the fluorescence lifetimes of the cofactors when bound to different enzymes result from differing levels of conformational restriction of the nicotinamide ring in the binding site. Despite identical fluorescence lifetimes in solution, studies on genetically modified cell lines in which NAD kinase was overexpressed or knocked down indicated that intracellular NADPH was associated with a significantly larger fluorescence lifetime when bound to enzymes (~4.4 ns) than enzyme-bound NADH (~1.5 ns). This suggested that variations in the NAD(P)H fluorescence decay upon metabolic perturbation by pharmacological or pathological means, reported both in this work and in the literature, result from changes in the relative concentrations of NADH and NADPH. NAD(P)H FLIM was used to observe elevated NADPH concentrations in the support cells of the mammalian cochlea, highlighting the potential of the technique as a label-free method for monitoring the metabolic state of complex tissue preparations.
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Müller, Christoph Alexander [Verfasser], and Jürgen [Akademischer Betreuer] Hennig. "Real-time metabolic imaging of pyruvate and lactate using hyperpolarised 13C magnetic resonance spectroscopic imaging with ME-bSSFP : : a method of clinical cancer imaging." Freiburg : Universität, 2020. http://d-nb.info/1226091237/34.
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Robar, James L. "Construction and calibration of detectors for high-resolution metabolic breast cancer imaging." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ29770.pdf.
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Robar, James L. "Construction and calibration of detectors for high-resolution metabolic breast cancer imaging." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=27395.
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Each of two detectors used in our Positron Emission Mammography (PEM) system consists of four 36mm x 36mm x 20mm bismuth germanate (BGO) detector blocks coupled to a crossed-wire anode photomultiplier tube (PMT). To achieve a high spatial resolution, the crystal blocks have been finely pixelated using a diamond saw. In each detector, 36 x 36 1.9mm x 1.9mm crystal elements are coupled directly to the PMT window and, on the opposite face of the blocks, 35 x 35 elements are offset by 0.9mm along both the x- and y-axes of the PMT. Techniques developed for the successful machining and surface-preparation of the detector blocks are described. Results indicating the detector block performance in terms of spatial and energy resolution are presented.As part of a system calibration routine, a novel method for crystal element identification has been developed. This robust and reproducible algorithm succeeds in identifying 59 x 49 crystal elements on each detector face. The results are used to generate a Look-Up-Table (LUT) that is accessed during data acquisition for the effective correction of spatial distortion inherent in the detectors. Crystal identification also facilitates an improvement of the capability for accurate energy discrimination, since the detector gain and energy resolution are considered on an element-by-element basis by accessing an energy LUT. Employing a third LUT, which contains the relative efficiencies of individual crystal elements results in a significant improvement in detector uniformity.
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Roque, Thais Soleimani. "Using metabolic medical imaging to model tumour growth and response to therapy." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:53c261bf-f06e-44b7-b28b-0ca0bba6145b.
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The number of cancer related deaths is predicted to reach over 13.1 million in 2030. Understanding the spatio-temporal evolution of tumours and their response to therapy is crucial to thwart this gloomy prognosis. Mathematical models have been used to elucidate the biological processes involved in tumour growth, but their complexity severely limits their clinical value. Effective models should base predictions on patient-specific data that can be obtained and tested in the clinic. This thesis aims to develop novel clinically-relevant methodologies to model solid tumour growth and reaction to therapy. Models are developed that predict the macroscopic tumour evolution as a result of complex biological processes happening at the microscopic scale (such as cell proliferation, hypoxia, necrosis and oxygenation) while retaining simplicity in terms of the number of parameters that require calibration. This facilitates integration of medical imaging-derived tumour descriptor maps (e.g. for cellularity and nutrient availability) to initialise, calibrate and verify the models. In addition to the models themselves, this thesis contributes to the literature by introducing novel frameworks to 1) derive maps of proliferative, hypoxic and necrotic cells using only Dynamic Contrast Enhanced Magnetic Resonance Imaging data; 2) apply these maps to constrain the models and obtain subject-specic predictions of tumour evolution; 3) account for tumour vascularisation, focusing on the angiogenesis-driven macroscopic changes observed longitudinally on medical imaging scans; and 4) produce a proof-of-concept updated model that could support medical decision in the treatment and management of cancer patients. The results demonstrate the feasibility of using information derived from imaging data to quantify and predict subject-specic global and local tumour evolution and reaction to therapy. Experimentally validated comparison between model predictions and tumour imaging data obtained at later time points of the tumours' evolution show noticeable improvements in prediction accuracy, model complexity and clinical value over state-of-the-art methods. Nevertheless, additional imaging information on complementary aspects of tumour growth and response to therapy could render our models even more relevant to clinical practice.
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Chen, Jing Andy. "Label Free Chemical Imaging Reveals Novel Metabolic Signatures in Living Model Organisms." Thesis, Purdue University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10846167.
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Cell and molecular biology often need direct monitoring of the dynamic distribution and interactions of metabolites in living cells and model organisms. However, this task is extremely challenging for a few reasons. Labeling metabolites with markers can potentially interrupt the dynamic cellular events that are aimed to be observed. Moreover, labeling dyes are usually toxic to cells. Lastly, many labeling methods require cell fixation thus cannot be used to study cellular dynamics. Label-free chemical imaging methods such as stimulated Raman scattering (SRS) circumvent these problems by generating signals based on the intrinsic optical property of target biological metabolites. As a result, label-free chemical imaging methods provide huge potential to make new biological discoveries which are not possible with traditional imaging technologies.
This Ph.D. thesis work focuses on applying two label-free chemical imaging methods—SRS and TA microscopy—to studying dynamics of metabolites. In detail, the dynamic distribution of retinoids in C. elegans was studied using SRS microscopy, and it was found that retinoids help C. elegans survive high glucose stress. In the second part of this thesis work, TA microscopy was introduced to image heme, a metabolite invisible to biologists for decades. The dynamic distribution and trafficking of heme was revealed in C. elegans model. In the last part of this thesis work, TA microscopy was expanded to monitoring the growth of hemozoin crystal in malaria parasite at different stages of infection, demonstrating TA microscopy as a powerful tool for studying hemozoin metabolism and anti-malaria drug screening.
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Schaefer, Patrick Michael [Verfasser]. "Metabolic imaging in Alzheimer´s Disease using NADH autofluorescence / Patrick Michael Schaefer." Ulm : Universität Ulm, 2018. http://d-nb.info/1152324438/34.
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Suttie, Joseph. "Characterising metabolic mechanisms of disease in cardiomyopathies using multiparametric cardiovascular magnetic resonance imaging." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555329.
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In addition to pathological ventricular remodeling, the failing heart is characterised by impaired myocardial energetics and profound alterations in glucose and fatty acid metabolism. Understanding these complex metabolic pathways is crucial to improving clinical risk stratification and developing targeted therapeutic interventions. Cardiac magnetic resonance imaging (CMR) and magnetic resonance spectroscopy (MRS) are powerful tools in the interrogation of cardiac disease. Although technically challenging, the assessment of myocardial energetics by 3'p MRS has been possible for several decades. More recent techniques have allowed for the rapid assessment of cardiac steatosis using 'H MRS. The relationship between cardiac steatosis and other parameters of myocardial function such as myocardial energetics, contractility, fibrosis and perfusion have not been previously investigated. I assessed these parameters in patients with dystrophinopathy, a cause of inherited dilated cardiomyopathy in which disease pathways have not been well described. This study found myocardial contractility is strongly correlated with the myocardial PCr/ATP ratio, and that in those patients with impaired myocardial energetics there is significant cardiac steatosis. These changes were independent of body mass index and occurred in patients with normal glucose and lipid profiles. In order to further elucidate the phenotype, we investigated these markers of myocardial dysfunction in dystrophinopathic patients with and without prior exposure to Coxsackie B infection, an acquired cause of dystrophinopathy. Previous Coxsackie B exposure predicts worsening myocardial fibrosis, but was not associated with parameters of metabolic dysfunction. 17 - Suttie J.J. In order to further investigate the significance of cardiac steatosis in inborn errors of metabolism, I phenotyped a cohort of patients with mitochondrial myopathy. Mitochondrial myopathies are associated with profound cardiac steatosis, impaired myocardial energetics, inflammation and fibrosis. Furthermore, we report cardiac steatosis also occurs in patients with impaired myocardial energetics due to hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy and asymptomatic aortic stenosis. Finally, even higher spatial resolution imaging may be achieved be achieved at higher field strength, and I therefore undertook the first validation of CMR cardiac functional imaging at 7 T. This work significantly expands our understanding of cardiac steatosis in the energetically failing heart and supports its potential role as a novel biomarker in a range of cardiomyopathies.
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Orphanidou, Eleni. "Advanced magnetic resonance imaging and metabolic studies of low grade gliomas in childhood." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3434/.
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Introduction: Paediatric low grade brain tumours present diagnostic and prognostic challenges, providing a need for better non-invasive imaging characterization. The value of \(^1\)H Magnetic Resonance Spectroscopy (MRS) performed on 5 scanners in the diagnosis and prognostication of an extensive bi-centre cohort of low-grade gliomas is investigated. Methods: Single voxel MRS was performed routinely in children with brain tumours at the Birmingham Children’s Hospital and Queen’s Medical Centre. Histopathological features were semi-quantified and in vitro \(^1\)H NMR used to study pilocytic astrocytoma cell lines. Magnetic Resonance Spectroscopic Imaging (MRSI) and texture analysis of MR images were performed. Results: MRS detects differences between subgroups of low grade brain tumours in children and between tumours of the same histology. High myo-inositol and glycerophosphocholine and low phosphocholine are markers of good prognosis. Histological correlates for MRS metabolites have been identified and paediatric pilocytic astrocytoma cell lines (‘typical’, metastatic and recurrence) have been discriminated. The value of MRSI in answering clinical questions has been demonstrated. Texture analysis achieved high accuracy in the diagnosis of paediatric posterior fossa tumours. Conclusion: Advanced MR techniques have a significant role in the study of paediatric brain tumours, and promising results from MRS, MRSI and texture analysis are reported here.
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Schroeder, Marie Allen. "Development of novel hyperpolarized magnetic resonance techniques for metabolic imaging of the heart." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:9c5b6638-c71e-4eec-835b-e2cea3b9106e.
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The advent of hyperpolarized magnetic resonance (MR) has provided new potential for real-time visualization of in vivo metabolic processes. The aim of the work in this thesis was to use hyperpolarized substrates to study rapid metabolic processes occurring in the healthy and diseased rat heart. Initial work, described in Chapter 2, optimized the hyperpolarization process to reproducibly generate tracers. Chapter 3 describes use of hyperpolarized 1-13C-pyruvate to investigate in vivo flux through the regulatory enzyme pyruvate dehydrogenase (PDH). Cardiac PDH activity was altered in several physiological and pathological states, namely fasting, type 1 diabetes, and high-fat feeding, and in vivo flux through PDH was measured using hyperpolarized MR. These measurements correlated with measurements of in vitro PDH activity obtained using a validated biochemical assay. The work in Chapter 4 investigated the physiological interaction between hyperpolarized tracer and cardiac tissue. The effect of hyperpolarized 1-13C-pyruvate concentration on its in vivo metabolism was analyzed using modified Michaelis-Menten kinetics. It was found that hyperpolarized MR could non-invasively follow mechanisms of metabolic regulation, in addition to reporting enzyme activity. In Chapter 5, hyperpolarized MR was incorporated into the isolated perfused rat heart. 1-13C-pyruvate in normal and ischaemic hearts revealed significant differences in lactate metabolism, and provided the foundation for a novel intracellular pH probe. Infusion of 2-13C-pyruvate in the isolated rat heart enabled the first real-time visualization of Krebs cycle intermediates. In summary, the work in this thesis has highlighted the potential of hyperpolarized MR to reveal novel information on heart disease.
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Beatty, Kimberly Elizabeth Grubbs Robert H. Tirrell David A. "Imaging the proteome : metabolic tagging of newly synthesized proteins with reactive methionine analogues /." Diss., Pasadena, Calif. : California Institute of Technology, 2008. http://resolver.caltech.edu/CaltechETD:etd-03052008-105142.
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Akhenblit, Paul. "Interrogating Tumor Metabolism with AcidoCEST MRI." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/612606.
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Tumor metabolism is a highly dysregulated process that is identified as a unique target for therapy. Current philosophy proposes that tumor metabolism is a plastic and flexible process which sustains proliferative and survival advantages. Tumors employ an anaerobic glycolytic pathway resulting in the overproduction of lactate. Additional thinking suggests that the conversion of pyruvate to lactate regenerates the NAD+ pool in the cell, maintaining a sustainable oxidative environment. Regardless of the reasons for lactate overproduction, its excretion and build up in the microenvironment results in acidic tumor microenvironments. Tumor acidosis has been measured with several different methods, but consistently averages from pH 6.6 to 7.0. Tumor acidity can thus be measured as a biomarker for tumor metabolism. This work examines the commonly explored energy pathways available to the cancer cell and a non-invasive MRI method to measure the efficacy of the tumor metabolism targeting agent. Appendix A is an introduction to tumor metabolism pathways and the large list of candidate therapies in interfering with energy production. Glucose, fatty acid, and glutamine metabolisms are all discussed along with PI3K/AKT/mTOR and HIF growth signals and ion transport. Magnetic resonance imaging and positron emission tomography are examined as imaging methods for non-invasively interrogating tumor acidosis. Appendix B presents the findings in a study where tumor metabolism was targeted with an mTOR inhibitor, where tumor growth rate was initially decreased and accompanied by an early, acute increase in tumor extracellular pH with acidoCEST MRI. Chapter 2 discusses the combination of a lactate dehydrogenase inhibitor in conjunction with doxorubicin in a breast cancer model. Tumor extracellular pH was shown to increase when measured with acidoCEST MRI, and an increase in cell death was measured. Chapter 4 discusses the studies and experimental designs that can be done in the near future.
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Bancroft, Brown Jeremy. "Micro-MRI and Metabolism Studies of Benign and Malignant Living Human Prostate Tissue." Thesis, University of California, San Francisco, 2019. http://pqdtopen.proquest.com/#viewpdf?dispub=13424970.
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Prostate cancer is among the most prevalent and deadly of malignancies in both the United States and worldwide. Ongoing diagnostic challenges in prostate cancer include differentiating low-risk and high-risk tumors, and monitoring responses to therapy in patients with aggressive disease. Prostate cancer metabolism is characterized by a shift to aerobic glycolysis with lactate production and efflux, as well as increased tricarboxylic acid cycle activity, which has led to the investigation and development of metabolic imaging strategies such as hyperpolarized 13C MRI. However, it is nontrivial to study human prostate cancer metabolism in vivo, and the capability to better characterize tumor metabolism from a variety of disease states would be valuable for metabolic imaging biomarker development. This dissertation focuses on developing ex vivo strategies to measure metabolism in benign and malignant living human prostate tissue. First, because prostate tissue heterogeneity can impact metabolic measurements, we present the engineering of a 600 MHz radiofrequency (RF) microcoil to assess the heterogeneity of freshly acquired human prostate biopsies using microscale diffusion-weighted imaging (DWI). Next, we demonstrate the capability of micro-DWI to determine the biopsy percentage of glandular tissue, setting the stage for establishing the percentage and grade of cancer using this approach. After this, we develop a protocol for nuclear magnetic resonance (NMR) quantification of lactate production and efflux and glutamate fractional enrichment in freshly acquired living human prostate biopsies cultured with [1,6-13C2]glucose. In this study we demonstrate a significantly higher lactate efflux rate coming from low-grade prostate cancer versus benign biopsies in an early-stage patient population. This sets the stage for studies of metabolic fluxes and steady-state metabolite levels in biopsies from patients with aggressive disease before and after non-surgical therapy. Finally, due to recent interest in the potential role of Myc amplification and glutaminolysis upregulation in treatment insensitive castrate-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), we present metabolic labeling results from a study of primary human prostate tissue slice cultures (TSCs) obtained at surgery and cultured with either [1,6-13C2]glucose or [3-13C]glutamine. Our results are consistent with prior thinking on the role of glucose and glutamine metabolism in treatment-naïve prostate cancer.
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Berwick, Jason. "Investigation of the V-signal oscillation using intrinsic optical imaging and imaging spectroscopy and its relevance to cortical metabolism." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312793.
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Tucker, David C. "Metabolic factors influencing fatigue during a 90 second maximum muscle contraction." Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009m/tucker.pdf.
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Fan, Audrey Peiwen. "Phase-based regional oxygen metabolism in magnetic resonance imaging at high field." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/60162.
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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2010.Includes bibliographical references (p. 45-48).
Venous oxygen saturation (Yv) in cerebral veins and the cerebral metabolic rate of oxygen (CMRO₂) are important indicators for brain function and disease. Phase-susceptibility measurements in magnetic resonance imaging (MRI) have been used to quantify Yv in candidate cerebral veins. However, currently there is no method to quantify regional CMRO₂ using MRI. Here we propose a novel technique to quantify CMRO₂ from independent MRI estimates of Yv and cerebral blood flow (CBF). Our approach used standard gradient-echo (GRE) and arterial spin labeling (ASL) to make these measurements. Results for in vivo Y, and CMRO₂ estimates on human subjects are presented from application of our technique at 3 Tesla (3T). We also extended our method to high-field human imaging at 7 Tesla (7T), which allows us to take advantage of improved signal-to-noise ratio (SNR) for the same scan duration to achieve higherresolution analysis of vessels of interest. While the higher field strength poses additional challenges, such as increased main field and excitation field inhomogeneities as well as more severe susceptibility artifacts, initial results suggest that substantial benefits can be realized with phase-based regional oxygen metabolism in MRI at high field.
by Audrey Peiwen Fan.
S.M.
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Soldà, Alice <1986>. "Electrochemical imaging of living cell metabolism: investigation on Warburg effect in cancer." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/7072/1/Solda_Alice_tesi.pdf.
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Cancer is one of the principal causes of death in the world; almost 8.2 million of deaths were counted in 2012. Emerging evidences indicate that most of the tumors have an increased glycolytic rate and a detriment of oxidative phosphorylation to support abnormal cell proliferation; this phenomenon is known as aerobic glycolysis or Warburg effect. This switching toward glycolysis implies that cancer tissues metabolize approximately tenfold more glucose to lactate in a given time and the amount of lactate released from cancer tissues is much greater than from normal ones. In view of these fundamental discoveries alterations of the cellular metabolism should be considered a crucial hallmark of cancer. Therefore, the investigation of the metabolic differences between normal and transformed cells is important in cancer research and it might find clinical applications. The aim of the project was to investigate the cellular metabolic alterations at single cell level, by monitoring glucose and lactate, in order to provide a better insight in cancer research. For this purpose, electrochemical techniques have been applied. Enzyme-based electrode biosensors for lactate and glucose were –ad hoc- optimized within the project and used as probes for Scanning Electrochemical Microscopy (SECM). The UME biosensor manufacturing and optimization represented a consistent part of the work and a full description of the sensor preparation protocols and of the characterization methods employed is reported. This set-up (SECM used with microbiosensor probes) enabled the non-invasive study of cellular metabolism at single cell level. The knowledge of cancer cell metabolism is required to design more efficient treatment strategies.
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Soldà, Alice <1986>. "Electrochemical imaging of living cell metabolism: investigation on Warburg effect in cancer." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/7072/.
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Cancer is one of the principal causes of death in the world; almost 8.2 million of deaths were counted in 2012. Emerging evidences indicate that most of the tumors have an increased glycolytic rate and a detriment of oxidative phosphorylation to support abnormal cell proliferation; this phenomenon is known as aerobic glycolysis or Warburg effect. This switching toward glycolysis implies that cancer tissues metabolize approximately tenfold more glucose to lactate in a given time and the amount of lactate released from cancer tissues is much greater than from normal ones. In view of these fundamental discoveries alterations of the cellular metabolism should be considered a crucial hallmark of cancer. Therefore, the investigation of the metabolic differences between normal and transformed cells is important in cancer research and it might find clinical applications. The aim of the project was to investigate the cellular metabolic alterations at single cell level, by monitoring glucose and lactate, in order to provide a better insight in cancer research. For this purpose, electrochemical techniques have been applied. Enzyme-based electrode biosensors for lactate and glucose were –ad hoc- optimized within the project and used as probes for Scanning Electrochemical Microscopy (SECM). The UME biosensor manufacturing and optimization represented a consistent part of the work and a full description of the sensor preparation protocols and of the characterization methods employed is reported. This set-up (SECM used with microbiosensor probes) enabled the non-invasive study of cellular metabolism at single cell level. The knowledge of cancer cell metabolism is required to design more efficient treatment strategies.
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Khalili-Mahani, Najmeh 1971. "Observing the stressed brain : magnetic resonance imaging of the neural correlates of hypothalamic pituitary adrenal axis function." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115857.
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The Hypothalamic Pituitary Adrenal (HPA) axis is the coordinator of adaptive responses to physical and psychological stress. The central nervous system plays a key role in modulation of both basal and adaptive HPA axis functions. In fact, since long ago, animal studies have shown that acute and chronic exposure to glucocorticoids (a stress hormone released due to HPA axis activation, cortisol in humans) affects the function and the morphology of brain areas such as the hippocampus and the cingulate cortex. This thesis is based on novel neuroimaging methodologies used to investigate the interactions of psychological stress, cortisol and the brain. It consists of three functional studies and a morphometric one. In the first functional study we show that the hippocampus (where glucocorticoid receptors are most abundant) plays a role in initiation of an HPA axis stress response. In the second study, we provide evidence that besides hippocampus, the neural activity in the so-called "default mode network" (DMN), especially the anterior cingulate cortex (ACC), relates to interindividual variations in HPA axis response to psychological stress. In the third study we have investigated the cortisol-modulation of the DMN. Again, we provide evidence for a role of the ACC and the orbitofrontal cortex in negative feedback inhibition of the HPA axis activity. Finally, we show a morphological link between the ACC and the cortisol response to awakening which is an index of basal HPA axis activity. Overall, our findings confirm the critical role of the ACC and mesolimbic system in HPA axis regulation. These findings also draw attention to the interactions between functional subregions of the medial prefrontal cortex and states of HPA axis function prior to stress onset---suggesting an interplay of the monitoring and the executive planning roles of the medial prefrontal cortex in behavioral adaptation to stress. Beyond stress research, our findings offer a framework for combining neuroimaging and neuroendocrinology to better understand the interindividual variances in behavior, and perhaps to better identify subgroups at risk of psychological disorders.
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Wang, Jiazheng. "Development of pulse sequences for hyperpolarized 13C magnetic resonance spectroscopic imaging of tumour metabolism." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273819.
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Metabolic imaging with hyperpolarized 13C-labeled cell substrates is a promising technique for imaging tissue metabolism in vivo. However, the transient nature of the hyperpolarization - and its depletion following excitation - limits the imaging time and the number of excitation pulses that can be used. A single-shot 3D imaging sequence has been developed and it is shown in this thesis to generate 13C MR images in tumour-bearing mice injected with hyperpolarized [1-13C]pyruvate. The pulse sequence acquires a stack-of-spirals at two spin echoes after a single excitation pulse and encodes the kz-dimension in an interleaved manner to enhance robustness to B0 inhomogeneity. Spectral-spatial pulses are used to acquire dynamic 3D images from selected hyperpolarized 13C-labeled metabolites. A nominal spatial/temporal resolution of 1.25 x 1.25 x 2.5 $mm^3$ x 2 s was achieved in tumour images of hyperpolarized [1-13C]pyruvate and [1-13C]lactate acquired in vivo. An advanced sequence is also described in this thesis in a later study to acquire higher resolution images with isotropic voxels (1.25 x 1.25 x 1.25 $mm^3$) at no cost of temporal resolution. EPI is a sequence widely used in hyperpolarized 13C MRI because images can be acquired rapidly with limited RF exposure. However, EPI suffers from Nyquist ghosting, which is normally corrected for by acquiring a reference scan. In this thesis a workflow for hyperpolarized 13C EPI is proposed that requires no reference scan and, therefore, that does not sacrifice a time point in the dynamic monitoring of tissue metabolism. To date, most of the hyperpolarized MRI on metabolism are based on 13C imaging, while 1H is a better imaging target for its 4 times higher gyromagnetic ratio and hence 16 times signal. In this thesis the world’s first dynamic 1H imaging in vivo of hyperpolarized [1-13C]lactate is presented, via a novel double-dual-spin-echo INEPT sequence that transfers the hyperpolarization from 13C to 1H, achieving a spatial resolution of 1.25 x 1.25 $mm^2$.
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Briley, Saebo Karen. "Degradation, Metabolism and Relaxation Properties of Iron Oxide Particles for Magnetic Resonance Imaging." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4311.
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Yang, Jun. "Approaches to prostate cancer imaging and therapy the use of pharmacokinetics, metabolism and biodistribution to identify new drugs /." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133362520.
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BELLANI, GIACOMO. "Imaging of lung metabolic activity by means of positron emission tomography during acute lung injury." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/7887.
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Neutrophilic inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Positron emission tomography (PET) with [F]-fluoro-2-deoxy-D-glucose (FDG) can be used to image cellular metabolism that, during lung inflammatory processes, likely reflects neutrophils activity. The aim of this study was to assess the magnitude and regional distribution of inflammatory metabolic activity in the lungs of patients with ALI/ARDS by PET with FDG. Fifteen patients with ALI/ARDS were enrolled, while four spontaneously breathing and two mechanically ventilated subjects, without known lung disease, served as controls. In each individual we performed an FDG PET/computed tomography of the thorax. FDG cellular influx rate constant (Ki) was computed for the imaged lung field and for regions of interest, grouping voxels with similar density. In all patients with ALI/ARDS, Ki was higher than in controls, also after accounting for the increased lung density. Ki values differed greatly among patients, but in all patients Ki of the normally aerated regions was much higher (2- to 24-fold) than in controls. Whereas in some patients the highest Ki values corresponded to regions with the lowest aeration, in others these regions had lower Ki than normally and mildly hypoaerated regions. In patients with ALI/ARDS, undergoing mechanical ventilation since days, the metabolic activity of the lungs is markedly increased across the entire lung density spectrum. The intensity of this activation and its regional distribution, however, vary widely within and between patients.
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MURTAJ, VALENTINA. "GENDER, AGE AND METABOLIC DYSFUNCTION AS RISK FACTOR FOR NEUROINFLAMMATORY DISEASES." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2021. http://hdl.handle.net/10281/306486.
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L'elevata prevalenza di disturbi metabolici e cognitivi rappresenta uno dei maggiori problemi della salute umana. Recenti scoperte indicano che l'obesità può influenzare le funzioni cerebrali, tuttavia l'effetto di una dieta ricca di grassi sul sistema nervoso centrale non è ancora completamente compreso. Lo scopo di questo studio è la valutazione dell'influenza della dieta grassa sulla neuro infiammazione e sulla funzione cerebrale regionale in un modello murino di insulino-resistenza, con particolare attenzione alle differenze dipendenti dal sesso.
I topi maschi e femmine C57BL/6J sono stati nutriti con dieta standard o dieta grassa (due tenori: 45% / 60% di grassi) per 35 settimane. Gli animali sono stati monitorati settimanalmente per analizzare le variazioni di peso corporeo, analisi ematochimiche (glucosio circolante, colesterolo totale, ALT e AST) e test di tolleranza al glucosio. Gli studi di imaging con tomografia a emissione di positroni (PET) sono stati eseguiti longitudinalmente utilizzando [18F] -FDG e [18F] -VC701 come radio-traccianti, per misurare rispettivamente il consumo di glucosio e l'attivazione di microglia / macrofagi all'interno del cervello. La risonanza magnetica (RM) e la spettroscopia a risonanza magnetica (SRM) sono state utilizzate per misurare gli effetti della dieta sul contenuto lipidico epatico e sull'accumulo di grasso peri addominale. Infine, l'analisi della trascrittomica post-mortem è stata applicata alla corteccia anteriore al fine di rivelare potenziali modifiche nell'espressione genica.
La dieta grassa introduce in modo significativo un aumento del peso corporeo, della tolleranza al glucosio e dei parametri ematochimici che variano in base al sesso. Anche l'accumulo di grasso peri addominale nel maschio e il contenuto di lipidi nel fegato, come rivelato alla spettroscopia RM, sono stati osservati in tale modello. Quest'ultimo effetto è stato particolarmente evidente nelle femmine. La PET [18F]-FDG ha mostrato un aumento relativo del metabolismo del glucosio nella regione anteriore del cervello, inclusi i bulbi olfattivi sia nei topi maschi che in quelli femmine, mentre l'aumento osservato nella corteccia anteriore è stato riscontrato solamente nei topi maschi alimentati con il 60% di dieta grassa. Inoltre, l'analisi della correlazione tra l'assorbimento del glucosio cerebrale e i diversi biomarcatori metabolici ha rivelato, principalmente nei topi maschi, modificazioni metaboliche cerebrali regionali associate a valori di BMI e parametri ematochimici. Lo studio PET condotto con il tracciante [18F]-VC701 ha mostrato una tendenza generale verso un aumento dell'assorbimento del tracciante in tutto il cervello dopo il consumo di dieta grassa nei topi maschi e femmine. L'analisi della trascrittomica nella corteccia anteriore ha mostrato una comune de-regolazione dei geni associati allo sviluppo del sistema nervoso, ma anche modificazioni specifiche legate al sesso.
Il nostro studio suggerisce che l'obesità indotta da regime alimentare di dieta grassa nei topi adulti, causa un deterioramento metabolico generale non confinato alla periferia ma che coinvolge anche regioni cerebrali selezionate. L'aumento del segnale del tracciante per la proteina TSPO suggerisce che l'obesità può indurre una reazione neuro-infiammatoria diffusa nel cervello dei topi di entrambi i sessi. La tecnica di imaging PET è stata usata per identificare la presenza di squilibrio metabolico e risposta neuro-infiammatoria del cervello di topo sotto regime alimentare di dieta grassa. Questo dato è rilevante poiché il nostro modello riproduce le alterazioni metaboliche periferiche tipiche della sindrome di insulino resistenza e del diabete di tipo 2.The high prevalence of metabolic and cognitive disorders represents one of the major issues of health systems. Recent findings indicate that obesity may affect brain functions however the effect of a high-fat diet (HFD) on the central nervous system is not fully understood. The aim of this study is the evaluation of the influence of HFD on neuroinflammation and regional brain function in a mouse model of Insulin Resistance (IR) focusing on sex-dependent differences induced by peripheral metabolic impairment. C57BL/6J male and female mice were fed with standard chow or HFD (45%/60%) for 35 weeks. Animals were monitored weekly for body weight, haemato-chemical analysis (circulating glucose, total cholesterol, ALT, and AST), and glucose tolerance test (GTT). Positron Emission Tomography (PET) imaging studies were performed longitudinally using [18F]-FDG and [18F]-VC701 as radiotracers, to measure respectively glucose consumption and microglia/macrophages activation within the brain. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) was used to measure the effects of diet on hepatic lipid content and peri abdominal fat accumulation. Finally, post-mortem transcriptome analysis was applied to the anterior cortex to reveal potential modification in gene expression. HFD induced a significant increase in body weight, glucose tolerance, and haemato-chemical parameter in a sex dependent manner. HFD diet increased peri abdominal fat accumulation in male and lipid content in the liver as revealed at MR spectroscopy. This last effect was particularly evident in females. PET [18F]-FDG showed a relative increase in glucose metabolism in the anterior region of the brain including the olfactory bulbs in both male and female mice while an increase in the anterior cortex was found in males mice fed with 60% HFD. Moreover, correlation analysis between glucose uptake and different metabolic biomarkers revealed, mainly in male mice, regional brain metabolic modifications associated with BMI values and haemato-chemical parameters. [18F]-VC701-PET showed a general trend toward an increase of tracer uptake all over the brain after diet consumption in both male and female HFD mice. Anterior cortex transcriptome analysis showed a common de-regulation of genes related to nervous system development but also sex-specific modifications. Our finding suggests that HFD induced obesity in adult mice causes a general metabolic impairment not confined in the periphery but involving also selected brain regions. The increased binding of the activated microglia associated with TSPO radioligand suggests that obesity can induce a diffuse neuro-inflammatory reaction in mice's brains. PET imaging technique is permitted to identify the presence of metabolic derangement and the neuro-inflammatory response of mice brain induced by HFD. This finding is relevant since our model reproduces the peripheral metabolic modification typical of IR and type 2 diabetes.
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Newbold, Marcus Clifford Thomas John. "Mapping metabolite concentrations in grey and white matter using magnetic resonance spectroscopic imaging (MRSI)." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392143.
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Lewis, Charlotte Reininger. "Desorption Electrospray Ionization (DESI) Mass Spectrometric Imaging of Spatially Regulated In Vivo Metabolic Rates." BYU ScholarsArchive, 2017. https://scholarsarchive.byu.edu/etd/6555.
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Desorption electrospray ionization (DESI) is an ambient ionization technique used for mass spectrometric imaging of biological samples. When coupled with isotopic ratio measurements of deuterium-labeled tissues, DESI provides a means of measuring metabolic rates on a spatially resolved basis. In vivo metabolic rates are desired to better understand diseases such as Alzheimer's, Parkinson's, Huntington's, and various forms of cancer that negatively impact metabolic rates within different organs of the human body. Although DESI has been used to image lipids and metabolites of a variety of tissues and other imaging techniques, such as NIMS, have been used to study kinetic turnover rates, DESI has not yet been used to study in vivo metabolic rates using deuterium labeled tissue. This thesis describes how we optimized our DESI source for imaging of biological tissue, how we developed a MATLAB graphical user interface (GUI) to process and interpret the large mass spectral data files, how we conducted our initial mouse brain study for proof-of-concept, and how we plan to implement our DESI imaging in a study with mouse models of Alzheimer's disease. Our initial mouse brain study involved labeling mice with deuterium enriched water, preparing tissue slices for DESI analysis, imaging the tissue slices using DESI coupled with a Bruker mass spectrometer, analyzing the mass spectral data using our custom-designed image_inspector program, confirming identification of lipids using MS/MS, and creating incorporation curves to measure in vivo metabolic rates.
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Kelly, Douglas James. "An automated fluorescence lifetime imaging multiwell plate reader : application to high content imaging of protein interactions and label free readouts of cellular metabolism." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/29131.
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This thesis reports on work performed in the development and application of an automated plate reading microscope implementing wide field time gated fluorescence lifetime imaging technology. High content analysis (HCA) imaging assays enabled by automated microscopy platforms allow hundreds of conditions to be tested in a single experiment. Though fluorescence lifetime imaging (FLIM) is established in life sciences applications as a method whereby quantitative information may be extracted from time-resolved fluorescence signals, FLIM has not been widely adopted in an HCA context. The FLIM plate reader developed throughout this PhD has been designed to allow HCA-FLIM experiments to be performed and has been demonstrated to be capable of recording multispectral, FLIM and bright field data from 600 fields of view in less than four hours. FLIM is commonly used as a means of reading out Förster resonance energy transfer (FRET) between fluorescent fusion proteins in cells. Using the FLIM plate reader to investigate large populations of cells per experimental condition without significant user input has allowed statistically significant results to be obtained in FRET experiments that present relatively small changes in mean fluorescent lifetime. This capability has been applied to investigations of FOXM1 SUMOylation in response to anthracycline treatment, and to studies of the spatiotemporal activation profiles of small GTPases. Furthermore, the FLIM plate reader allows FLIM-FRET to be applied to protein-protein interaction screening. The application of the instrument to screening RASSF proteins for interaction with MST1 is discussed. The FLIM plate reader was also configured to utilise ultraviolet excitation radiation and optimised for the measurement of autofluorescence lifetime for label-free assays of biological samples. Experiments investigating the autofluorescence lifetime of live cells under the influence of metabolic modulators are presented alongside the design considerations necessary when using UV excitation for HCA-FLIM.
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Brooks, Augustin Marchand Standish. "Metabolic outcomes of islet transplantation and correlation of graft function with hepatic imaging and immune response." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2997.
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Introduction Recipients of an islet transplant at all UK NHS-funded centres were invited to take part in an ethically approved experimental medicine follow-up study. Objectives were to determine metabolic outcomes post-intervention and identify potential surrogate markers for graft failure. Methods Assessment of islet recipients was undertaken pre-transplant, 1 month post-transplant and 3-6 monthly thereafter. Clinical review included HbA1c, hypoglycaemia frequency, insulin requirements, donor specific antibody (DSA) screening, magnetic resonance imaging (MRI) for hepatic fat assessment and continuous glucose monitoring (CGM) one week prior to standardised meal tolerance test (MTT). Results Twenty recipients received 35 islet infusions (single graft:n=7; two:n=11; three:n=2; transplant mass per recipient (median[IQR]) 8770(6536-13045) IEQ/kg), with all recipients receiving induction and maintenance immunosuppression. Graft function was maintained in 80% of recipients at 24(13.5-36) months. Frequency of severe hypoglycaemia reduced from 20(7-50) to 0.3(0-1.6) episodes per patient-year (p<0.001), with improved hypoglycaemia awareness (Gold score: pre-transplant 6(5-7); post-transplant 3(1.5-4.5); p<0.03) and HbA1c 6.2(5.7-8.4)% post-transplant, and cessation of exogenous insulin in 45% of recipients. In a single site sub-study, CGM demonstrated a continuous relationship between stimulated C-peptide and glucose variability, hyperglycaemia risk and hypoglycaemia risk. No significant difference in liver fat fraction was noted pre and post-transplant (p=0.94), and no direct correlation with 90 minute C-peptide on MTT at 12 months was identified. DSA was detected in 5/23(21.7%) grafts in 14 recipients and was associated with rapid graft failure. Conclusions The primary goals of the UK islet transplant program to prevent recurrent life-threatening hypoglycaemia and restore optimal glycaemic control in recipients have been attained up to 36 months post-transplant. Demonstration of a continuous relationship between endogenous C-peptide secretory capacity and parameters of glycaemic control has substantial implications for therapeutic interventions maintaining endogenous insulin production in individuals with type 1 diabetes. Therapeutic interventions preventing DSA formation post-transplant might improve graft outcomes.
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Tayyabi, Ehsen. "Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37338.
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Adverse drug reactions are common causes of medical injuries. Drug-induced hepatotoxicity remains one of the leading causes of emergency room visits, FDA non-approval, and drug withdrawal from the market. We have investigated the ability of endogenous nucleophilic amino acid residues (K, H, and C) to selectively bind to reactive electrophilic drug metabolites, focusing on acetyl-para-aminophenol (APAP, i.e. Tylenol®), for which hepatotoxicity has recently re- emerged as a major health concern for Canadians. Three peptide sequences were synthesized bearing terminal nucleophilic residues, brominated phenylalanine residues, and c-terminal amides. These peptides were coupled to carboxy methyl dextran coated iron oxide nanoparticles (CMX- IONPs) with a hepatocyte targeting group. IONPs are known for their ability to act as T2-weighted MRI contrast agents, giving us the ability to track them in vivo. This study begins to establish a nanotechnology-based method for the in vivo trapping of NAPQI, the reactive metabolite of APAP, using a cysteine bearing IONP.
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Msayib, Yunus. "Quantifying impaired metabolism following acute ischaemic stroke using chemical exchange saturation transfer magnetic resonance imaging." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:a98323ce-5998-436d-bca4-09df549cf191.
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In ischaemic stroke a disruption of cerebral blood flow leads to impaired metabolism and the formation of an ischaemic penumbra in which tissue at risk of infarction is sought for clinical intervention. In stroke trials, therapeutic intervention has largely been based on perfusion-weighted measures, but these have not been shown to be good predictors of tissue outcome. The aim of this thesis was to develop analysis techniques for magnetic resonance imaging (MRI) of chemical exchange saturation transfer (CEST) in order to quantify metabolic signals associated with tissue fate in patients with acute ischaemic stroke. This included addressing robustness for clinical application, and developing quantitative tools that allow exploration of the in-vivo complexity. Tissue-level analyses were performed on a dataset of 12 patients who had been admitted to the John Radcliffe Hospital in Oxford with acute ischaemic stroke and recruited into a clinical imaging study. Further characterisation of signals was performed on stroke models and tissue phantoms. A comparative study of CEST analysis techniques established a model-based approach, Bloch-McConnell model analysis, as the most robust for measuring pH-weighted signals in a clinical setting. Repeatability was improved by isolating non-CEST effects which attenuate signals of interest. The Bloch-McConnell model was developed further to explore whether more biologically-precise quantification of CEST effects was both possible and necessary. The additional model complexity, whilst more reflective of tissue biology, diminished contrast that distinguishes tissue fate, implying the biology is more complex than pH alone. The same model complexity could be used reveal signal patterns associated with tissue outcome that were otherwise obscured by competing CEST processes when observed through simpler models. Improved quantification techniques were demonstrated which were sufficiently robust to be used on clinical data, but also provided insight into the different biological processes at work in ischaemic tissue in the early stages of the disease. The complex array of competing processes in pathological tissue has underscored a need for analysis tools adequate for investigating these effects in the context of human imaging. The trends herein identified at the tissue level support the use of quantitative CEST MRI analysis as a clinical metabolic imaging tool in the investigation of ischaemic stroke.
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RACCAGNI, ISABELLA. "PET imaging as a biomarker of tumor response to therapy." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/76240.
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Le tecniche di imaging molecolare permettono di visualizzare e caratterizzare processi biologici e rivestono un ruolo fondamentale in oncologia, consentendo di identificare marcatori per la diagnosi e la risposta al trattamento. In questo lavoro di tesi è stato valutato il ruolo della PET come possibile marcatore di risposta al trattamento in a) un modello con k-ras oncogenico e b) un modello di glioma, focalizzando l’attenzione sulle alterazioni del metabolismo e l’ipossia.
L’incremento della glicolisi e del consumo di glutammina sono associati a mutazioni dell’oncogene ras in diversi tumori. Il disaccoppiamento di tali processi determina una riprogrammazione del metabolismo per supportare l’aumentata proliferazione fornendo un interessante target terapeutico. Scopo dello studio è la valutazione in vivo delle alterazioni metaboliche e della risposta alla terapia nel modello ottenuto mediante inoculo di fibroblasti con k-ras oncogenico (NIH-RAS). A tale scopo gruppi di topi sono stati monitorati longitudinalmente mediante PET-[18F]FDG e [18F]FLT per la valutazione del metabolismo glucidico e della proliferazione cellulare. I tumori sono stati sottoposti ad analisi immunoistochimiche per confermare i dati ottenuti in vivo. Nello stesso modello è stato valutato l’effetto di un inibitore dell’autofagia (Clorochina) e della glutaminasi (BPTES) singolarmente e in combinazione mediante PET-[18F]FDG e [18F]FLT. Gli animali hanno sviluppato in breve tempo tumori glicolitici e caratterizzati da un’omogenea captazione di [18F]FDG e [18F]FLT. Le immagini PET hanno mostrato un aumento della captazione di [18F]FDG nel tempo e un andamento stabile della proliferazione come mostrato dalla costante captazione di [18F]FLT. Clorochina e BPTES in combinazione hanno determinato un rallentamento della crescita tumorale rispetto ai controlli, ma non sono state osservate variazioni nella captazione di [18F]FDG e [18F]FLT. La presenza di vie alternative per la produzione di glutammato e la necessità di dosi più elevate potrebbero spiegare l’assenza di efficacia di questi trattamenti.
L’ipossia rappresenta un fenomeno sfavorevole per la progressione tumorale. L’espressione di HIF1α, principale regolatore dell’ipossia, è associata alla resistenza alla terapia in molti tumori, compreso il glioma. Per questo, una migliore comprensione della modulazione dell’attività di HIF1α nel processo di risposta alla terapia è di particolare interesse.
Cellule di glioma U251-HRE-mCherry in grado di esprimere l’enzima luciferasi sotto il controllo di HRE (Hypoxia Responsive Element) e mCherry sotto controllo di un promotore costitutivo sono state utilizzate per valutare la modulazione di HIF1α in seguito a trattamento con Temozolomide (TMZ) in vitro e in vivo. La crescita tumorale è stata monitorata in vivo in animali sottoposti ad inoculo intracerebrale tramite bioluminescenza, fluorescenza, RM e PET con [18F]FAZA e [18F]FLT. In seguito, è stato valutato in vivo l’effetto di due diversi regimi di TMZ. Mediante bioluminescenza è stato possibile monitorare la crescita tumorale e identificare aree ipossiche. I dati ottenuti sono stati confermati dalle immagini di fluorescenza e PET-[18F]FAZA. Le analisi ex vivo per Ki67 hanno invece confermato i dati PET-[18F]FLT ed hanno mostrato un’elevata proliferazione cellulare. Entrambi i dosaggi di TMZ hanno determinato una diminuzione dell’attività di HIF1α a tempi precoci. Al contrario, il segnale di fluorescenza e la captazione di [18F]FLT hanno subìto una diminuzione solo a tempi più tardivi.
L’attività di HIF1α può essere considerata un marcatore di risposta al TMZ e questo modello un utile strumento per la valutazione in vivo di farmaci per il trattamento del glioma.Molecular imaging allows the non-invasive visualization and characterization of biological processes. It can be used in oncology to identify biomarkers for the evaluation of tumor progression and response to therapy. In this thesis work, the animal PET was used as potential biomarker of tumor response to therapy focusing on altered metabolism and hypoxia in a) a model of oncogenic k-ras and b) in a model of glioma. Metabolic alterations, such as increased glycolysis and glutamine consumption, are associated with mutations in k-ras gene. The decoupling of glucose and glutamine uptake leads to a reprogramming of their metabolism to support cell proliferation representing a target for cancer therapy. The aim of this study is to investigate metabolic alterations in k-ras transformed fibroblasts (NIH-RAS) in in vivo studies and to assess response to therapy. Animals subcutaneously implanted with NIH-RAS performed [18F]FDG- and [18F]FLT-PET at several time points to evaluate glucose metabolism and cell proliferation, respectively. Tumors were collected and evaluated for different markers by immunohistochemistry (IHC) to confirm in vivo results. In the same model, the efficacy of chloroquine (autophagy blocker) and BPTES (glutaminase inhibitor) alone or in combination was monitored by [18F]FDG- and [18F]FLT-PET before and 48 hours after treatments. All animals developed fast growing and highly glycolytic tumors in few days that appear homogeneous for both [18F]FDG and [18F]FLT uptake. PET imaging showed a significant increase in [18F]FDG uptake while cell proliferation remained stable over time, as depicted by [18F]FLT uptake. IHC analyses confirmed the high aggressiveness of these cells. Chloroquine and BPTES combined treatment slowed down tumor growth only if compared to vehicle, without affecting glucose metabolism or cell proliferation. The presence of alternative pathways for glutamate production and the need of higher doses of treatments may provide explanations to the lack of treatments’ efficacy. Hypoxia is implicated in many aspects of tumor progression and it is involved in the intracellular stabilization of the hypoxia regulator gene HIF-1α. Since the expression of HIF-1α is associated with poor prognosis and therapy resistance in glioblastoma, a better comprehension of its involvement in tumor response to treatment can be of great interest for clinical translation. U251-HRE-mCherry cells expressing Luciferase under control of a Hypoxia Responsive Element (HRE) and mCherry under the control of a constitutive promoter have been used to assess HIF-1α modulation and cell survival after treatment, both in vitro and in vivo. In vivo analyses characterized the model obtained by stereotaxic injection of glioma U251-HRE cells in mice brain. Tumor progression was monitored comparing bioluminescence, fluorescence and PET with [18F]FAZA and [18F]FLT. Afterwards, two regimens of temozolomide (TMZ) were administered starting 21 days after cells injection. TMZ efficacy was monitored by optical and fluorescence imaging, [18F]FLT-PET and MRI. Bioluminescent signals provided information about tumor growth and hypoxia presence, confirmed by both fluorescence acquisition and [18F]FAZA PET. IHC for Ki67 confirmed data obtained by [18F]FLT-PET, showing a high rate of cell proliferation. Both TMZ regimens showed a decrease of HIF-1α-dependent Luciferase activity at early time after TMZ administration. On the contrary, mCherry fluorescence, such as [18F]FLT uptake, decreased only at the end of treatments. HIF-1α activity reduction can be considered a biomarker of tumour response to TMZ and the U251-HRE-mCherry cell model a feasible tool to evaluate HIF-1α activity and treatment effects in in vivo studies.
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Zhang, Yifan. "Metabolic Energy Balances in Ketotic Rat Brain." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1370371336.
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Fällmar, David. "Visual assessment of perfusion and metabolism in neurodegenerative dementia." Doctoral thesis, Uppsala universitet, Radiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-304731.
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A worldwide demographic shift is currently occurring, with rapidly increasing numbers of elderly individuals. Since the incidence of neurodegenerative disease generally increases with age, this entails an increase in dementia prevalence. There are several strong incentives for establishing robust and widely available imaging methods for the early diagnosis of these diseases. Atrophy patterns are evident only late in the disease process, and the distinction from healthy ageing can often be elusive. For early diagnosis, physiologic parameters such as perfusion or metabolism must be assessed. The available modalities all have restricted clinical usefulness. The main aim of this thesis was to advance the clinical usefulness of perfusion and metabolism imaging in patients with neurodegenerative dementia, with a focus on visual assessment. A cohort of patients with neurodegenerative dementia was included, along with an age-matched control group. All subjects underwent MRI, including a pseudocontinuous ASL sequence and FDG-PET. In papers II and III, a subgroup containing both patients and controls underwent a second FDG-PET with reduced dose. In paper IV, the material was combined with a similar cohort from Amsterdam. Paper I showed that spatial smoothing increased the correlation between visually assessed perfusion and metabolism levels as displayed with FDG-PET. However, the distinction between patients and healthy controls was less satisfactory due to false positives. Paper II showed that differences in regional standard uptake value ratios between normal- and low-dose FDG-PET were small and without clinically significant bias. Paper III showed that the diagnostic performance of Z-score maps showing regions of significant deficits in metabolism was highly similar in normal- and low-dose FDG-PET images. Paper IV showed that ASL perfusion-based Z-score maps can be used for diagnostic purposes with high specificity, but inferior sensitivity, compared to FDG-PET. In conclusion, the included studies address aspects of the visual assessment of perfusion and metabolism neuroimaging, with a focus on clinical usefulness in diagnosing neurodegenerative dementia.
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Ibrahim, Hassana Aisha. "Interactions between fMRI BOLD-activation during Reading Tasks and MRS-measured Metabolite Levels." Yale University, 2008. http://ymtdl.med.yale.edu/theses/available/etd-08092007-144458/.
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Recent studies in the field of dyslexia have used magnetic resonance spectroscopy (MRS) to explore neurochemical manifestations of neurobiological differences in the brains of dyslexic adults compared to controls. This study examines the potential relationship between functional magnetic resonance imaging (fMRI) BOLD (blood oxygen level demand) activation scores in response to cognitive tasks and MRS-measured levels of a metabolite and a neurotransmitter, N-acetylaspartate (NAA) and gamma-aminobutyric acid (GABA) respectively, in the occipital region of brains of seven-year old children. Preliminary results from this multi-arm, longitudinal study indicate a significant positive correlation between fMRI BOLD signal elicited in response to picture-cues in the occipital region of interest bilaterally, and both GABA (R2=0.477 p=0.05, 2-tailed) and NAA (R2=0.587 p=0.01, 2-tailed) levels. The results suggest that the functional neuroanatomical circuitry involved in a cognitive task also has neurochemical indicators.
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Melo, Marcelo Dantas Tavares de. "Avaliação da perfusão e do metabolismo glicolítico miocárdicos na miocardiopatia não-compactada isolada." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-15122017-121538/.
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Introdução: O miocárdio não-compactado é uma doença genética rara de fisiopatologia desconhecida e controversa. Vários fatores têm sido implicados na fisiopatologia, como a disfunção da microcirculação, a perda da torção ventricular, distúrbios mitocondriais e mutações. A alteração do metabolismo cardíaco ocorre precocemente a disfunção diastólica e sistólica, reforçando a relevância desse estudo na análise combinada de tomografia de emissão de pósitron (PET) com 18F-Fluor-2-desoxiglicose e cintilografia de perfusão miocárdica com 99mTc-sestamibi pela tomografia por emissão de fóton simples (SPECT) e suas implicações clínicas. Métodos: Trinta pacientes com miocárdio não-compactado (41 ± 12 anos, 53% do sexo masculino), diagnosticados pelos critérios da ressonância magnética cardíaca, e 8 indivíduos saudáveis (42 ± 12 anos, 50% do sexo masculino) foram recrutados prospectivamente para serem submetidos a análise de perfusão miocárdica pelo SPECT e da captação miocárdica de glicose marcada pela PET. Resultados: Os pacientes apresentaram valores de captação de glicose miocárdica (CMG) menor que os controles (36.9 +- 8.8 vs. 44.6 +- 5.4 umol/min/100g, respectivamente, P = 0.02). Analisando a captação nos 17 segmentos de ambos os grupos, a CGM foi significativamente reduzida em 8 segmentos dos pacientes (P < 0,05). A diferença da média da captação miocárdica de glicose de todos os segmentos do grupo controle em relação a média dos segmentos compactados dos pacientes foi de 8,3 ?mol/min/100g (p < 0,001). Déficit de perfusão foi demonstrado em 15 (50%) dos pacientes, correspondendo a 45 segmentos do ventrículo esquerdo, destes 64,4% com padrão match e 35,6% com padrão mismatch pela análise de perfusão e metabolismo cardíaco. Nas análises univariada e multivariada foram observadas que o betabloqueador aumenta a CMG (coeficiente beta = 10.1, P = 0.008), como também ocorre um aumento gradual da CMG naqueles com doses mais elevadas (P para tendência linear = 0.01). Conclusão: A redução da captação miocárdica de glicose suporta a hipótese de que um mecanismo metabólico celular possa ter um papel na fisiopatologia do miocárdio não compactado. O betabloqueador demonstrou um efeito incremental dosedependente na captação miocárdica de glicose nos pacientes com miocárdio não-compactado, essa modulação do substrato cardíaco necessita de mais estudos para comprovação do benefício clínico nessa populaçãoBackground: Noncompaction cardiomyopathy (NCC) is a rare genetic disease with unknown and controversial pathophysiology. Several factors have been implicated such as microvascular dysfunction, loss of ventricular torsion, mitochondrial disorders, and genetic mutations. The change in cardiac metabolism occurs before the diastolic and systolic dysfunction, reinforcing the relevance of this study by the combined analysis of positron emission tomography with 18F-Fluor-2-deoxyglucose (PET) and myocardial perfusion scintigraphy with 99mTc-sestamibi by single-photon emission computed tomography (SPECT) and their clinical implications. Methods: Thirty patients (41 ± 12 years, 53% male) with NCC, diagnosed by cardiovascular magnetic resonance criteria, and 8 age-matched healthy controls (42 ± 12 years, 50% male) were prospectively recruited to undergo FDG-PET with measurement of the myocardial glucose uptake rate (MGU) and SPECT in order to investigate perfusion-metabolism patterns. Result: Patients with LVNC had lower global MGU compared with that in controls (36.9 +- 8.8 vs. 44.6 +- 5.4 +-mol/min/100g, respectively, P = 0.02). Of 17 LV segments, MGU levels were significantly reduced in 8, and also a reduction was observed when compacted segments from LVNC were compared with the segments from control subjects (P < 0,05). The difference in mean myocardial glucose uptake of all segments of the control group compared to the mean of the compact segments of the patients was 8.3 ?mol/min/100g (p < 0,001). Perfusion defects were also found in 15 (50%) patients (45 LV segments: 64.4% match, and 35.6% mismatch perfusionmetabolism pattern). Univariate and multivariate analyses showed that betablocker therapy was associated with increased MGU (beta coefficient=10.1, P = 0.008). Moreover, a gradual increase occurred in MGU across the beta-blocker dose groups (P for trend = 0.01). Conclusions: The reduction of MGU documented by FDG-PET in LVNC supports the hypothesis that a cellular metabolic pathway may play a role in the pathophysiology of LVNC. Betablocker demonstrated an incremental dose-dependent effect on myocardial glucose uptake in patients with NCC. The beneficial effect of beta-blocker mediating myocardial metabolism in the clinical course of LVNC requires further investigation
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Hou, Jue. "Characterizing Breast Cancer Invasive Potential Using Combined Label-Free Multiphoton Metabolic Imaging of Cellular Lipids and Redox State." Thesis, University of California, Irvine, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10288401.
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Aerobic glycolysis (Warburg effect) is accompanied by significant alterations in cellular redox state and constitutes one of the hallmarks of cancer cell metabolism. Label-free multi-photon microscopy (MPM) methods based on two-photon excited fluorescence (TPEF) have been used extensively to form high-resolution images of redox state in cells and tissues based on intrinsic NADH and FAD+ fluorescence. However, changes in cellular redox alone are insufficient to fully characterize cancer metabolism and predict invasive potential. We demonstrate that label-free MPM measurements of TPEF-derived redox state (optical redox ratio, ORR = FAD+/(FAD + NADH)) combined with coherent Raman imaging of lipid formation can be used to quantitatively characterize cancer cells and their relative invasive potential. In addition, we confirm, using coherent Raman and deuterium labeling methods, that glucose is a significant source for the cellular synthesis of lipid biomass in glycolytic breast cancer cells. Live cell metabolism was imaged in 3D models of primary mammary epithelial cells (PME) and 2 cancer cell lines, T47D and MDA-MB-231. While we observed overlap in the distribution of the optical redox ratio between these different cell lines, the combination of ORR and lipid volume fraction derived from coherent Raman signals provided complementary independent measures and clear separation. Furthermore, we observed an increase in both lipid synthesis and consumption rates in E2-treated T47D cancer cells cultured in deuterated glucose by tracking the formation and disappearance of deuterated lipids. These results suggest that due to the relatively wide range of ORR values that reflect the natural diversity of breast cancer cellular redox states, the addition of lipid signatures obtained from coherent Raman imaging can improve our ability to characterize and understand key metabolic features that are hallmarks of the disease.
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Zöllner, Helge [Verfasser], and Thomas [Gutachter] Heinzel. "Metabolic investigations in patients with hepatic encephalopathy by magnetic resonance imaging and spectroscopy / Helge Zöllner ; Gutachter: Thomas Heinzel." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1203370008/34.
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Asiri, Sumayyah. "Role of Cu metabolism in the cisplatin-sensitive and resistant ovarian cancer cells." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29652.
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Ovarian cancer is the fourth most common cancer among women worldwide, leading to high mortality rates. Platinum anti-cancer drugs have been widely used in the treatment of ovarian cancers, but the development of resistance to these drugs is a rapidly growing impediment for their clinical use. Studies of the cell morphology using IncuCyte Zoom and HoloMonitor M4 have shown that A2780.CisR cells contained heterogeneous cell populations that partially underwent epithelial-to-mesenchymal transition (EMT). Mesenchymal A2780.CisR cells were likely to be more resistant to a cytotoxic natural killer (NKL) cell line, compared with the epithelial A2780 cells. Mesenchymal phenotype was associated with lower total Cu content and higher total Fe content in A2780.CisR compared with A2780 cells under physiologically relevant conditions (2.0 M Cu(II) or 10 M Fe(III) for 24 h). Conversely, live cell confocal microscopy studies with a novel ratiometric Cu(I)-sensitive fluorescent dye, InCCu1, revealed higher cellular content of labile Cu in A2780.CisR cells compared with A2780 cells. Moreover, the InCCu1 dye showed promise for differential staining of multiple cellular organelles, including mitochondria, endosomes/lysosomes, fat droplets and budding extracellular vesicles. Fat droplets were more abundant in A2780.CisR compared with A2780 cells and concentrated at the advancing edges of cellular protrusions (shown by InCCu1 and Nile Red staining). Comparison of the biochemical content of cell membranes using ATR-FTIR (attenuated total reflection Fourier transform infrared) spectroscopy technique showed higher relative content of fatty acids and cholesterol in the membranes and surrounding environments of A2780.CisR compared with A2780 cells.
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Wang, Charlie Wang. "High Energy Phosphate Metabolism Measurement by Phosphorus-31 Magnetic Resonance Fingerprinting." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1509364666422789.
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