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Title: Quantification of Imaging Markers at Different MRI Contrast Weightings, Vasculature, and Across Field Strengths
Creator: Nguyen, Vivian S.
Date: 2024
Description: Quantitative MRI measures physical characteristics of tissue, which creates a set scale with units that allows longitudinal monitoring and...
Show moreQuantitative MRI measures physical characteristics of tissue, which creates a set scale with units that allows longitudinal monitoring and cross-patient and cross-center studies. It enables earlier detection of disease, complements biopsy, and provides a clear numeric scale for differentiation of disease states. However, quantitative MRI acquisitions and post-processing are not trivial, which makes it hard to implement the clinical setting. This along with the variability in clinically used acquisitions and post-processing techniques leads to difficulty in establishing reliable, consistent, and accurate quantitative information. There is a critical need for rigorous validation of quantitative imaging biomarkers, both for current and novel quantitative imaging techniques. This dissertation seeks to both validate current quantitative MR imaging techniques and develop new ones in the heart and brain by: 1) examining the data variability and the loss in tag fidelity that occurs when quantitative cardiac tagging is incorrectly run post-Gadolinium injection; 2) quantifying the negative impact of unexpected relaxometric behavior observed in low field MR imaging for low inversion times during T1 mapping; 3) validating retrospectively calculated T1 as a biomarker for Multiple Sclerosis progression; 4) and prototyping an oxygen extraction fraction (OEF) mapping technique for the purpose of stroke prediction and establishment of a numeric scale for tissue health for stroke patients.Assessment of pre-Gadolinium and post-Gadolinium cardiac tag quality showed that post-Gadolinium tags are less saturated (p = 0.012) and have a wider range of saturation, contrast, and sharpness. This results in a loss of information in the late cardiac cycle and impeding quantification of myocardial function.Investigation of 64mT T1 mapping revealed unique relaxometric behavior in that at low inversion times (<250 ms), the signal response curve displayed an increase in signal intensity or a plateau in signal intensity dependent on T1 relaxation time. Inclusion of this increase or plateau in signal intensity negatively impacted T1 fitting algorithms, leading to their failure or incorrectly calculated T1 values. The maximum peak signal intensity before the null point was found to be 210 ms, which impacts current low field T1 mapping protocols which use an initial inversion time of 80-110 ms.Validation of retrospectively calculated T1 as a biomarker in Multiple Sclerosis revealed that T1 of normal appearing brain tissue correlates with measures of Multiple Sclerosis progression (EDSS, BPF, and disease duration) with normal appearing white matter T1 correlating with BPF (r = -0.49, p = 0.0018); putamen T1 correlating with EDSS (r = 0.48, p = 2.40e-03), with BPF (r = 0.69, p = 2.04e-06), and disease duration (r = -0.37; p = 0.02); and globus pallidus T1 correlating with disease duration (r = -0.42; p = 0.0093). Lesion T1 is reflective of MS severity whereas MTR is not.Finally, development of an oxygen extraction fraction (OEF) mapping technique showed that application of independent component analysis (ICA) to cardiac gated spiral-trajectory phase images yielded components that feature stenosis features observed in magnitude images. These ICA components form the basis of OEF mapping from phase images. This dissertation presents four studies that seek to improve either current quantitative MR imaging protocols in the heart, or to develop and validate new quantitative MR imaging techniques in the brain for the purpose of monitoring disease progression or predicting disease.
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Title: NON-DESTRUCTIVE CANCER DETECTION IN LYMPH NODE USING PAIRED-AGENT MOLECULAR IMAGING
Creator: Li, Chengyue
Date: 2020
Description: Identification of cancer spread to tumor-draining lymph nodes through lymph node dissection and histology offers critical information for...
Show moreIdentification of cancer spread to tumor-draining lymph nodes through lymph node dissection and histology offers critical information for guiding treatment in many cancer types, including breast, melanoma, head and neck, lung and gynecologic cancers, as the lymphatic system serves as the primary route for metastasis. Lymph node biopsy involves localization of tumor-draining lymph nodes, followed by their surgical removal and histological assessment. However, the procedure is associated with overtreatment concerns and some considerable morbidity, including lymphedema, seroma formation, and restricted arm movement. Moreover, conventional histological analyses are time-consuming and laborious, yet pathologists generally examine less than 1% of the volume of each lymph node, leading to undetected micrometastasis (tumor clusters 0.2-2mm in diameter) in 30-60% of cases. In response to these limitations in standard lymph node dissection protocol, there is a significant need for the development of lymph node imaging strategies that are capable of identifying metastatic cancer as a means of staging a patient’s cancer without the need for invasive and time-intensive conventional pathology. Paired-agent imaging molecular imaging protocols have been spearheaded by our group and entail co-administration of a control imaging agent with a molecular targeted agent as a way to account for nonspecific uptake and retention. The overall goal of my thesis was to methodically design, optimize and evaluate the clinical utility of a paired-agent lymph node imaging protocol to achieve levels of sensitivity and specificity in nodal staging not possible with current conventional methods, less invasively and at a fraction of the time and cost.
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Title: IMPACT OF DATA SHAPE, FIDELITY, AND INTER-OBSERVER REPRODUCIBILITY ON CARDIAC MAGNETIC RESONANCE IMAGE PIPELINES
Creator: Obioma, Blessing Ngozi
Date: 2020
Description: Artificial Intelligence (AI) holds a great promise in the healthcare. It provides a variety of advantages with its application in clinical...
Show moreArtificial Intelligence (AI) holds a great promise in the healthcare. It provides a variety of advantages with its application in clinical diagnosis, disease prediction, and treatment, with such interests intensifying in the medical image field. AI can automate various cumbersome data processing techniques in medical imaging such as segmentation of left ventricular chambers and image-based classification of diseases. However, full clinical implementation and adaptation of emerging AI-based tools face challenges due to the inherently opaque nature of such AI algorithms based on Deep Neural Networks (DNN), for which computer-trained bias is not only difficult to detect by physician users but is also difficult to safely design in software development. In this work, we examine AI application in Cardiac Magnetic Resonance (CMR) using an automated image classification task, and thereby propose an AI quality control framework design that differentially evaluates the black-box DNN via carefully prepared input data with shape and fidelity variations to probe system responses to these variations. Two variants of the Visual Geometric Graphics with 19 neural layers (VGG19) was used for classification, with a total of 60,000 CMR images. Findings from this work provides insights on the importance of quality training data preparation and demonstrates the importance of data shape variability. It also provides gateway for computation performance optimization in training and validation time.
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Title: Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator: Kaczmarek, Julia A.
Date: 2023
Description: The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
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Title: Correlating Microstructural Properties to Macroscopic Shear Mechanics to Improve the Understanding of Tissue Biomechanics
Creator: Cahoon, Stacey Marie
Date: 2023
Description: Understanding tissue biomechanics is of interest for modeling organ injury from external loads, development of tissue surrogate materials, and...
Show moreUnderstanding tissue biomechanics is of interest for modeling organ injury from external loads, development of tissue surrogate materials, and creating new biomarkers for disease. Probing the response of soft tissue in shear can provide information on histopathology, provided a methodology exists that connects the macroscopic mechanical properties with cell-level properties. Two of the available methods to measure the macroscopic shear viscoelastic properties of soft tissue are oscillatory shear rheometry and ultrasound shear wave elastography (SWE). Due to its accuracy, rheometry is the gold standard, but it is destructive, requires excised homogeneous samples, and can only be applied ex-vivo. SWE is an emerging non-invasive imaging technique which requires validation, ostensibly by comparing with rheometry. Histology is the gold standard for providing morphological information on the cell level, which can determine tissue pathology. The challenge is to connect the macroscopic mechanical metrics derived from SWE and rheometry to the tissue microstructure. To address this challenge, mathematical models can be used that employ multiple, judiciously chosen measurements of macroscopic shear properties and histology to estimate intrinsic mechanical properties at the cell level.A class of homogeneous and composite lipid phantoms mimicking the mechanical properties of brain white matter were fabricated to test a novel stereotactic system and an optimized SWE imaging protocol. The shear stiffness measurements obtained with SWE on the whole phantom were validated with rheometry performed on a series of samples made with the same material as the phantoms. The same procedure was applied to porcine brain white matter excised from fresh whole brains (n=3). Cylindrical cores were extracted from the corpus callosum area, sliced into discs and microscopic sections were subsequently removed for histology. Good agreement was found between the SWE and rheometry measurements of shear stiffness, which generally increases with the level of compressive prestress. Immunofluorescence was used to stain separately the axon neurofilaments and myelin sheaths, and digital image analysis of the confocal microscopy images allowed the estimation of axon volume fraction and axon-to-myelin ratio in the corpus callosum. Using these metrics and a composite mechanical model, a connection between the macroscopic shear measurements and the viscoelastic properties of axon and glia matrix was made for porcine brain tissue. Similarly, rheometry was used to measure the macroscopic properties of decellularized porcine myocardium extracellular matrix (ECM) in two different fiber locations, and for three different fiber orientations. The mechanical properties were found to be dependent upon fiber location, but not on fiber orientation. Since collagen is a primary supportive structure for the ECM, several microscopic slices were probed with immunofluorescence to compute the collagen I and collagen IV volume fractions. Another mechanical model was employed to establish a connection between the macroscopic properties and the mechanical properties of the collagen matrix in decellularized porcine myocardial ECM.This dissertation highlights the use and integration of three different experimental techniques (rheometry, ultrasound SWE, and histology) to correlate key microstructural properties of soft, fibrous tissues (ex-vivo healthy porcine brain white matter and myocardium ECM) with macroscopic shear mechanics. The consideration of the effect of compressive prestress is noteworthy. The reported baseline data for the tissues under shear loading and prestress are pertinent to the physiological function of these tissues, and therefore constitute preliminary data and a necessary first step before a systematic study of the biomechanics of the same tissues in vivo is performed.
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Title: Intraoperative Assessment of Surgical Margins in Head And Neck Cancer Resection Using Time-Domain Fluorescence Imaging
Creator: Cleary, Brandon M.
Date: 2023
Description: Rapid and accurate determination of surgical margin depth in fluorescence guided surgery has been a difficult issue to overcome, leading to...
Show moreRapid and accurate determination of surgical margin depth in fluorescence guided surgery has been a difficult issue to overcome, leading to over- or under-resection of cancerous tissues and follow-up treatments such as ‘call-back’ surgery and chemotherapy. Current techniques utilizing direct measurement of tumor margins in frozen section pathology are slow, which can prevent surgeons from acting on information before a patient is sent home. Other fluorescence techniques require the measurement of margins via captured images that are overlayed with fluorescent data. This method is flawed, as measuring depth from captured images loses spatial information. Intensity-based fluorescence techniques utilizing tumor-to-background ratios do not decouple the effects of concentration from the depth information acquired. Thus, it is necessary to perform an objective measurement to determine depths of surgical margins. This thesis focuses on the theory, device design, simulation development, and overall viability of time-domain fluorescence imaging as an alternative method of determining surgical margin depths. Characteristic regressions were generated using a thresholding method on acquired time-domain fluorescence signals, which were used to convert time-domain data to a depth value. These were applied to an image space to generate a depth map of a modelled tissue sample. All modeling was performed on homogeneous media using Monte Carlo simulations, providing high accuracy at the cost of increased computational time. In practice, the imaging process should be completed within a span of under 20 minutes for a full tissue sample, rather than 20 minutes for a single slice of the sample. This thesis also explores the effects of different thresholding levels on the accuracy of depth determination, as well as the precautions to be taken regarding hardware limitations and signal noise.
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Title: Correlating Microstructural Properties to Macroscopic Shear Mechanics to Improve the Understanding of Tissue Biomechanics
Creator: Cahoon, Stacey Marie
Date: 2023
Description: Understanding tissue biomechanics is of interest for modeling organ injury from external loads, development of tissue surrogate materials, and...
Show moreUnderstanding tissue biomechanics is of interest for modeling organ injury from external loads, development of tissue surrogate materials, and creating new biomarkers for disease. Probing the response of soft tissue in shear can provide information on histopathology, provided a methodology exists that connects the macroscopic mechanical properties with cell-level properties. Two of the available methods to measure the macroscopic shear viscoelastic properties of soft tissue are oscillatory shear rheometry and ultrasound shear wave elastography (SWE). Due to its accuracy, rheometry is the gold standard, but it is destructive, requires excised homogeneous samples, and can only be applied ex-vivo. SWE is an emerging non-invasive imaging technique which requires validation, ostensibly by comparing with rheometry. Histology is the gold standard for providing morphological information on the cell level, which can determine tissue pathology. The challenge is to connect the macroscopic mechanical metrics derived from SWE and rheometry to the tissue microstructure. To address this challenge, mathematical models can be used that employ multiple, judiciously chosen measurements of macroscopic shear properties and histology to estimate intrinsic mechanical properties at the cell level.A class of homogeneous and composite lipid phantoms mimicking the mechanical properties of brain white matter were fabricated to test a novel stereotactic system and an optimized SWE imaging protocol. The shear stiffness measurements obtained with SWE on the whole phantom were validated with rheometry performed on a series of samples made with the same material as the phantoms. The same procedure was applied to porcine brain white matter excised from fresh whole brains (n=3). Cylindrical cores were extracted from the corpus callosum area, sliced into discs and microscopic sections were subsequently removed for histology. Good agreement was found between the SWE and rheometry measurements of shear stiffness, which generally increases with the level of compressive prestress. Immunofluorescence was used to stain separately the axon neurofilaments and myelin sheaths, and digital image analysis of the confocal microscopy images allowed the estimation of axon volume fraction and axon-to-myelin ratio in the corpus callosum. Using these metrics and a composite mechanical model, a connection between the macroscopic shear measurements and the viscoelastic properties of axon and glia matrix was made for porcine brain tissue. Similarly, rheometry was used to measure the macroscopic properties of decellularized porcine myocardium extracellular matrix (ECM) in two different fiber locations, and for three different fiber orientations. The mechanical properties were found to be dependent upon fiber location, but not on fiber orientation. Since collagen is a primary supportive structure for the ECM, several microscopic slices were probed with immunofluorescence to compute the collagen I and collagen IV volume fractions. Another mechanical model was employed to establish a connection between the macroscopic properties and the mechanical properties of the collagen matrix in decellularized porcine myocardial ECM.This dissertation highlights the use and integration of three different experimental techniques (rheometry, ultrasound SWE, and histology) to correlate key microstructural properties of soft, fibrous tissues (ex-vivo healthy porcine brain white matter and myocardium ECM) with macroscopic shear mechanics. The consideration of the effect of compressive prestress is noteworthy. The reported baseline data for the tissues under shear loading and prestress are pertinent to the physiological function of these tissues, and therefore constitute preliminary data and a necessary first step before a systematic study of the biomechanics of the same tissues in vivo is performed.
Show less

Title: Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator: Kaczmarek, Julia A.
Date: 2023
Description: The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
Show less

Title: Quantification of Imaging Markers at Different MRI Contrast Weightings, Vasculature, and Across Field Strengths
Creator: Nguyen, Vivian S.
Date: 2024
Description: Quantitative MRI measures physical characteristics of tissue, which creates a set scale with units that allows longitudinal monitoring and...
Show moreQuantitative MRI measures physical characteristics of tissue, which creates a set scale with units that allows longitudinal monitoring and cross-patient and cross-center studies. It enables earlier detection of disease, complements biopsy, and provides a clear numeric scale for differentiation of disease states. However, quantitative MRI acquisitions and post-processing are not trivial, which makes it hard to implement the clinical setting. This along with the variability in clinically used acquisitions and post-processing techniques leads to difficulty in establishing reliable, consistent, and accurate quantitative information. There is a critical need for rigorous validation of quantitative imaging biomarkers, both for current and novel quantitative imaging techniques. This dissertation seeks to both validate current quantitative MR imaging techniques and develop new ones in the heart and brain by: 1) examining the data variability and the loss in tag fidelity that occurs when quantitative cardiac tagging is incorrectly run post-Gadolinium injection; 2) quantifying the negative impact of unexpected relaxometric behavior observed in low field MR imaging for low inversion times during T1 mapping; 3) validating retrospectively calculated T1 as a biomarker for Multiple Sclerosis progression; 4) and prototyping an oxygen extraction fraction (OEF) mapping technique for the purpose of stroke prediction and establishment of a numeric scale for tissue health for stroke patients.Assessment of pre-Gadolinium and post-Gadolinium cardiac tag quality showed that post-Gadolinium tags are less saturated (p = 0.012) and have a wider range of saturation, contrast, and sharpness. This results in a loss of information in the late cardiac cycle and impeding quantification of myocardial function.Investigation of 64mT T1 mapping revealed unique relaxometric behavior in that at low inversion times (<250 ms), the signal response curve displayed an increase in signal intensity or a plateau in signal intensity dependent on T1 relaxation time. Inclusion of this increase or plateau in signal intensity negatively impacted T1 fitting algorithms, leading to their failure or incorrectly calculated T1 values. The maximum peak signal intensity before the null point was found to be 210 ms, which impacts current low field T1 mapping protocols which use an initial inversion time of 80-110 ms.Validation of retrospectively calculated T1 as a biomarker in Multiple Sclerosis revealed that T1 of normal appearing brain tissue correlates with measures of Multiple Sclerosis progression (EDSS, BPF, and disease duration) with normal appearing white matter T1 correlating with BPF (r = -0.49, p = 0.0018); putamen T1 correlating with EDSS (r = 0.48, p = 2.40e-03), with BPF (r = 0.69, p = 2.04e-06), and disease duration (r = -0.37; p = 0.02); and globus pallidus T1 correlating with disease duration (r = -0.42; p = 0.0093). Lesion T1 is reflective of MS severity whereas MTR is not.Finally, development of an oxygen extraction fraction (OEF) mapping technique showed that application of independent component analysis (ICA) to cardiac gated spiral-trajectory phase images yielded components that feature stenosis features observed in magnitude images. These ICA components form the basis of OEF mapping from phase images. This dissertation presents four studies that seek to improve either current quantitative MR imaging protocols in the heart, or to develop and validate new quantitative MR imaging techniques in the brain for the purpose of monitoring disease progression or predicting disease.
Show less

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