Medicine and Health Sciences Commons^™

Intracellular Acidification In Brain Tumors Induced By Topiramate : In-Vivo Detection Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging, Kamini Y. Marathe

Electronic Thesis and Dissertation Repository

Glioblastoma Multiforme (GBM) is the most aggressive and malignant form of primary brain tumor. In many tumors, increased intracellular pH (pH_i) is a hallmark of aggressiveness. This increased pH_i has been shown to be related to cell proliferation and evasion of apoptosis as well as resistance to chemotherapy. As such, monitoring pH_i and the tumor pH_i response to pharmacologic challenge, may aid in treatment planning and patient management for this deadly cancer. A magnetic resonance imaging (MRI) method called Chemical Exchange Saturation Transfer (CEST) has been used to detect changes in pH_i. Our group …

Investigation Of Quatitative Image Features From Pretreatment Ct And Fdg-Pet Scans In Stage Iii Nsclc Patients Undergoing Defintive Radiation Therapy, David Fried

Dissertations & Theses (Open Access)

The purpose of this work was to determine if quantitative image features (QIFs) extracted from computed tomography (CT) and flourodeoxyglucose (FDG) positron emission tomography (PET) could provide prognostic information to improve outcome models. Our goal for this work was to determine if it may one day be feasible to incorporate QIFs into personalized cancer care. QIFs were used to quantitatively characterize patient disease as seen on imaging. A leave-one-out cross-validation procedure was used to assess the prognostic ability of QIFs extracted from CT and PET in addition to conventional prognostic factors (CPFs). QIFs were found to improve model fit for …

Pulmonary Imaging To Better Understand Asthma, Sarah Svenningsen

Electronic Thesis and Dissertation Repository

Asthma is characterized using the spirometry measurement of the forced expiratory volume in one second (FEV₁). Simple and inexpensive, FEV₁ provides a global estimate of lung function but this metric cannot regionally identify airways responsible for airflow limitation, asthma symptoms or control. Work that brought about an understanding that airway abnormalities are heterogeneously distributed within the lung in asthma patients has motivated the development of pulmonary imaging approaches, such as hyperpolarized helium-3 (³He) and xenon-129 (¹²⁹Xe) magnetic resonance imaging (MRI). These methods provide a way to visualize and quantify lung regions accessed by …

The Development And Validation Of A Molecular Imaging Probe Targeted To Cathepsin D For The In-Vivo Detection Of Alzheimer Disease, Jonatan Snir

Electronic Thesis and Dissertation Repository

Background: Currently there is no widely accepted test to diagnose AD. The involvement of the lysosomal system in Alzheimer’s disease (AD) progression provides an opportunity to develop associated biomarkers. The lysosomal enzyme Cathepsin D (CatD) has been shown to be over-expressed in the AD brain before clinical onset. We have developed a dual modality contrast agent (CA) to detect CatD activity which consists of an HIV-1 Tat Cell Penetrating Peptide (CPP) conjugated to a CatD cleavage sequence and two imaging moieties consisting of a fluorescently- tagged probe and a DOTA cage for chelating Gallium-68. The purpose of this work was …

Feasibility Of Using Arterial Spin Labeling For Detecting Longitudinal Changes In Cerebral Blood Flow, Tracy Ssali

Electronic Thesis and Dissertation Repository

The ability of the perfusion MRI technique, arterial spin labeling (ASL), to quantify cerebral blood flow (CBF) makes it attractive for longitudinal studies of changes in brain function, such as those related to chronic pain. However, ASL's poor spatial resolution makes image alignment between sessions difficult, leading to increased variance and greater Type-I errors. In addition, variability due to differences in basal blood flow between sessions and confounding effects such as the arterial transit time (ATT) have the potential to reduce reproducibility over time. The focus of this thesis is to investigate the ability of ASL to detect long-term changes …

Hyperpolarized 129xe Magnetic Resonance Imaging Of Radiation-Induced Lung Injury, Ozkan Doganay

Electronic Thesis and Dissertation Repository

Lung cancer is the largest contributor to cancer-related mortality worldwide. Only 20% of stage III non-small cell lung cancer patients survive after 5-years post radiation therapy (RT). Although RT is an important treatment modality for lung cancer, it is limited by Radiation-Induced Lung Injury (RILI). RILI develops in two phases: (i) the early phase (days-weeks) referred to radiation pneumonitis (RP), and (ii) the late phase (months). There is a strong interest in early detection of RP using imaging to improve outcomes of RT for lung cancer. This thesis describes a promising approach based on ¹²⁹Xe gas as a contrast …

Noninvasive Quantification Of Alveolar Morphometry In Elderly Never- And Ex-Smokers, Gregory A Paulin, Alexei Ouriadov, Eric Lessard, Khadija Sheikh, David G Mccormack, Grace Parraga

Medical Biophysics Publications

Diffusion-weighted magnetic resonance imaging (MRI) provides a way to generate in vivo lung images with contrast sensitive to the molecular displacement of inhaled gas at subcellular length scales. Here, we aimed to evaluate hyperpolarized (3)He MRI estimates of the alveolar dimensions in 38 healthy elderly never-smokers (73 ± 6 years, 15 males) and 21 elderly ex-smokers (70 ± 10 years, 14 males) with (n = 8, 77 ± 6 years) and without emphysema (n = 13, 65 ± 10 years). The ex-smoker and never-smoker subgroups were significantly different for FEV1/FVC (P = 0.0001) and DLCO (P = 0.009); while ex-smokers …

Role Of Cerebrovascular Abnormality In Neurodegenerative Disease And Subcortical Ischemic Disease: Ct Perfusion And Pet Imaging, Jun Yang

Electronic Thesis and Dissertation Repository

Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical …

Mapping The Impact And Plasticity Of Cortical-Cardiovascular Interactions In Vascular Disease Using Structural And Functional Mri, Udunna C. Anazodo

Electronic Thesis and Dissertation Repository

There is growing interest in the role of vascular disease in accelerating age-related decline in cerebrovascular structural and functional integrity. Since an increased number of older adults are surviving chronic diseases, of which cardiovascular disease (CVD) is prevalent, there is an urgent need to understand relationships between cardiovascular dysfunction and brain health. It is unclear if CVD puts the brains of older adults, already experiencing natural brain aging, at greater risk for degeneration. In this thesis, the role of CVD in accelerating brain aging is explored. Because physical activity is known to provide neuroprotective benefits to brains of older adults, …

Towards Adaptive Radiotherapy Through Development Of Treatment Response Prediction, Anthony V. Lausch

Electronic Thesis and Dissertation Repository

Despite modern treatment advances, overall survival (OS) remains poor for many cancers such as liver and brain. Cancer is a fundamentally heterogeneous and adaptable disease and therefore personalized adaptive treatment strategies may be a key towards improving OS. Radiotherapy, a commonly used cancer treatment technique which employs ionizing radiation to kill tumours, holds promise for delivering adaptive treatment. However, effective adaptation requires the ability to assess and predict tumour treatment response. Therefore development of treatment response prediction tools represents a critical first step towards improving patient outcomes via treatment adaptation. The overall goal of this thesis is to develop treatment …

Investigation Of Endogenous In-Vivo Sodium Concentration In Human Prostate Cancer Measured With 23na Magnetic Resonance Imaging, Justin C. Peterson

Electronic Thesis and Dissertation Repository

Prostate cancer (PCa) is the most common malignancy in men. Aggressive prostate tumours must be identified, differentiated from indolent tumours, and treated to ensure survival of the patient. Currently, clinicians use a combination of multi-parametric magnetic resonance imaging (mpMRI) contrasts to improve PCa detection. While these techniques provide very good spatial resolution, the specificity is often insufficient to unequivocally identify malignant lesions.

Utilizing specialized MRI hardware developed for sensitive in-vivo detection of sodium, this work has investigated differences in sodium concentration between healthy and malignant prostate tissue. Patients with biopsy-proven PCa underwent conventional mpMRI and sodium MRI followed by radical …

Development Of A Small Animal Conformal Irradiator With Dual Energy X-Ray Computed Tomography Imaging For Kilovoltage Dosimetry, Michael D. Jensen

Electronic Thesis and Dissertation Repository

External beam radiotherapy has become technically sophisticated with image guided radiation therapy (IGRT) and intensity modulated radiation therapy (IMRT). These technologies allow for precise delivery of radiation to geometric targets in cancer patients. However, many questions remain on how to best define targets based on biological information, such as functional imaging, and how to combine radiation with other cancer therapies. To help answer these questions, small animal preclinical studies are needed to generate data to inform clinical trials. However, the precise radiation delivery capabilities of IGRT and IMRT have not been available in the preclinical labs. To enable translational experiments …

Characterization Of Maga Expression And Iron Uptake In P19 Cells: Implications For Use As A Gene-Based Contrast Agent, Linshan Liu

Electronic Thesis and Dissertation Repository

Magnetic resonance imaging (MRI) is one of the non-invasive imaging modalities used in longitudinal cell tracking. Previous studies suggest that MagA, a putative iron transport protein from magnetotactic bacteria, is a useful gene-based magnetic resonance contrast agent. Hemagglutinin (HA)-tagged MagA was stably expressed in undifferentiated embryonic mouse teratocarcinoma, multipotent P19 stem cells to provide a suitable model for tracking these cells during differentiation. Western blot and immunocytochemistry confirmed the expression and membrane localization of MagA-HA in P19 cells. Elemental iron analysis using inductively-coupled plasma mass spectrometry revealed significant iron uptake in both parental and MagA-HA-expressing P19 cells, cultured in the …

Improving Attenuation Correction In Hybrid Positron Emission Tomography, Hua Asher Ai

Dissertations & Theses (Open Access)

Hybrid positron emission tomography imaging techniques such as PET/CT and PET/MR have undergone significant developments over the last two decades and have played increasingly more important roles both in research and in the clinic. A unique advantage PET has over other clinical imaging modalities is its capability of accurate quantification. However, as the most critical component of PET quantification, attenuation correction in hybrid PET systems is challenged in several different aspects, including the spatial- temporal mismatch between the PET emission images and the associated attenuation images provided by the complementary modality, and the difficulty in bone identification in the MR-based …

Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith

Dissertations & Theses (Open Access)

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – …

Evaluation Of Radiation Dose-Response In A Breast Cancer Brain Metastasis Model, Niloufar Zarghami

Electronic Thesis and Dissertation Repository

The second incidence of brain metastases is from breast cancer. Radiotherapy, a standard treatment for brain metastasis, limits cancer division by inducing DNA double-stranded breaks (DSBs). Currently, identical radiation doses are prescribed for all types of brain metastases but little is known about their histological responses. In this thesis, we initiated a radiation dose-response study in a triple-negative human breast cancer brain metastasis mouse model using a custom designed 3D-printed restrainer to assist half-brain irradiation. We quantified the amount of DSBs in tumors and mouse brain tissues using γ-H2AX marker at 30 minutes (acute) and 11 days (longitudinal) after treatment …

Copd: Do Imaging Measurements Of Emphysema And Airway Disease Explain Symptoms And Exercise Capacity?, Miranda Kirby, Damien Pike, Don D Sin, Harvey O Coxson, David G Mccormack, Grace Parraga

Medical Biophysics Publications

PURPOSE: To determine the role of imaging measurements of emphysema and airway disease in determining chronic obstructive pulmonary disease (COPD) symptoms and exercise limitation in patients with COPD, particularly in patients with mild-to-moderate disease.

MATERIALS AND METHODS: Participants (n = 116) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade U (unclassified) or grade I-IV COPD provided informed consent to an ethics board-approved HIPAA-compliant protocol and underwent spirometry and plethysmography, completed the St George's Respiratory Questionnaire (SGRQ), completed a 6-minute walk test for the 6-minute walk distance (6MWD), and underwent hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging and …

Serum Vitamin D Status Is Associated With The Presence But Not The Severity Of Primary Open Angle Glaucoma., Aurélien Goncalves, Dan Milea, Philippe Gohier, Ghislaine Jallet, Stéphanie Leruez, Mani Baskaran, Tin Aung, Cédric Annweiler

Medical Biophysics Publications

OBJECTIVES: Vitamin D is involved in visual health and function. Our objective was to determine whether age-related vitamin D insufficiency was associated with the presence and the severity of primary open angle glaucoma (POAG) in a case-control study of older adults.

STUDY DESIGN: Case-control study.

MAIN OUTCOME MEASURES: One hundred fifty cases diagnosed with moderate-to-severe POAG (mean, 75.1±8.5 years; 42.0% female) and 164 healthy controls (mean, 73.0±7.9 years; 59.8% female) were included. POAG diagnosis was based on classical diagnostic criteria of optic nerve cupping and/or RNFL thinning, measured with optical coherence tomography. Severe POAG was defined as Humphrey visual field …

Ventilation Heterogeneity In Ex-Smokers Without Airflow Limitation., Damien Pike, Miranda Kirby, Fumin Guo, David G Mccormack, Grace Parraga

Medical Biophysics Publications

RATIONALE AND OBJECTIVES: Hyperpolarized (3)He magnetic resonance imaging (MRI) ventilation abnormalities are visible in ex-smokers without airflow limitation, but the clinical relevance of this is not well-understood. Our objective was to phenotype healthy ex-smokers with normal and abnormally elevated ventilation defect percent (VDP).

MATERIALS AND METHODS: Sixty ex-smokers without airflow limitation provided written informed consent to (3)He MRI, computed tomography (CT), and pulmonary function tests in a single visit. (3)He MRI VDP and apparent diffusion coefficients (ADCs) were measured for whole-lung and each lung lobe as were CT measurements of emphysema (relative area [RA] with attenuation ≤-950 HU, RA950) and …

Structural Studies Of The Ig58 Domain Of The Giant Muscle Protein Obscurin, Matthew C. Oehler

Senior Honors Projects, 2010-2019

Obscurin (720-900 kD) is a giant sarcomeric signaling protein that is the only known link

between the cytoskeleton and the surrounding membrane structure. Mutations to obscurin

and to obscurin binding partners have been linked to human muscle diseases such as

hypertrophic cardiomyopathies and muscular dystrophy. These diseases likely occur due

to the abrogation of specific molecular interactions necessary for suitable function. To

more fully understand how specific mutations lead to disease, here we solve the highresolution

structure of obscurin Ig58. The literature shows that an Arg8Gln mutation to

the Ig58 domain of obscurin is associated with hypertrophic cardiomyopathy (HCM).

Chemical …

Characterization Of Low Density Intracranial Lesions Using Dual-Energy Computed Tomography, Jessica L. Nute

Dissertations & Theses (Open Access)

Calcific and hemorrhagic foci of susceptibility are frequently encountered on routine brain MR studies. Both etiologies cause variations in local magnetic field strength, leading to dark regions on the MR images that cannot be classified. Single-energy CT (SECT) can be used to identify lesions with attenuation over 100 HU as calcific, however lesions with lower attenuation cannot be reliably identified. While calcific lesions are unlikely to cause harm, hemorrhagic lesions carry a risk of subsequent intracranial bleeding; as such, identification of hemorrhage is vital in preventing the inappropriate use of anticoagulant medications in patients with hemorrhagic lesions.

Given there currently …

Sec17 Can Trigger Fusion Of Trans-Snare Paired Membranes Without Sec18, Michael Zick, Amy Orr, Matthew L. Schwartz, Alexey J. Merz, William Wickner

Dartmouth Scholarship

Sec17 [soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein; α-SNAP] and Sec18 (NSF) perform ATP-dependent disassembly of cis-SNARE complexes, liberating SNAREs for subsequent assembly of trans-complexes for fusion. A mutant of Sec17, with limited ability to stimulate Sec18, still strongly enhanced fusion when ample Sec18 was supplied, suggesting that Sec17 has additional functions. We used fusion reactions where the four SNAREs were initially separate, thus requiring no disassembly by Sec18. With proteoliposomes bearing asymmetrically disposed SNAREs, tethering and trans-SNARE pairing allowed slow fusion. Addition of Sec17 did not affect the levels of trans-SNARE complex but triggered sudden fusion of trans-SNARE paired proteoliposomes. …

Novel Techniques For Investigating The Regulation Of Skeletal Muscle Hemodynamics, Baraa K. Al-Khazraji

Electronic Thesis and Dissertation Repository

The effect of the sympathetic nervous system (SNS) on blood flow distribution within skeletal muscle microvasculature is conditional upon regional activation of SNS receptors. Due to a lack of appropriate experimental models and techniques, no study has systematically evaluated the effect of SNS receptor activation in continuously branching skeletal muscle arteriolar trees. In line with previous work, we hypothesize that there will be a spatially-dependent distribution of sympathetic receptor activation along the arteriolar tree. Specifically, we anticipate a progressive decrease of adrenergic activation and a progressive increase of peptidergic and purinergic activation with increasing arteriolar order. We developed a novel …

Survival Prediction In High-Grade Gliomas Using Ct Perfusion Imaging., Timothy Pok Chi Yeung, Yong Wang, Wenqing He, Benedetta Urbini, Roberta Gafà, Linda Ulazzi, Slav Yartsev, Glenn Bauman, Ting-Yim Lee, Enrico Fainardi

Medical Biophysics Publications

Patients with high-grade gliomas usually have heterogeneous response to surgery and chemoirradiation. The objectives of this study were (1) to evaluate serial changes in tumor volume and perfusion imaging parameters and (2) to determine the value of these data in predicting overall survival (OS). Twenty-nine patients with World Health Organization grades III and IV gliomas underwent magnetic resonance (MR) and computed tomography (CT) perfusion examinations before surgery, and 1, 3, 6, 9, and 12 months after radiotherapy. Serial measurements of tumor volumes and perfusion parameters were evaluated by receiver operating characteristic analysis, Cox proportional hazards regression, and Kaplan-Meier survival analysis …

Non-Invasive Quantification Of Alveolar Morphometry Measurements In Older Never-Smokers, Gregory A. Paulin

Electronic Thesis and Dissertation Repository

Diffusion-weighted noble gas pulmonary magnetic resonance imaging (MRI) provides in vivo images with a contrast uniquely sensitive to molecular displacement at cellular and sub-cellular length scales. We estimated the external airway radius (R) and internal airway radius (r) of the alveolar dimensions to evaluate potential differences in acinar duct morphometries in healthy older never-smokers and compared those with a group of ex-smokers. The acinar duct and alveolar MRI morphometry results were within the physiologically-valid range of parameters. Estimated values of internal (r) and external (R) airway radius as well as alveolar sheath (h) and …

In-Vivo Longitudinal Mri Study: An Assessment Of Melanoma Brain Metastases In A Clinically Relevant Mouse Model., Mariama N Henry, Yuhua Chen, Catherine D Mcfadden, Felicia C Simedrea, Paula J Foster

Medical Biophysics Publications

Brain metastases are an important clinical problem. Few animal models exist for melanoma brain metastases; many of which are not clinically relevant. Longitudinal MRI was implemented to examine the development of tumors in a clinically relevant mouse model of melanoma brain metastases. Fifty thousand human metastatic melanoma (A2058) cells were injected intracardially into nude mice. Three Tesla MRI was performed using a custom-built gradient insert coil and a mouse solenoid head coil. Imaging was performed on consecutive days at four time points. Tumor burden and volumes of metastases were measured from balanced steady-state free precession image data. Metastases with a …

Impact Of Incremental Perfusion Loss On Oxygen Transport In A Capillary Network Mathematical Model., Graham M Fraser, Michael D Sharpe, Daniel Goldman, Christopher G Ellis

Medical Biophysics Publications

OBJECTIVES: To quantify how incremental capillary perfusion loss, such as that seen in experimental models of sepsis, affects tissue oxygenation using a computation model of oxygen transport.

METHODS: A computational model was applied to capillary networks with dimensions 84x168x342 (NI) and 70x157x268 (NII) μm, reconstructed in vivo from rat skeletal muscle. Functional capillary density (FCD) loss was applied incrementally up to ~40% and combined with high tissue oxygen consumption to simulate severe sepsis.

RESULTS: A loss of ~40% FCD loss decreased median tissue PO2 to 22.9 and 20.1 mmHg in NI and NII compared to 28.1 and 27.5 mmHg under …

Three-Dimensional Computed Tomography Measurements Of Pulmonary Artery Volumes: Development And Application, Tamas J. Lindenmaier

Electronic Thesis and Dissertation Repository

Chronic obstructive pulmonary disease (COPD) is a major contributor to hospitalizations and healthcare costs in North America. While the hallmark of COPD is airflow limitation, it is also associated with abnormalities of the cardiovascular system. Enlargement of the pulmonary artery (PA) is a morphological marker of pulmonary hypertension, and was previously shown to predict acute exacerbations using a one-dimensional (1D) diameter measurement of the main PA. We hypothesized that a three-dimensional (3D) quantification of PA size would be more sensitive than 1D methods and encompass morphological changes along the entire central PA. Hence, we developed a 3D measurement of the …

The Dissociative Subtype Of Posttraumatic Stress Disorder: Unique Resting-State Functional Connectivity Of Basolateral And Centromedial Amygdala Complexes., Andrew A Nicholson, Maria Densmore, Paul A Frewen, Jean Théberge, Richard W J Neufeld, Margaret C Mckinnon, Ruth A Lanius

Medical Biophysics Publications

Previous studies point towards differential connectivity patterns among basolateral (BLA) and centromedial (CMA) amygdala regions in patients with posttraumatic stress disorder (PTSD) as compared to controls. Here, we describe the first study to compare directly connectivity patterns of the BLA and CMA complexes between PTSD patients with and without the dissociative subtype (PTSD+DS and PTSD-DS, respectively). Amygdala connectivity to regulatory prefrontal regions and parietal regions involved in consciousness and proprioception were expected to differ between these two groups based on differential limbic regulation and behavioural symptoms. PTSD patients (n=49), with (n=13) and without (n=36) the dissociative subtype, and age-matched healthy …

A Biomechanical Approach For In Vivo Lung Tumor Motion Prediction During External Beam Radiation Therapy, Abbas Samani, Elham Karami, Ting-Yim Lee, Stewart Gaede

Medical Biophysics Publications

No abstract provided.