<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting more than 6 million individuals in the United States and more than 50 million worldwide. Currently, there exists no cure for AD and there are very few treatments to limit disease progression. Understanding the mechanisms through which AD develops and the risk factors associated with disease onset and progression is imperative in diagnosis and treatment of AD. Metal dysregulation has been implicated in disease pathogenesis through a number of mechanisms. Toxic heavy metals, such as lead (Pb) and mercury (Hg) are known to have deleterious effects on the central nervous system (CNS) and have been shown to increase AD pathology in animal models. However, there are significant knowledge gaps on how these metals deposit in human and animal brains at the microscopic scale, how they interact with essential metals in brain, and the relation of heavy metal exposure and AD. In this project, we aimed to investigate the distribution of heavy metals and their interactions with essential elements in transgenic mouse and human brain tissue models. We report, for the first time, Pb distribution and its co-deposition with Se in mouse brains following subchronic Pb exposure, Hg distribution and its co-deposition with Se in post-mortem AD and no cognitive impairment (NCI) brains, and the association of Pb, Hg, and other metals in these brains. All the data were obtained using synchrotron x-ray fluorescence (XRF), a powerful technique that allows for localization and quantification of multiple biological elements, as well as heavy metals, with a high spatial resolution and low detection limit. The work will shed light on the role essential metals, especially Se, play in neurotoxicity of Pb and Hg, and pave the way for potential future directions on heavy metal exposure and neurodegeneration.</p>

High-grade gliomas (HGGs) are a type of malignant brain cancer, which include glioblastomas (GBMs). In adults, GBM is the most common malignant primary brain cancer. Attempts to treat patients with GBMs have been conducted for over a century, but the prognosis has only marginally improved. Current standard treatment involves surgical resection of the gross tumor volume (GTV), followed by radiotherapy and chemotherapy. Despite the efforts, the median survival for patients diagnosed with GBMs is less than 15 months. The inability to accurately determine the full extent of the tumor invaded regions in the brain is assumed to be the reason for the incurability of GBMs.  In radiotherapy, the microscopic infiltration of normal tissue by tumor cells in the vicinity of the GTV is accounted for by extending the target into a clinical target volume (CTV). Current recommended margin widths for GBMs range from 15 to 30 mm. Despite a generous margin, the persistent recurrence of GBMs following treatment indicates that the CTV delineations currently used might fail to encompass the entirety of the tumor cell distribution, leaving clonogenic tumor cells untreated. To improve the CTV delineation and possibly treatment of GBMs, novel approaches in determining the tumor infiltrated regions have been suggested in the form of mathematical modeling.  The aim of this project is to develop a mathematical model for the infiltration of glioma cells into normal brain tissue and implement it into a framework for predicting the full extent of tumor-invaded tissue for HGGs.    This thesis is comprised of papers I–II, an overview of the methodology, results, and discussion of the work. The work herein is presented in order of: 1) model development; 2) model verification. Paper I explores the robustness and results of a mathematical model for tumor spread in terms of its input parameters. By applying the model to a large dataset, the behavior of the model could be investigated statistically, and optimal input parameters determined. The results of the tumor invasion simulations were compared in terms of volumes to the conventionally delineated CTVs, which were found not to adhere to the pathways of the simulated spread. Paper II used the resulting simulated invasions from paper I to predict the overall survival (OS) of the same cohort of cases. OS prediction was better predicted by the simulated volumes of the tumor spread than the size of the GTV. The results showed the potential of improving OS prediction and furthermore demonstrated a new methodology for indirect model verification that does not rely on histopathological data. Planned future work will revolve around dose prescription and plan optimization based on the simulated tumor spread, model investigation using artificial intelligence methods, and finally, practical implementation of the model into research versions of treatment planning systems.

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<p>This thesis describes the development of a method to measure <em>in vivo</em> gadolinium (Gd) content by prompt gamma neutron activation analysis (PGNAA). PGNAA is a quantitative measurement technique that is completely non-invasive. Gadolinium has the highest thermal neutron capture cross section of all the stable elements. Gadolinium-based contrast agents are widely used in magnetic resonance imaging (MRI). The primary intention of this work is to quantify <em>in vivo</em> Gd retention to investigate the potential toxicity of these agents. This study involves the optimization of the McMaster University ²³⁸Pu/Be PGNAA facility for Gd measurements. Monte Carlo simulations were performed in parallel with the experimental work using MCNP version 5. Excellent agreement has been demonstrated between the Monte Carlo model of the system and the experimental measurements (both sensitivity and dosimetry). The initial study on the sensitivity of Gd demonstrated the feasibility of the measurement system. The Monte Carlo dosimetry simulations and experimental survey measurements demonstrated consistently that the radiation exposures for a single measurement were quite low, with an effective dose rate of 1.1 µSv/hr for a leg muscle measurement, 74 µSv/hr for a kidney measurement, and 48 µSv/hr for a liver measurement. The initial studies confirmed the Gd measurement feasibility which ultimately led to an <em>in vivo</em> pilot study on 10 healthy volunteers. The pilot study was successful with 9 out of 10 volunteers having measureable Gd in muscle above the <em>in vivo</em> detection limit of 0.58 ppm within 1 hour of administration, and the remaining participant had detectable Gd 196 minutes post administration. The concentrations measured ranged from 6.9 to 56 uncertainties different from zero. The system has been validated in humans and can now be used in future studies of short or long-term retention of Gd after contrast administration in at risk populations, such as those with reduced kidney function, patients with multiple exposures over the treatment period, and patients who are prescribed higher dosages. In addition, experiments and simulations were extended to another high neutron absorbing element, samarium (Sm).</p> / Doctor of Philosophy (PhD)

<p>We investigated the use of multiplexing and an electro-optical coupling system in the design of magnetic resonance compatible positron emission tomography (PET) detectors. Reducing the number of output channels is an effective way to minimize cost and complexity and complements the substitution of coaxial cables for fiber optics. In this work, we first compared the system performance of two multiplexing schemes using both simulation and experimental studies. Simulations were performed using the LTSPICE environment to investigate differences in resulting flood histograms and rising edge slopes. Experiments were performed using Lutetium-Yttrium Oxyorthosilicate (LYSO) crystals of coupled to a SensL ArraySL-4 silicon photomultiplier (SiPM) connected to interchangeable circuit boards containing the two multiplexing schemes of interest. Three crystal configurations were tested: single crystal element (3x3x20 mm³), 2x2 array (crystal pitch: 3x3x20 mm³) and 6x6 array (crystal pitch: 2.1x2.1x20 mm³). Good agreement was found between the simulations and experiment results. The capacitive multiplexer is able to achieve improved time resolution of good uniformity (average of 1.11±0.01ns and 1.90±0.03ns for the arrays, respectively) and crystal separation, compared to the resistive multiplexing (average of 1.95±0.03ns and 3.33±0.10ns). The resistive multiplexing demonstrates slightly improved energy resolution (11±0.1% and 22±0.6%, compared to 12±0.1% and 24±0.4% for the capacitive array). The relevancy of this work to the PET block detector design using SiPM arrays is also discussed, including light sharing, edge compression and gain variation among SiPM pixels. This work also examines the effect of the electro-optical coupling system by comparing the system performance between cases with and without it. The coupling system is found to adversely affect performance, increasing global energy resolution by ~6%, average timing resolution by ~120% and distorting the flood histogram.</p> / Master of Applied Science (MASc)

The commission on radiological protection through publication 118 decided to recommend a change to the eye dose limit in 2011. ICRP recommendations made in publications, especially ‘publication 60’ and its subsequent update ‘publication 103’ has served as standards for regulatory authorities worldwide in limiting ionizing radiation exposure both to workers and members of the public. For example in Canada, the Canadian Nuclear Safety Commission (CNSC) generally directly adopts recommendations from ICRP. The previous dose limit for the lens of the eye was 150 mSv year-1, based on Publication 60 and 103. Regulatory agencies worldwide have been using this value and subsequently nuclear facilities, hospitals and universities have designed their radiation protection program based on this dose limit for several decades. The new revised eye dose limit now being equivalent to the whole body dose limit will pose significant challenges for sectors where the eye exposure was not characterized as the limit was previously five times over the whole body exposure. A two-step approach was used in conducting this study, firstly a through literature search was conducted on the effects of ionizing radiation to the eye, its radiobiology, fundamentals in established both dose limits was analyzed. Secondly, the authors spent time researching institutions that use ionizing radiation and interviewed engineers, medical physicists, radiation safety officers and regulators from a wide array of fields and industries. Based on the ICRP publications, the review of the literature and the interviews conducted with the nuclear industry, there is consensus in Canada and among IAEA member states that the dose limit for the lens of the eye should be reduced from the original proposed limit of 150 mSv per year. However not to the recommendations suggested by ICRP 118, but, to a standard reasonable and an achievable limit that is 50 mSv per year. / Thesis / Master of Science (MSc) / The International Commission on Radiological Protection (“ICRP”), the independent governing body responsible for radiation protection, since the early 1950s has been issuing recommendations that are widely used as radiological protection standards by regulatory agencies worldwide, primarily UN member states. Since its inception in 1928, the ICRP has served as the basis for radiation protection and value based judgements in protecting both human and non-human biota. In 2011, the commission published (ICRP Pub. 118) its review of epidemiological studies and decided to recommend a change to the previously established eye dose limit. Based on the review of the literature and the research conducted within the academic, veterinary, nuclear and medical industry, there is general consensus in Canada and among IAEA members states that the dose limit for the lens of the eye should be reduced from the original proposed limit, but not to the recommendations suggested by ICRP 118.

Gadolinium (Gd) is commonly used in contrast agents (GBCAs) to improve magnetic resonance imaging. GBCAs improve tumor imaging and were thought to be stable and clear from the body through excretion after administration. However, they have been found to dissociate and remain in organs such as the liver and kidneys. In these studies, a non-invasive Cd-109 based K x-ray fluorescence (K-XRF) “Clover-Leaf” detection system to study liver and kidney Gd levels was investigated to improve the minimum detection limit (MDL). Two Cd-109 sources, one with a relatively low activity of 0.78 GBq and a second high activity source of 5 GBq irradiated a human torso water phantom containing liver and kidney phantoms with Gd concentrations ranging from 0-100 ppm. The MDL was calculated from two different time measurements 5 hours (weak source) and 30 minutes (strong source). In addition, liver and kidney phantom measurements with overlaying tissue thicknesses from 6-26 mm were investigated. At present, the K-XRF detection system is able to detect the Gd in each phantom with both sources. The MDL for the liver and kidney with the weaker source is 2.95 ppm and 3.60 ppm, respectively. The MDL for the stronger source is 3.61 ppm and 3.87 ppm, respectively. The overlaying tissue thickness MDLs decreased exponentially since the thickness increased which increases the scattering and attenuation. Simulations with MCNP successfully modelled the experiments. MCNP simulations of the kidney with varying Gd concentrations in the cortex and medulla suggest that the XRF measurement is not sensitive to the Gd distribution in the phantom. To conclude, this detection system can measure Gd in liver and kidney phantoms and has low MDLs. Future work should focus on varying the detection capabilities, measuring the effects to the organs at risk, possible clinical trials, and improving the MCNP model and peak extraction. / Thesis / Master of Science (MSc)

<p dir="ltr">Introduction: Radiotherapy is a treatment modality that is prescribed for more than 50% of cancer patients around the globe. Through decades of clinical application, RT has witnessed considerable advancements achieving significant tumor control with minimal damage to healthy tissues. Recently, a paradigm shift has recognized RT's potential to induce anti-tumor immune responses, where patients receiving radiation to the primary tumor also resolved lesions outside the treatment field. This out-of-field response also referred to as an abscopal effect, is believed to promote immunogenic cell death (ICD) initiated by the radiation-induced DNA damage and subsequent activation of the cGAS-STING-IFNβ pathways. However, clinical realization of an abscopal effect remains rare. We <i><u>hypothesize</u></i> by selectively irradiating cancer cells with high metastatic potential within a solid tumor (intra-tumor radiotherapy treatment planning) with high metastatic potential, a more efficient anti-tumor response can be achieved while minimizing inflammatory responses from surrounding tumor and normal tissues, obfuscating a potential adaptive immune response, thus help in overcoming the rarity observed in the clinical practice. To achieve this <i><u>objective</u></i>, radiotherapy treatment plans targeting hypoxic regions (known to harbor a metastatic phenotype) within a solid tumor and optimally activating IFNβ will be investigated.</p><p dir="ltr">Methods: Hypoxic conditions within tumor microenvironments significantly reduce DNA damage, conferring a radioresistant phenotype that leads to RT failure. To address the inherent radioresistance and immunosuppression of hypoxic tumors, high linear energy transfer (LET) modalities are used. Our research aims to enhance the specificity and efficiency of ICD, particularly in highly metastatic (hypoxic) regions within the tumor, by employing heavy charged particle (HCP) beams to optimize DSB induction. Empirical mathematical models have been developed to predict the dose-response of IFNb based on in vitro data and Monte Carlo methods of DSB-induction. These methods are used in maximizing type I interferon (IFNβ) production and subsequent immune response while minimizing the inflammatory response and damage to surrounding tissue. Immunogenic treatment plans, iTPS, have been developed to integrate charged particle beam models for proton, helium, and carbon ions and the above-empirical models into FLUKA Monte Carlo simulations and subsequently evaluated in clinical case studies of brain and lung cancer. Next, new biophysical models accounting for tumor hypoxia were developed and integrated into the iTPS, and clinical case studies were reevaluated.</p><p dir="ltr">Results: SA(1): Developed and integrated charged particle beam models into FLUKA MC for both homogeneous and heterogeneous treatment planning. Empirical equations for RBE_{DSB, pO2}, LET, and IFNβ dose-response were incorporated into FLUKA for voxel-based simulations across oxygen levels. SA(2): RBE_DSB-weighted optimization yielded uniform IFNβ production. High LET enabled carbon ion beams to require the lowest doses, achieving superior peak-to-entrance ratios of 15.85 compared to 10.78 and 7.60 for helium and proton beams, respectively. Patient simulations demonstrated carbon ions' superiority, with D_95% values of 7.68 Gy for the brain and 7.60 Gy for lung tumors, excelling in IFNβ production. SA(3): An optimized treatment plan for uniform IFNβ in hypoxia utilizing empirical equations for RBE_DSB across hypoxia levels was created for different charged particles. MCC13 adjustments based on OER_DSB from MCDS were confirmed by measured data in U251 cell lines, showing an OER of 1.5 between normoxia and 1% hypoxia, closely matching MCDS predictions within a 7% discrepancy. Carbon ions achieved optimal IFNβ at 11.02 Gy for brain tumors under 0.1% hypoxia in FLUKA simulations.</p><p dir="ltr">Conclusions: Our results from both homogeneous target and patient cases demonstrate that charged particles have the potential to elicit higher levels of IFNβ at lower doses compared to photon irradiations in different pO₂ levels. High LET irradiation not only ensures a highly localized IFNβ response in the target but also effectively spares surrounding normal tissues, thereby minimizing treatment-related toxicity. This finding underscores the superiority of high LET irradiation in achieving targeted immunogenic effects while enhancing the therapeutic window by reducing damage to normal cells.</p>

The use of non-ionizing radiation in the magnetic resonance imaging (MRI) made it a safer diagnostic technique in comparison to the X-ray imaging method. MRI can also produce soft tissue images with a very high contrast without contrast agent which is another advantage that made MRI an important imaging technique for studying the mechanism of the deep brain stimulation (DBS) and for targeting the desired regions in the brain that should be stimulated. For these and other advantages, the number of MRI examinations have increased hugely around the world including Sweden. Despite the consideration that MRI is a safe modality, it is not free from risks and hazards. The radiofrequency (RF)-induced heating of the tissues and the metallic implants is one of the safety concerns in MRI which certainly includes patients with DBS implant.The purpose of this project, motivated by the dangers accompanying the RF-induced heating in implantable DBS lead, is to investigate the effect of the exposure to the RF fields in MRI on these leads. After temperature measurements were made, the observations were focused on the amount of temperature increase, and the time required for the temperature to increase and then to decrease to its initial value. Some factors that could affect the lead temperature were studied and that includes the effect of the lead configuration, the lead surrounding medium, the exposure level, and the orientation of the lead coil with respect to the RF field.The result showed that the temperature of the lead (placed in air) increased more but slower when the lead was formed as a coil than when it was randomly configured. It was also showed that the lead coil temperature rise was higher and faster when the coil was placed in air than when it was immersed in deionized water or in saline. The lead coil temperature rise was higher, but slower when the coil was immersed in saline compared to deionized water. Also, exposure level affected the temperature rise such that the higher exposure level showed higher and faster temperature rise of the lead coil. When the lead coil was placed in air and oriented perpendicular to the strongest magnetic field component, its temperature increased higher and faster. On the other hand, the results when the lead coil was immersed in deionized water or in saline showed a deviation from when it was placed in air such that two magnetic field components had the same effect on the lead coil temperature. The time required for the temperature to decrease to its initial value, after the end of the exposure, depended on the magnitude of the RF magnetic flux density, orientation of the lead coil with respect to the RF magnetic field, and the lead surrounding medium. The stronger RF magnetic field is, the longer time is for the temperature to decrease. Consequently, when the lead coil was directed perpendicularly to the strongest component of the RF magnetic field, it took longer time for the temperature to decrease. The time for the temperature to decrease was longer when the lead coil was immersed in water (deionized or saline) than when the lead coil was placed in air. It also took longer time for the temperature to decrease when the lead coil was immersed in saline than in deionized water.