Advanced signal processing methods in dynamic contrast enhanced magnetic resonance imaging

Tato dizertační práce představuje metodu zobrazování perfúze magnetickou rezonancí, jež je výkonným nástrojem v diagnostice, především v onkologii. Po ukončení sběru časové sekvence T1-váhovaných obrazů zaznamenávajících distribuci kontrastní látky v těle začíná fáze zpracování dat, která je předmětem této dizertace. Je zde představen teoretický základ fyziologických modelů a modelů akvizice pomocí magnetické rezonance a celý řetězec potřebný k vytvoření obrazů odhadu parametrů perfúze a mikrocirkulace v tkáni. Tato dizertační práce je souborem uveřejněných prací autora přispívajícím k rozvoji metodologie perfúzního zobrazování a zmíněného potřebného teoretického rozboru.This dissertation describes quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), which is a powerful tool in diagnostics, mainly in oncology. After a time series of T1-weighted images recording contrast-agent distribution in the body has been acquired, data processing phase follows. It is presented step by step in this dissertation. The theoretical background in physiological and MRI-acquisition modeling is described together with the estimation process leading to parametric maps describing perfusion and microcirculation properties of the investigated tissue on a voxel-by-voxel basis. The dissertation is divided into this theoretical analysis and a set of publications representing particular contributions of the author to DCE-MRI.

Patient-Specific Method of Generating Parametric Maps of Patlak K(i) without Blood Sampling or Metabolite Correction: A Feasibility Study.

Currently, kinetic analyses using dynamic positron emission tomography (PET) experience very limited use despite their potential for improving quantitative accuracy in several clinical and research applications. For targeted volume applications, such as radiation treatment planning, treatment monitoring, and cerebral metabolic studies, the key to implementation of these methods is the determination of an arterial input function, which can include time-consuming analysis of blood samples for metabolite correction. Targeted kinetic applications would become practical for the clinic if blood sampling and metabolite correction could be avoided. To this end, we developed a novel method (Patlak-P) of generating parametric maps that is identical to Patlak K(i) (within a global scalar multiple) but does not require the determination of the arterial input function or metabolite correction. In this initial study, we show that Patlak-P (a) mimics Patlak K(i) images in terms of visual assessment and target-to-background (TB) ratios of regions of elevated uptake, (b) has higher visual contrast and (generally) better image quality than SUV, and (c) may have an important role in improving radiotherapy planning, therapy monitoring, and neurometabolism studies

Glymphatic transport is reduced in rats with spontaneous pituitary tumor

BACKGROUND AND OBJECTIVE: Pituitary tumor in patients induces adverse alterations in the brain, accompanied by cognitive deficits. Dysfunction of glymphatic waste clearance results in accumulation of neurotoxic products within the brain, leading to cognitive impairment. However, the status of glymphatic function in the brain with pituitary tumor is unknown. Using magnetic resonance imaging (MRI) and an advanced mathematical modeling, we investigated the changes of glymphatic transport in the rats carrying spontaneous pituitary tumor. METHODS: Rats (22-24 months, female, Wistar) with and without pituitary tumor (n = 7/per group) underwent the identical experimental protocol. MRI measurements, including T2-weighted imaging and dynamic 3D T1-weighted imaging with intracisternal administration of contrast agent, were performed on each animal. The contrast-induced enhancement in the circle of Willis and in the glymphatic influx nodes were observed on the dynamic images and verified with time-signal-curves (TSCs). Model-derived parameters of infusion rate and clearance rate that characterize the kinetics of glymphatic tracer transport were evaluated in multiple representative brain regions. RESULTS: Our imaging data demonstrated a higher incidence of partially enhanced circle of Willis (86 vs. 14%; p \u3c 0.033) and a lower incidence of enhancement in glymphatic influx nodes of pituitary (71 vs. 100%) and pineal (57 vs. 86%) recesses in the rats with pituitary tumor than in the rats with normal appearance of pituitary gland, indicating an intensification of impaired peri-vascular pathway and impeded glymphatic transport due to the presence of pituitary tumor. Consistently, our kinetic modeling and regional cerebral tissue quantification revealed significantly lower infusion and clearance rates in all examined regions in rats with spontaneous pituitary tumor than in non-tumor rats, representing a suppressed glymphatic transport in the brain with pituitary tumor. CONCLUSION: Our study demonstrates the compromised glymphatic transport in the rat brain with spontaneous pituitary tumor. The reduced efficiency in cerebral waste clearance increases the risk for neurodegeneration in the brain that may underlie the cognitive impairment commonly seen in patients with pituitary tumors

GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.

Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness

Quantitative PET-CT Perfusion Imaging of Prostate Cancer

Functional imaging of 18F-Fluorocholine PET holds promise in the detection of dominant prostatic lesions. Quantitative parameters from PET-CT Perfusion may be capable of measuring choline kinase activity, which could assist in identification of the dominant prostatic lesion for more accurate targeting of biopsies and radiation dose escalation. The objectives of this thesis are: 1) investigate the feasibility of using venous TACs in quantitative graphical analysis, and 2) develop and test a quantitative PET-CT Perfusion imaging technique that shows promise for identifying dominant prostatic lesions. Chapter 2 describes the effect of venous dispersion on distribution volume measurements with the Logan Plot. The dispersion of venous PET curves was simulated based on the arterio-venous transit time spectrum measured in a perfusion CT study of the human forearm. The analysis showed good agreement between distribution volume measurements produced by the arterial and venous TACs. Chapter 3 details the mathematical implementation of a linearized solution of the 3-Compartment kinetic model for hybrid PET-CT Perfusion imaging. A noise simulation determined the effect of incorporating CT perfusion parameters into the PET model on the accuracy and variability of measurements of the choline kinase activity. Results indicated that inclusion of CT perfusion parameters known a priori can significantly improve the accuracy and variability of imaging parameters measured with PET. Chapter 4 presents the implementation of PET-CT Perfusion imaging in a xenograft mouse model of human prostate cancer. Image-derived arterial TACs from the left ventricle were corrected for partial volume and spillover effects and validated by comparing to blood sampled curves. The PET-CT Perfusion imaging technique produced parametric maps of the choline kinase activity, k3. The results showed that the partial volume and spillover corrected arterial TACs agreed well with the blood sampled curves, and that k3max was significantly correlated with tumor volume, while SUV was not. In summary, this thesis establishes a solid foundation for future clinical research into 18F-fluorocholine PET imaging for the identification of dominant prostatic lesions. Quantitative PET-CT Perfusion imaging shows promise for assisting targeting of biopsy and radiation dose escalation of prostate cancer

A Comprehensive View on MRI Techniques for Imaging Blood-Brain Barrier Integrity

The blood-brain barrier (BBB) is the interface between the blood and brain tissue, which regulates the maintenance of homeostasis within the brain. Impaired BBB integrity is increasingly associated with various neurological diseases. To gain a better understanding of the underlying processes involved in BBB breakdown, magnetic resonance imaging (MRI) techniques are highly suitable for noninvasive BBB assessment. Commonly used MRI techniques to assess BBB integrity are dynamic contrast-enhanced and dynamic susceptibility contrast MRI, both relying on leakage of gadolinium-based contrast agents. A number of conceptually different methods exist that target other aspects of the BBB. These alternative techniques make use of endogenous markers, such as water and glucose, as contrast media. A comprehensive overview of currently available MRI techniques to assess the BBB condition is provided from a scientific point of view, including potential applications in disease. Improvements that are required to make these techniques clinically more easily applicable will also be discussed.</p

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150514/1/cpt1211.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150514/2/cpt1211_am.pd

Impaired Cerebral Perfusion in Multiple Sclerosis: Relevance of Endothelial Factors.

Magnetic resonance imaging techniques measuring in vivo brain perfusion and integrity of the blood-brain barrier have developed rapidly in the past decade, resulting in a wide range of available methods. This review first discusses their principles, possible pitfalls, and potential for quantification and outlines clinical application in neurological disorders. Then, we focus on the endothelial cells of the blood-brain barrier, pointing out their contribution in regulating vascular tone by production of vasoactive substances. Finally, the role of these substances in brain hypoperfusion in multiple sclerosis is discussed