Spectral factor analysis for multi-isotope imaging in nuclear medicine

Abstract. In nuclear medicine, simultaneous dual-isotope imaging is used to determine the distribution of two radiotracers from a single acquisition and for emission/transmission (E/T) imaging in SPECT. However, no general solution to the cross-talk problem caused by scattered and unscattered photons has been found yet and accurate quantification cannot be performed. We describe a general method of spectral factor analysis (SFA) for multi-isotope acquisitions. SFA corrects for cross-talk due to unscattered and scattered photons in planar or SPECT imaging involving two or more radiotracers and for E/T scans. A Tc-99m/I-123 phantom study shows that quantitative accuracy is within 10% with SFA, while errors up to 170% are observed using conventional spectral windows

Production of Medical Radioisotopes with High Specific Activity in Photonuclear Reactions with γ\gamma Beams of High Intensity and Large Brilliance

We study the production of radioisotopes for nuclear medicine in $(\gamma,x{\rm n}+y{\rm p})$ photonuclear reactions or ($\gamma,\gamma'$) photoexcitation reactions with high flux [($10^{13}-10^{15}$)$\gamma$/s], small diameter $\sim (100 \, \mu$m$)^2$ and small band width ($\Delta E/E \approx 10^{-3}-10^{-4}$) $\gamma$ beams produced by Compton back-scattering of laser light from relativistic brilliant electron beams. We compare them to (ion,$x$n$+ y$p) reactions with (ion=p,d,$\alpha$) from particle accelerators like cyclotrons and (n,$\gamma$) or (n,f) reactions from nuclear reactors. For photonuclear reactions with a narrow $\gamma$ beam the energy deposition in the target can be managed by using a stack of thin target foils or wires, hence avoiding direct stopping of the Compton and pair electrons (positrons). $(\gamma,\gamma')$ isomer production via specially selected $\gamma$ cascades allows to produce high specific activity in multiple excitations, where no back-pumping of the isomer to the ground state occurs. We discuss in detail many specific radioisotopes for diagnostics and therapy applications. Photonuclear reactions with $\gamma$ beams allow to produce certain radioisotopes, e.g. $^{47}$Sc, $^{44}$Ti, $^{67}$Cu, $^{103}$Pd, $^{117m}$Sn, $^{169}$Er, $^{195m}$Pt or $^{225}$Ac, with higher specific activity and/or more economically than with classical methods. This will open the way for completely new clinical applications of radioisotopes. For example $^{195m}$Pt could be used to verify the patient's response to chemotherapy with platinum compounds before a complete treatment is performed. Also innovative isotopes like $^{47}$Sc, $^{67}$Cu and $^{225}$Ac could be produced for the first time in sufficient quantities for large-scale application in targeted radionuclide therapy.Comment: submitted to Appl. Phys.

Multi-Isotope Multi-Pinhole SPECT Bildgebung in kleinen Labortieren: Experimentelle Messungen und Monte Carlo Simulationen

Single photon emission computed tomography (SPECT) in small laboratory animals has become an integral part of translational medicine. It enables non-invasive validation of drug targeting, safety and efficacy in living organisms, which is progressively gaining importance in pharmaceutical industry. The increasing demand for efficiency in pharmaceutical research could be addressed by novel multitracer study designs. Multi-isotope multi-pinhole sampling allows validation of multiple tracers in a single experiment and consolidation of consecutive research trials. Due to physical and technical limitations, however, image quality and quantification can be substantially reduced. Advanced corrective procedures are required to establish multi-isotope multi-pinhole SPECT as a reliable and quantitative imaging technique for widespread use. For this purpose, the present work aimed to investigate the technical capabilities and physical limitations of multi-isotope multi-pinhole SPECT imaging in small laboratory animals. Based on experimental measurements and Monte Carlo simulations, specific error sources have been identified and procedures for quantitative image correction have been developed. A Monte Carlo simulation model of a state-of-the art SPECT/CT system has been established to provide a generalized framework for in-silico optimization of imaging hardware, acquisition protocols and reconstruction algorithms. The findings of this work can be used to improve image quality and quantification of SPECT in-vivo data for multi-isotope applications. They guide through the laborious process of multi-isotope protocol optimization and support the 3R welfare initiative that aims to replace, reduce and refine animal experimentation.Die Einzelphotonen-Emissionscomputertomographie (SPECT) in kleinen Labortieren hat sich als wichtiger Bestandteil der translationalen Medizin etabliert. Sie ermöglicht die nicht-invasive Validierung der Zielgenauigkeit, Wirksamkeit und Sicherheit von Wirkstoffen in lebenden Organismen und gewinnt zunehmend an Bedeutung in der pharmazeutischen Industrie. Die Forderung nach mehr Effizienz in der pharmazeutischen Forschung könnte durch neuartige Multitracer-Studien adressiert werden. Die Multi-Isotopen Akquisition mit Multi-Pinhole Kollimatoren ermöglicht die Validierung mehrerer Tracer in einem einzelnen Experiment und die Konsolidierung konsekutiver Bildgebungsstudien. Aufgrund physikalischer und technischer Limitationen ist die Bildqualität und Quantifizierbarkeit bei diesem Verfahren jedoch häufig reduziert. Um die Multi-Isotopen SPECT als zuverlässige und quantitative Bildgebungsmethode für den breiten Einsatz zu etablieren sind komplexe Korrekturverfahren erforderlich. Ziel der vorliegenden Arbeit war daher, die technischen Möglichkeiten und physikalischen Limitationen der Multi-Isotopen SPECT-Bildgebung in kleinen Labortieren systematisch zu untersuchen. Mithilfe von experimentellen Messungen und Monte Carlo Simulationen wurden spezifische Fehlerquellen identifiziert und Verfahren zur quantitativen Bildkorrektur entwickelt. Zudem wurde das Monte-Carlo Modell eines neuartigen SPECT/CT-Systems etabliert, um eine Plattform für die in-silico Optimierung von Bildgebungshardware, Aufnahmeprotokollen und Rekonstruktionsalgorithmen zu schaffen. Die Ergebnisse dieser Arbeit können die Bildqualität und Quantifizierbarkeit von SPECT in-vivo Daten für Multi-Isotopen Anwendungen verbessern. Sie führen beispielhaft durch den Prozess der Multi-Isotopen Protokolloptimierung und unterstützen die 3R-Initiative mit dem Ziel, experimentelle Tierversuche zu vermeiden (Replace), zu vermindern (Reduce) und zu verbessern (Refine)

Spectral tracing of deuterium for imaging glucose metabolism.

Cells and tissues often display pronounced spatial and dynamical metabolic heterogeneity. Common glucose-imaging techniques report glucose uptake or catabolism activity, yet do not trace the functional utilization of glucose-derived anabolic products. Here we report a microscopy technique for the optical imaging, via the spectral tracing of deuterium (STRIDE), of diverse macromolecules derived from glucose. Based on stimulated Raman-scattering imaging, STRIDE visualizes the metabolic dynamics of newly synthesized macromolecules, such as DNA, protein, lipids and glycogen, via the enrichment and distinct spectra of carbon-deuterium bonds transferred from the deuterated glucose precursor. STRIDE can also use spectral differences derived from different glucose isotopologues to visualize temporally separated glucose populations using a pulse-chase protocol. We also show that STRIDE can be used to image glucose metabolism in many mouse tissues, including tumours, brain, intestine and liver, at a detection limit of 10 mM of carbon-deuterium bonds. STRIDE provides a high-resolution and chemically informative assessment of glucose anabolic utilization

Multimodal nanoparticles for quantitative imaging

The scope of this thesis is research related to applications of nanoparticles in quantitative preclinical imaging. Nanoparticles are a versatile platform that can interact with biological systems at many different length scales and can furthermore be rendered visible for basically any medical imaging technique by modification with appropriate contrast providing moieties. Thus, nanoparticles can be used as a new class of contrast agents for basically all imaging modalities, e.g. as long circulating blood pool agents in CT, or as MRI contrast agents. Vice versa, non-invasive imaging techniques can be used to for example follow the biodistribution of nanoparticles in vivo and apply nanoparticles as a tool to investigate biological processes related to disease processes. Dual modal imaging applying multifunctional and dual-labeled nanoparticles offer new approaches to quantitative imaging, giving new insights into technology development on one side and biological read-outs on the other. For instance, quantification of biological processes that lie at the basis in the development of disease may lead to earlier detection and better disease diagnosis and treatment. Results and concepts presented in this thesis have high impact on therapeutic application of nanoparticles, for example when they are used as drug delivery systems. Imaging can provide valuable information on drug delivery and biodistribution in a quantitative manner, which may help in development of new therapeutic strategies. Nanoparticles are promising structures for quantitative imaging. Its surface can be utilized to attach almost any desirable molecule. Nanoparticles are relatively large in size (typically 10-200 nm) and can for instance accommodate a high payload of contrast agent per particle on its surface or inside the particle, thereby increasing the signal/particle by five orders of magnitude. In addition, also multiple imaging probes for different imaging modalities can be incorporated providing a double read-out. For the understanding of biological processes, targeting ligands such as antibodies, proteins and peptides can be attached to its surface. Despite the wide variety of possibilities with nanoparticles, they have hardly been studies for quantitative imaging purposes. Therefore, the aim of the research described in this thesis was to explore and develop several nanoparticles for quantitative imaging by using existing or newly developed imaging techniques. Chapter 1 gives a general introduction in the field of nanoparticles for quantitative imaging. Several imaging techniques are described such as CT, Spectral CT, SPECT and MRI, and how nanoparticles can play an important role in research. Chapter 2 describes the development of a novel nanoparticulate CT contrast agent. Several amphiphilic molecules were investigated in this chapter in the combination with different iodinated oils for their influence on the size stability of the nanoparticles. In Chapter 3, the dose dependent biodistribution of the nanoparticles is investigated as well as strategies to vary the biodistribution. The effect of a co-injection with liposomes and soy bean oil emulsions was investigated using CT, SPECT and ¿-counting. The final optimized blood pool CT contrast agent from chapter 2 and 3 can be used for qualitative imaging in CT as well as in quantitative imaging in Spectral CT. Chapter 4 describes the very first use of this novel imaging technique Spectral CT in quantitative imaging. For this, the nanoparticles of chapter 2 were extended to a multimodal nanoparticulate contrast agent for CT, Spectral CT and SPECT. Spectral CT quantification was compared to quantification using SPECT and ICP-MS to demonstrate the correlations and accuracy of the techniques. In Chapter 5, the development is described of a dual-isotope SPECT imaging protocol as a tool for pre-clinical testing of new molecular imaging tracers. New molecular targeting probes are consistently investigated as a tool to enable target specific binding of nanoparticles to cellular surfaces of interest. Dual-isotope SPECT can be used in which the biodistribution of two different ligands labelled with two different radionuclides can be studied in the same animal, thereby excluding experimental and physiological inter-animal variations. The developed dual-isotope protocol was tested using a known angiogenesis specific ligand (cRGD peptide) in comparison to a potential non-specific control (cRAD peptide). Chapter 6 describes the use of a multimodal radiolabeled paramagnetic liposomal contrast agent that allows simultaneous imaging with SPECT and MRI. A double read-out is then possible and demonstrates the additional advantages of the combination of the two techniques. SPECT can for instance quantify the nanoparticle concentration and MRI can spatially localize the nanoparticle. The combination however gives an indirect read-out of the water exchange, which in return reveals insights in biological processes and environments. Chapter 7 describes a study that investigates the use of nanoparticles in the quantitative imaging technique fluorine MRI. The use of gadolinium-complexes as signal modulating ingredients into the nanoparticle formulation has emerged as a promising approach towards improvement of the fluorine signal. Paramagnetic lipids based on gadolinium complexes can be incorporated to increase the 19F MR signal per particle. Here, 3 different paramagnetic lipids were investigated on its influence at five different field strengths. This furthermore also provides important insights in the dependency of the magnetic field on fluorine signal intensity. The final Chapter 8 describes the future perspectives of the use of multimodal nanoparticles for quantitative imaging

Applications of laser wakefield accelerator-based light sources

Laser-wakefield accelerators (LWFAs) were proposed more than three decades ago, and while they promise to deliver compact, high energy particle accelerators, they will also provide the scientific community with novel light sources. In a LWFA, where an intense laser pulse focused onto a plasma forms an electromagnetic wave in its wake, electrons can be trapped and are now routinely accelerated to GeV energies. From terahertz radiation to gamma-rays, this article reviews light sources from relativistic electrons produced by LWFAs, and discusses their potential applications. Betatron motion, Compton scattering and undulators respectively produce x-rays or gamma-rays by oscillating relativistic electrons in the wakefield behind the laser pulse, a counter-propagating laser field, or a magnetic undulator. Other LWFA-based light sources include bremsstrahlung and terahertz radiation. We first evaluate the performance of each of these light sources, and compare them with more conventional approaches, including radio frequency accelerators or other laser-driven sources. We have then identified applications, which we discuss in details, in a broad range of fields: medical and biological applications, military, defense and industrial applications, and condensed matter and high energy density science

Nuclear Physics for Cultural Heritage

Nuclear physics applications in medicine and energy are well known and widely reported. Less well known are the many important nuclear and related techniques used for the study, characterization, assessment and preservation of cultural heritage. There has been enormous progress in this field in recent years and the current review aims to provide the public with a popular and accessible account of this work. The Nuclear Physics Division of the EPS represents scientists from all branches of nuclear physics across Europe. One of its aims is the dissemination of knowledge about nuclear physics and its applications. This review is led by Division board member Anna Macková, Head of the Tandetron Laboratory at the Nuclear Physics Institute of the Czech Academy of Sciences, and the review committee includes four other members of the nuclear physics board interested in this area: Faiçal Azaiez, Johan Nyberg, Eli Piasetzky and Douglas MacGregor. To create a truly authoritative account, the Scientific Editors have invited contributions from leading experts across Europe, and this publication is the combined result of their work. The review is extensively illustrated with important discoveries and examples from archaeology, pre-history, history, geography, culture, religion and curation, which underline the breadth and importance of this field. The large number of groups and laboratories working in the study and preservation of cultural heritage across Europe indicate the enormous effort and importance attached by society to this activity