Simultaneous dynamic glucose-enhanced (DGE) MRI and fiber photometry measurements of glucose in the healthy mouse brain

Glucose is the main energy source in the brain and its regulated uptake and utilization are important biomarkers of pathological brain function. Glucose Chemical Exchange Saturation Transfer (GlucoCEST) and its time-resolved version Dynamic Glucose-Enhanced MRI (DGE) are promising approaches to monitor glucose and detect tumors, since it is radioactivity-free, does not require 13C labelling and it is easily translatable to the clinics. The main principle of DGE is clear. However, what remains to be established is to which extent the signal reflects vascular, extracellular or intracellular glucose. To elucidate the compartmental contributions to the DGE signal, we coupled it with FRET-based fiber photometry of genetically encoded sensors, a technique that combines quantitative glucose readout with cellular specificity. The glucose sensor FLIIP was used with fiber photometry to measure astrocytic and neuronal glucose changes upon injection of D-glucose, 3OMG and L-glucose, in the anaesthetized murine brain. By correlating the kinetic profiles of the techniques, we demonstrate the presence of a vascular contribution to the signal, especially at early time points after injection. Furthermore, we show that, in the case of the commonly used contrast agent 3OMG, the DGE signal actually anticorrelates with the glucose concentration in neurons and astrocytes. Keywords: fiber photometry; genetically encoded sensors; glucoCEST; kinetic modelling; two-photon microscopy

PET iterative reconstruction incorporating an efficient positron range correction method

Positron range is one of the main physical effects limiting the spatial resolution of positron emission tomography (PET) images. If positrons travel inside a magnetic field, for instance inside a nuclear magnetic resonance (MR) tomograph, the mean range will be smaller but still significant. In this investigation we examined a method to correct for the positron range effect in iterative image reconstruction by including tissue-specific kernels in the forward projection operation. The correction method was implemented within STIR library (Software for Tomographic Image Reconstruction). In order to obtain the positron annihilation distribution of various radioactive isotopes in water and lung tissue, simulations were performed with the Monte Carlo package GATE [Jan et al. 2004 [1]] simulating different magnetic field intensities (0 T, 3 T, 9.5 T and 11 T) along the axial scanner direction. The positron range kernels were obtained for 68Ga in water and lung tissue for 0 T and 3 T magnetic field voxellizing the annihilation coordinates into a three-dimensional matrix. The proposed method was evaluated using simulations of material-variant and material-invariant positron range corrections for the HYPERImage preclinical PET-MR scanner. The use of the correction resulted in sharper active region boundary definition, albeit with noise enhancement, and in the recovery of the true activity mean value of the hot regions. Moreover, in the case where a magnetic field is present, the correction accounts for the non-isotropy of the positron range effect, resulting in the recovery of resolution along the axial plane

Longitudinal PET imaging of tumor hypoxia during the course of radiotherapy

Hypoxia results from an imbalance between oxygen supply and consumption. It is a common phenomenon in solid malignant tumors such as head and neck cancer. As hypoxic cells are more resistant to therapy, tumor hypoxia is an indicator for poor prognosis. Several techniques have been developed to measure tissue oxygenation. These are the Eppendorf O2 polarographic needle electrode, immunohistochemical analysis of endogenous (e.g., hypoxia-inducible factor-1α (HIF-1a)) and exogenous markers (e.g., pimonidazole) as well as imaging methods such as functional magnetic resonance imaging (e.g., blood oxygen level dependent (BOLD) imaging, T1-weighted imaging) and hypoxia positron emission tomography (PET). Among the imaging modalities, only PET is sufficiently validated to detect hypoxia for clinical use. Hypoxia PET tracers include 18F-fluoromisonidazole (FMISO), the most commonly used hypoxic marker, 18F-flouroazomycin arabinoside (FAZA), 18Ffluoroerythronitroimidazole (FETNIM), 18F-2-nitroimidazolpentafluoropropylacetamide (EF5) and 18F-flortanidazole (HX4). As technical development provides the opportunity to increase the radiation dose to subregions of the tumor, such as hypoxic areas, it has to be ensured that these regions are stable not only from imaging to treatment but also through the course of radiotherapy. The aim of this review is therefore to characterize the behavior of tumor hypoxia during radiotherapy for the whole tumor and for subregions by using hypoxia PET tracers, with focus on head and neck cancer patients

Simultaneous dynamic glucose-enhanced (DGE) MRI and fiber photometry measurements of glucose in the healthy mouse brain

Glucose is the main energy source in the brain and its regulated uptake and utilization are important biomarkers of pathological brain function. Glucose Chemical Exchange Saturation Transfer (GlucoCEST) and its time-resolved version Dynamic Glucose-Enhanced MRI (DGE) are promising approaches to monitor glucose and detect tumors, since they are radioactivity-free, do not require 13C labeling and are is easily translatable to the clinics. The main principle of DGE is clear. However, what remains to be established is to which extent the signal reflects vascular, extracellular or intracellular glucose. To elucidate the compartmental contributions to the DGE signal, we coupled it with FRET-based fiber photometry of genetically encoded sensors, a technique that combines quantitative glucose readout with cellular specificity. The glucose sensor FLIIP was used with fiber photometry to measure astrocytic and neuronal glucose changes upon injection of D-glucose, 3OMG and L-glucose, in the anaesthetized murine brain. By correlating the kinetic profiles of the techniques, we demonstrate the presence of a vascular contribution to the signal, especially at early time points after injection. Furthermore, we show that, in the case of the commonly used contrast agent 3OMG, the DGE signal actually anticorrelates with the glucose concentration in neurons and astrocytes.ISSN:1053-8119ISSN:1095-957

SAFIR-I: Design and Performance of a High-Rate Preclinical PET Insert for MRI

(1) Background: Small Animal Fast Insert for MRI detector I (SAFIR-I) is a preclinical Positron Emission Tomography (PET) insert for the Bruker BioSpec 70/30 Ultra Shield Refrigerated (USR) preclinical 7T Magnetic Resonance Imaging (MRI) system. It is designed explicitly for high-rate kinetic studies in mice and rats with injected activities reaching 500MBq, enabling truly simultaneous quantitative PET and Magnetic Resonance (MR) imaging with time frames of a few seconds in length. (2) Methods: SAFIR-I has an axial field of view of 54.2mm and an inner diameter of 114mm. It employs Lutetium Yttrium OxyorthoSilicate (LYSO) crystals and Multi Pixel Photon Counter (MPPC) arrays. The Position-Energy-Timing Application Specific Integrated Circuit, version 6, Single Ended (PETA6SE) digitizes the MPPC signals and provides time stamps and energy information. (3) Results: SAFIR-I is MR-compatible. The system’s Coincidence Resolving Time (CRT) and energy resolution are between separate-uncertainty 209.0(3)ps and separate-uncertainty 12.41(02) Full Width at Half Maximum (FWHM) at low activity and separate-uncertainty 326.89(12)ps and separate-uncertainty 20.630(011) FWHM at 550MBq, respectively. The peak sensitivity is ∼1.6. The excellent performance facilitated the successful execution of first in vivo rat studies beyond 300MBq. Based on features visible in the acquired images, we estimate the spatial resolution to be ∼2mm in the center of the Field Of View (FOV). (4) Conclusion: The SAFIR-I PET insert provides excellent performance, permitting simultaneous in vivo small animal PET/MR image acquisitions with time frames of a few seconds in length at activities of up to 500MBq

Initial Characterization of the SAFIR Prototype PET-MR Scanner

The SAFIR collaboration is currently developing a high-rate positron emission tomography (PET) insert to study fast kinetic processes in small animals. Our insert is designed for simultaneous image acquisition with a preclinical 7 T magnetic resonance (MR) imaging device. In contrast to existing preclinical PET scanners and inserts, our hardware is optimized for high-rate measurements with source activities up to 500 MBq. As a first step, the SAFIR Prototype insert was constructed. This already incorporates the final components, but has a reduced axial field-of-view (35.6 mm). We use lutetiumyttrium oxyorthosilicate crystals (2.12 mm × 2.12 mm × 13 mm) one-to-one coupled to silicon photomultipliers. All analog signals are digitized within the insert. We use 49 MR-compatible dc- dc converters in the insert to provide the power to all readout electronics. After shimming, no degradation of the homogeneity of the static B0 field in the MR scanner was observed. During full operation, we saw a minor reduction in the signal-to-noise ratio of the MR data of 4.9%. With a low activity point source (22Na 0.65 MBq) we obtained a coincidence energy resolution of 13.8% full width at half maximum (FWhM) and a coincidence timing resolution of 194 ps (FWhM). First PET/MR rat brain and high-rate mouse cardiac images (84.9 MBq) are shown in this article