Simultaneous in vivo positron emission tomography and magnetic resonance imaging

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are widely used in vivo imaging technologies with both clinical and biomedical research applications. The strengths of MRI include high-resolution, high-contrast morphologic imaging of soft tissues; the ability to image physiologic parameters such as diffusion and changes in oxygenation level resulting from neuronal stimulation; and the measurement of metabolites using chemical shift imaging. PET images the distribution of biologically targeted radiotracers with high sensitivity, but images generally lack anatomic context and are of lower spatial resolution. Integration of these technologies permits the acquisition of temporally correlated data showing the distribution of PET radiotracers and MRI contrast agents or MR-detectable metabolites, with registration to the underlying anatomy. An MRI-compatible PET scanner has been built for biomedical research applications that allows data from both modalities to be acquired simultaneously. Experiments demonstrate no effect of the MRI system on the spatial resolution of the PET system and <10% reduction in the fraction of radioactive decay events detected by the PET scanner inside the MRI. The signal-to-noise ratio and uniformity of the MR images, with the exception of one particular pulse sequence, were little affected by the presence of the PET scanner. In vivo simultaneous PET and MRI studies were performed in mice. Proof-of-principle in vivo MR spectroscopy and functional MRI experiments were also demonstrated with the combined scanner

Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [18F]-fluoro-azomycinarabino-furanoside ([18F]FAZA)

<p>Abstract</p> <p>Background</p> <p>[¹⁸F]FAZA is a PET biomarker with great potential for imaging tumor hypoxia. Aim of our study was to compare [¹⁸F]FAZA uptake in mice with subcutaneous exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas and to analyze the influence of different breathing protocols in CT26 colon carcinomas as well as the reversibility or irreversibility of [¹⁸F]FAZA uptake.</p> <p>Methods</p> <p>We injected subcutaneous CT26 colon carcinoma or polyomavirus middle-T (PyV-mT) mammary carcinoma-bearing mice intravenously with¹⁸F-FAZA and performed PET scans 1-3 h post injection (<it>p.i.</it>). To analyze the impact of oxygen supply in CT26 carcinomas we used three different breathing protocols: (P0) air; (P1) 100% oxygen 1 h prior injection until 3 h <it>p.i.</it>; (P2) 100% oxygen breathing starting 2 min prior tracer injection until 1 h <it>p.i. </it>and during the PET scans; mice were breathing air between the 2 h and 3 h 10 min static scans. Normalized PET images were analyzed by using defined regions of interest. Finally, some mice were dissected for pimonidazole immunohistochemistry.</p> <p>Results</p> <p>There was no difference in¹⁸F-FAZA uptake 1-3 h <it>p.i. </it>between the two carcinoma types (CT26: 1.58 ± 0.45%ID/cc; PyV-mT: 1.47 ± 0.89%ID/cc, 1 h <it>p.i.</it>, tumor size < 0.5 cm³). We measured a significant tracer clearance, which was more pronounced in muscle tissue (P0). The [¹⁸F]FAZA tumor-to-muscle-ratios in CT26 colon carcinoma-bearing mice 2 h and 3 h, but not 1 h <it>p.i. </it>were significantly higher when the mice breathed air (P0: 3.56 ± 0.55, 3 h) compared to the oxygen breathing protocols (P1: 2.45 ± 0.58; P2: 2.77 ± 0.42, 3 h). Surprisingly, the breathing protocols P1 and P2 showed no significant differences in T/M ratios, thus indicating that the crucial [¹⁸F]FAZA uptake phase is during the first hour after [¹⁸F]FAZA injection. Importantly, the muscle clearance was not affected by the different oxygen breathing conditions while the tumor clearance was lower when mice were breathing air.</p> <p>Conclusion</p> <p>Exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas showed no differences in [¹⁸F]FAZA uptake 1-3 h <it>p.i. </it>Our analysis using various breathing protocols with air (P0) and with pure oxygen (P1, P2) clearly indicate that [¹⁸F]FAZA is an appropriate PET biomarker for <it>in vivo </it>analysis of hypoxia revealing an enhanced tracer uptake in tumors with reduced oxygen supply. [¹⁸F]FAZA uptake was independent of tumor-type.</p

A near-infrared probe for non-invasively monitoring cerebrospinal fluid flow by F-18-positron emitting tomography and fluorescence

PURPOSE:Knowing the precise flow of cerebrospinal fluid (CSF) is important in the management of multiple neurological diseases. Technology for non-invasively quantifying CSF flow would allow for precise localization of injury and assist in evaluating the viability of certain devices placed in the central nervous system (CNS). METHODS:We describe a near-infrared fluorescent dye for accurately monitoring CSF flow by positron emission tomography (PET) and fluorescence. IR-783, a commercially available near-infrared dye, was chemically&nbsp;modified and&nbsp;radiolabeled with fluorine-18 to give [18F]-IR783-AMBF3. [18F]-IR783-AMBF3 was intrathecally injected into the rat models with normal and aberrant CSF flow and evaluated by the fluorescence and PET/MRI or PET/CT imaging modes. RESULTS:IR783-AMBF3 was clearly distributed in CSF-containing volumes by PET and fluorescence. We compared IR783-AMBF3 (fluorescent at&nbsp;778/793 nm, ex/em) to a shorter-wavelength, fluorescein equivalent (fluorescent at&nbsp;495/511 nm, ex/em). IR783-AMBF3 was superior for its ability to image through blood (hemorrhage) and for imaging CSF-flow, through-skin, in subdural-run lumboperitoneal shunts. IR783-AMBF3 was safe under the tested dosage both in vitro and in vivo. CONCLUSION:The superior imaging properties of IR783-AMBF3 could lead to enhanced accuracy in the treatment of patients and would assist surgeons in non-invasively diagnosing diseases of the CNS

Compton PET: a layered structure PET detector with high performance

In most high-resolution PET detector designs, there is an inherent trade-off between spatial resolution and detector efficiency. We have developed and tested a new geometry for the detector module which avoids this trade-off. The module uses a layered structure, in which four crystal slabs are stacked in the depth direction and optically separated by enhanced specular reflector (ESR) film. The scintillation light within each layer is measured by 16 SiPMs located on the four sides of the crystal. Analog signals from all SiPMs (4  ×  16) on the four sides of the crystal are digitized individually using a 64-channel TOFPET-2 module. The four-sided readout method reduces the problem of light trapping resulting from total internal reflection when reading out the end(s) of traditional scintillation crystal arrays, thus increasing the light collection efficiency. In this work, we demonstrate the readout of a complete layered detector with 4 layers. The high light collection efficiency results in a FWHM energy resolution of 10.3%, and a FWHM timing resolution of 348 ps. The distribution of scintillation light detected by the SiPMs was used to decode the interaction position of each gamma ray using a trained neural network. A FWHM spatial resolution of 1.1  ±  0.1 mm was achieved. This design allows the detection efficiency of the module to be increased by adding additional crystal slabs along the depth direction. Since the position, energy, and timing are measured for each layer independently, increasing the system sensitivity by adding more layers will not affect the spatial/energy/timing resolution. Furthermore, the layered structure allows partial recovery of position information for events that undergo Compton scatter within the detector

Optimization of a depth of interaction encoding PET block detector for a PET/MRI insert

Preclinical positron emission tomography, combined with magnetic resonance imaging (PET/MRI), is increasingly used as a tool to simultaneously characterize functional processes in vivo. Many emerging preclinical applications, however, are limited by PET detection sensitivity, especially when generating short imaging frames for quantitative studies. One such application is dynamic multifunctional imaging, which probes multiple aspects of a biological process, using relationships between the datasets to quantify interactions. These studies have limited accuracy due to the relatively low sensitivity of modern preclinical PET/MRI systems. The goal of this project is to develop a preclinical PET/MRI insert with detection sensitivity above 15% (250-750 keV) to improve quantitation in dynamic PET imaging. To achieve this sensitivity, we have developed a detector module incorporating a 2 cm thick crystal block, which will be arranged into a system with 8 cm axial FOV, targeting mice and rats. To maintain homogenous spatial resolution, the detector will incorporate dual-ended depth-of-interaction (DOI) encoding with silicon photomultiplier (SiPM) based photodetector arrays. The specific aim of this work is to identify a detector configuration with adequate performance for the proposed system. We have optimized the SiPM array geometry and tested two crystal array materials with pitch ranging from 0.8 to 1.2 mm and various surface treatments and reflectors. From these configurations, we have identified the best balance between crystal separation, energy resolution, and DOI resolution. The final detector module uses two rectangular SiPM arrays with 5  ×  6 and 5  ×  4 elements. The photodetector arrays are coupled to a 19  ×  19 array of 1 mm pitch LYSO crystals with polished surfaces and a diffuse reflector. The prototype design has 14.3%  ±  2.9% energy resolution, 3.57  ±  0.88 mm DOI resolution, and resolves all elements in the crystal array, giving it sufficient performance to serve as the basis for the proposed high sensitivity PET/MRI insert

Compton PET: A Simulation Study for a PET Module with Novel Geometry and Machine Learning for Position Decoding.

This paper describes a simulation study of a positron emission tomography (PET) detector module that can reconstruct the kinematics of Compton scattering within the scintillator. We used a layer structure, with which we could recover the positions and energies for the multiple interactions of a gamma ray in the different layers. Using the Compton scattering formalism, the sequence of interactions can be estimated. The true first interaction position extracted in the Compton scattering will help minimize the degradation of the reconstructed image resolution caused by intercrystal scatter events. Because of the layer structure, this module also has readily available user-defined resolution for the depth of interaction. The semi-monolithic crystals enable high light collection efficiency and an energy resolution of ~10% has been achieved in the simulation. We used machine learning to decode the gamma ray interaction locations, achieving an average spatial resolution of 0.40 mm. Our proposed detector design provides a pathway to increase the sensitivity of a system without affecting other key performance features

Un-collimated single-photon imaging system for high-sensitivity small animal and plant imaging

In preclinical single-photon emission computed tomography (SPECT) system development the primary objective has been to improve spatial resolution by using novel parallel-hole or multi-pinhole collimator geometries. However, such high-resolution systems have relatively poor sensitivity (typically 0.01-0.1%). In contrast, a system that does not use collimators can achieve very high-sensitivity. Here we present a high-sensitivity un-collimated detector single-photon imaging (UCD-SPI) system for the imaging of both small animals and plants. This scanner consists of two thin, closely spaced, pixelated scintillator detectors that use NaI(Tl), CsI(Na), or BGO. The performance of the system has been characterized by measuring sensitivity, spatial resolution, linearity, detection limits, and uniformity. With (99m)Tc (140 keV) at the center of the field of view (20 mm scintillator separation), the sensitivity was measured to be 31.8% using the NaI(Tl) detectors and 40.2% with CsI(Na). The best spatial resolution (FWHM when the image formed as the geometric mean of the two detector heads, 20 mm scintillator separation) was 19.0 mm for NaI(Tl) and 11.9 mm for CsI(Na) at 140 keV, and 19.5 mm for BGO at 1116 keV, which is somewhat degraded compared to the cm-scale resolution obtained with only one detector head and a close source. The quantitative accuracy of the system's linearity is better than 2% with detection down to activity levels of 100 nCi. Two in vivo animal studies (a renal scan using (99m)Tc MAG-3 and a thyroid scan with (123)I) and one plant study (a (99m)TcO4(-) xylem transport study) highlight the unique capabilities of this UCD-SPI system. From the renal scan, we observe approximately a one thousand-fold increase in sensitivity compared to the Siemens Inveon SPECT/CT scanner. UCD-SPI is useful for many imaging tasks that do not require excellent spatial resolution, such as high-throughput screening applications, simple radiotracer uptake studies in tumor xenografts, dynamic studies where very good temporal resolution is critical, or in planta imaging of radioisotopes at low concentrations

Performance assessment of a software-based coincidence processor for the EXPLORER total-body PET scanner

Coincidence processing in positron emission tomography (PET) is typically done during acquisition of the data. However, on the EXPLORER total-body PET scanner we plan, in addition, to store unpaired single events (i.e. singles) for post-acquisition coincidence processing. A software-based coincidence processor was developed for EXPLORER and its performance was assessed. Our results showed that the performance of the coincidence processor could be significantly impacted by the type of data storage (Peripheral Component Interconnect Express (PCIe)-attached solid state drive (SSD) versus RAID 6 hard disk drives (HDDs)) especially when multiple data files were processed in parallel. We showed that a 48-thread computer node with dual Intel Xeon E5-2650 v4 central processing units (CPUs) and a PCIe SSD was sufficient to process approximately 120 M singles s-1 at an incoming singles rate of approximately 150 Mcps. With two computer nodes, near real-time coincidence processing became possible at this incoming singles rate

Development of an Ultra High Resolution PET Scanner for Imaging Rodent Paws: PawPET.

A positron emission tomography (PET) scanner with submillimeter spatial resolution, capable of in vivo imaging of murine extremities was built based on two dual ended readout, hybrid depth of interaction (DOI) PET detectors. Each was composed of a 36 × 36 array of 0.43 mm × 0.43 mm × 8 mm unpolished lutetium oxyorthosilicate crystals separated by a 50 μm white diffuse reflector. The array was coupled to a position-sensing photomultiplier tube at one end and to an avalanche photodiode at the other end. The detector characterization included crystal identification accuracy, DOI, energy, and timing resolution measurements. The scanner was characterized in terms of its spatial resolution and its sensitivity and mouse images were acquired of a mouse paw injected with 18-F-NaF. Out of the 36 × 36 crystals only 33 × 33 crystals were identified. The coincidence timing, DOI, and energy resolution of the scanner was measured to be 2.8 ns, 1.4 mm, and 27%, respectively. The scanner's spatial resolution was measured with a line source and determined from an ordered subsets expectation maximization reconstruction to be 0.56 mm. The sensitivity of the scanner was measured to be 0.6% at the center of the field of view

A Time-Walk Correction Method for PET Detectors Based on Leading Edge Discriminators

The leading edge timing pick-off technique is the simplest timing extraction method for PET detectors. Due to the inherent time-walk of the leading edge technique, corrections should be made to improve timing resolution, especially for time-of-flight PET. Time-walk correction can be done by utilizing the relationship between the threshold crossing time and the event energy on an event by event basis. In this paper, a time-walk correction method is proposed and evaluated using timing information from two identical detectors both using leading edge discriminators. This differs from other techniques that use an external dedicated reference detector, such as a fast PMT-based detector using constant fraction techniques to pick-off timing information. In our proposed method, one detector was used as reference detector to correct the time-walk of the other detector. Time-walk in the reference detector was minimized by using events within a small energy window (508.5 - 513.5 keV). To validate this method, a coincidence detector pair was assembled using two SensL MicroFB SiPMs and two 2.5 mm × 2.5 mm × 20 mm polished LYSO crystals. Coincidence timing resolutions using different time pick-off techniques were obtained at a bias voltage of 27.5 V and a fixed temperature of 20 °C. The coincidence timing resolution without time-walk correction were 389.0 ± 12.0 ps (425 -650 keV energy window) and 670.2 ± 16.2 ps (250-750 keV energy window). The timing resolution with time-walk correction improved to 367.3 ± 0.5 ps (425 - 650 keV) and 413.7 ± 0.9 ps (250 - 750 keV). For comparison, timing resolutions were 442.8 ± 12.8 ps (425 - 650 keV) and 476.0 ± 13.0 ps (250 - 750 keV) using constant fraction techniques, and 367.3 ± 0.4 ps (425 - 650 keV) and 413.4 ± 0.9 ps (250 - 750 keV) using a reference detector based on the constant fraction technique. These results show that the proposed leading edge based time-walk correction method works well. Timing resolution obtained using this method was equivalent to that obtained using a reference detector and was better than that obtained using constant fraction discriminators