Ciprian Catana

Simultaneous PET-MRI: a new approach for functional and morphological imaging

Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.

Toward Implementing an MRI-Based PET Attenuation-Correction Method for Neurologic Studies on the MR-PET Brain Prototype

Several factors have to be considered for implementing an accurate attenuation-correction (AC) method in a combined MR-PET scanner. In this work, some of these challenges were investigated, and an AC method based entirely on the MRI data obtained with a single dedicated sequence was developed and used for neurologic studies performed with the MR-PET human brain scanner prototype. Methods: The focus was on the problem of bone–air segmentation, selection of the linear attenuation coefficient for bone, and positioning of the radiofrequency coil. The impact of these factors on PET data quantification was studied in simulations and experimental measurements performed on the combined MR-PET scanner. A novel dual-echo ultrashort echo time (DUTE) MRI sequence was proposed for head imaging. Simultaneous MR-PET data were acquired, and the PET images reconstructed using the proposed DUTE MRI–based AC method were compared with the PET images that had been reconstructed using a CT-based AC method. Results: Our data suggest that incorrectly accounting for the bone tissue attenuation can lead to large underestimations (>20%) of the radiotracer concentration in the cortex. Assigning a linear attenuation coefficient of 0.143 or 0.151 cm−1 to bone tissue appears to give the best trade-off between bias and variability in the resulting images. Not identifying the internal air cavities introduces large overestimations (>20%) in adjacent structures. On the basis of these results, the segmented CT AC method was established as the silver standard for the segmented MRI-based AC method. For an integrated MR-PET scanner, in particular, ignoring the radiofrequency coil attenuation can cause large underestimations (i.e., ≤50%) in the reconstructed images. Furthermore, the coil location in the PET field of view has to be accurately known. High-quality bone–air segmentation can be performed using the DUTE data. The PET images obtained using the DUTE MRI– and CT-based AC methods compare favorably in most of the brain structures. Conclusion: A DUTE MRI–based AC method considering all these factors was implemented. Preliminary results suggest that this method could potentially be as accurate as the segmented CT method and could be used for quantitative neurologic MR-PET studies.

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.

PET/MRI for Neurologic Applications

PET and MRI provide complementary information in the study of the human brain. Simultaneous PET/MRI data acquisition allows the spatial and temporal correlation of the measured signals, creating opportunities impossible to realize using stand-alone instruments. This paper reviews the methodologic improvements and potential neurologic and psychiatric applications of this novel technology. We first present methods for improving the performance and information content of each modality by using the information provided by the other technique. On the PET side, we discuss methods that use the simultaneously acquired MRI data to improve the PET data quantification. On the MRI side, we present how improved PET quantification can be used to validate several MRI techniques. Finally, we describe promising research, translational, and clinical applications that can benefit from these advanced tools.

Evidence for brain glial activation in chronic pain patients

Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.

MRI-Based Nonrigid Motion Correction in Simultaneous PET/MRI

Respiratory and cardiac motion is the most serious limitation to whole-body PET, resulting in spatial resolution close to 1 cm. Furthermore, motion-induced inconsistencies in the attenuation measurements often lead to significant artifacts in the reconstructed images. Gating can remove motion artifacts at the cost of increased noise. This paper presents an approach to respiratory motion correction using simultaneous PET/MRI to demonstrate initial results in phantoms, rabbits, and nonhuman primates and discusses the prospects for clinical application. Methods: Studies with a deformable phantom, a free-breathing primate, and rabbits implanted with radioactive beads were performed with simultaneous PET/MRI. Motion fields were estimated from concurrently acquired tagged MR images using 2 B-spline nonrigid image registration methods and incorporated into a PET list-mode ordered-subsets expectation maximization algorithm. Using the measured motion fields to transform both the emission data and the attenuation data, we could use all the coincidence data to reconstruct any phase of the respiratory cycle. We compared the resulting SNR and the channelized Hotelling observer (CHO) detection signal-to-noise ratio (SNR) in the motion-corrected reconstruction with the results obtained from standard gating and uncorrected studies. Results: Motion correction virtually eliminated motion blur without reducing SNR, yielding images with SNR comparable to those obtained by gating with 5–8 times longer acquisitions in all studies. The CHO study in dynamic phantoms demonstrated a significant improvement (166%–276%) in lesion detection SNR with MRI-based motion correction as compared with gating (P < 0.001). This improvement was 43%–92% for large motion compared with lesion detection without motion correction (P < 0.001). CHO SNR in the rabbit studies confirmed these results. Conclusion: Tagged MRI motion correction in simultaneous PET/MRI significantly improves lesion detection compared with respiratory gating and no motion correction while reducing radiation dose. In vivo primate and rabbit studies confirmed the improvement in PET image quality and provide the rationale for evaluation in simultaneous whole-body PET/MRI clinical studies.

MRI-Assisted PET Motion Correction for Neurologic Studies in an Integrated MR-PET Scanner

Head motion is difficult to avoid in long PET studies, degrading the image quality and offsetting the benefit of using a high-resolution scanner. As a potential solution in an integrated MR-PET scanner, the simultaneously acquired MRI data can be used for motion tracking. In this work, a novel algorithm for data processing and rigid-body motion correction (MC) for the MRI-compatible BrainPET prototype scanner is described, and proof-of-principle phantom and human studies are presented. Methods: To account for motion, the PET prompt and random coincidences and sensitivity data for postnormalization were processed in the line-of-response (LOR) space according to the MRI-derived motion estimates. The processing time on the standard BrainPET workstation is approximately 16 s for each motion estimate. After rebinning in the sinogram space, the motion corrected data were summed, and the PET volume was reconstructed using the attenuation and scatter sinograms in the reference position. The accuracy of the MC algorithm was first tested using a Hoffman phantom. Next, human volunteer studies were performed, and motion estimates were obtained using 2 high-temporal-resolution MRI-based motion-tracking techniques. Results: After accounting for the misalignment between the 2 scanners, perfectly coregistered MRI and PET volumes were reproducibly obtained. The MRI output gates inserted into the PET list-mode allow the temporal correlation of the 2 datasets within 0.2 ms. The Hoffman phantom volume reconstructed by processing the PET data in the LOR space was similar to the one obtained by processing the data using the standard methods and applying the MC in the image space, demonstrating the quantitative accuracy of the procedure. In human volunteer studies, motion estimates were obtained from echo planar imaging and cloverleaf navigator sequences every 3 s and 20 ms, respectively. Motion-deblurred PET images, with excellent delineation of specific brain structures, were obtained using these 2 MRI-based estimates. Conclusion: An MRI-based MC algorithm was implemented for an integrated MR-PET scanner. High-temporal-resolution MRI-derived motion estimates (obtained while simultaneously acquiring anatomic or functional MRI data) can be used for PET MC. An MRI-based MC method has the potential to improve PET image quality, increasing its reliability, reproducibility, and quantitative accuracy, and to benefit many neurologic applications.

Bimodal MR–PET Agent for Quantitative pH Imaging

The scope of Magnetic Resonance Imaging (MRI) is moving beyond anatomical and functional imaging to also convey information at the molecular level. Molecular MRI is enabled by the introduction of protein-targeted contrast agents[1] as well as “smart” or activatable contrast agents.[2] MR contrast agents induce relaxation of tissue water, and the extent of this relaxation enhancement, termed relaxivity (r1), depends on a number of molecular factors including the hydration state of the contrast agent and its rotational diffusion rate. In a seminal paper, Meade and colleagues demonstrated that the relaxivity of a specifically designed contrast agent could be changed in the presence of the enzyme beta-galactosidase, thereby creating an imaging agent whose signal was activated by the presence of the enzyme.[3, 4] Numerous publications have followed in the last decade that describe “smart” agents responsive to other enzymes, to pH, to specific metal ion concentrations, to partial oxygen pressure and to temperature.[5, 6] The impressive gains in smart agent development have been slow to make their way into in vivo imaging studies, however. This can be appreciated from equation 1 which relates the water relaxation rate (1/T1) to r1. MR signal is a function T1 (Eq. 1, 1/T10 = relaxation rate in absence of agent), which depends on both r1 and contrast agent concentration ([Gd]). In vitro, the gadolinium concentration is known and fixed; any signal change is due to relaxivity change. In vivo, the agent concentration is unknown, will change with time, and may vary in diseased versus normal tissue. 1T1=r1⋅[Gd]+1T10 (1) A smart agent to noninvasively map pH with both high temporal and spatial resolution would have broad utility. Decreased extracellular pH is associated with cancer and ischemic diseases such as stroke, ischemic heart disease, and kidney disease.[7] pH could be a very useful biomarker to identify disease and monitor response to therapy, but it remains a challenge to routinely assess pH in vivo. Implanting a pH electrode is invasive and offers little spatial information. 31P NMR can measure pH via the pH-dependent chemical shift of inorganic phosphate.[8] Other papers have described using exogenous agents with pH-sensitive chemical shifts.[7, 9] Yet, these NMR spectroscopic techniques are limited by low sensitivity resulting in trade offs in imaging time (longer, more averages required) and resolution (lower, bigger volume elements required). Chemical exchange saturation transfer (CEST) agents have also been described for pH imaging, but these also require millimolar concentrations for detection.[10, 11] Recently hyperpolarized 13C-carbonate MR was used to image pH.[12] There are several Gd-based smart agents whose relaxivity is pH dependent due to changes in complex hydration with pH.[6, 7] To address the problem of complex concentration, Aime et al. proposed a R2/R1 ratiometric method[13] but given the relatively large R2 present in living tissues compared to R1, the in vivo accuracy of such an approach has yet to be proven. Combining fluorine MRI for quantification with a pH sensitive Gd-based agent has also been suggested,[14] although the sensitivity of F-19 imaging is in the millimolar range. An early pH sensitive agent was GdDOTA-4AMP.[15] This agent was used to map pH in vivo in renal acidosis[16] and brain tumor[17] models. To estimate the in vivo concentration of agent, these investigators first injected GdDOTP, which has pH-independent relaxivity, and imaged. They assumed that the pharmacokinetics of GdDOTP was the same as for GdDOTA-4AMP and that differences in the signal vs time curves for GdDOTP and GdDOTA-4AMP were due to differences in relaxivity. These studies demonstrated the potential for in vivo pH mapping and showed that MRI with GdDOTA-4AMP was sensitive enough to detect pH differences. The limitations of this approach were the need for two sequential injections and the assumption that both contrast agents have identical pharmacokinetics. Positron emission tomography (PET) offers exquisite sensitivity and the ability to perform absolute quantification. Quantitative PET imaging is routinely used in human and animal studies, for example to measure neuroreceptor occupancy levels[18] or to measure tissue perfusion.[19] The recent application of MR-compatible avalanche photodiode detector technology has now made it possible to have a functioning PET detector inside the MR magnet.[20, 21] This allows for the simultaneous acquisition of PET and MR data, and ability to obtain both temporally and spatially registered imaging data sets. We hypothesized that simultaneous MR-PET imaging with a bimodal MR-PET smart agent would result in quantification of both concentration and relaxivity. This dual label approach could enable a range of quantitative smart probes for in vivo applications. Here, a bimodal MR-PET agent designed for quantitative pH imaging at concentrations commonly used for in vivo MRI (0.1–1 mM) is described. The established pH sensitive MR agent GdDOTA-4AMP was modified to incorporate a fluorine atom (either 18F or 19F). The highly charged, hydrophilic GdDOTA-4AMP necessitated a strategy to introduce the 18F atom under aqueous conditions, and we chose the versatile Cu(I)-catalyzed Huisgen cycloaddition (“click reaction”) for this purpose.[22] GdDOTA-4AMP-F was prepared in six steps (Scheme 1) with a 25% overall yield starting from an established bifunctional chelator, tBu protected DOTAGA, 1.[23] 1 was activated and coupled with propargylamine, and subsequently deprotected in neat TFA to give 3. The introduction of the phosphonate groups was accomplished by coupling with aminomethyl-phosphonic acid diethyl ester, followed by mild deprotection of the phosphonate groups with trimethylsilyl bromide in DMF. The formation of the Gd(III) complex from the chloride salt, followed by reaction of fluoroethylazide and the alkyne intermediate 6, was performed in one pot. [F-18]fluoroethylazide was prepared in two steps from 2-azidoethanol, while the [F-19] version was prepared in two steps from 2-fluoroethanol (see Supp. Info).[22] Scheme 1 Synthesis of Gd-DOTA-4AMP-F and structure of Gd-DOTA-4AMP. The introduction of the fluorine-containing moiety into GdDOTA-4AMP-F did not modify the pH dependence of the longitudinal relaxivity with respect to the parent compound GdDOTA4-AMP.[24] GdDOTA-4AMP-F retains a monotonic decrease in relaxivity between pH 6.0 and 8.5 (Figure 1). In this pH range the relaxivity varied between 7.4 and 3.9 mM−1s−1 (60 MHz, 37 °C) when measured in an isotonic salt mixture. When the relaxivity was measured in rabbit plasma, the profile was found to be very similar to the profile measured in the salt solution. This indicates little if any protein binding and suggests that the pH-relaxivity relationship will be valid in vivo. Figure 1 Relaxivity of GdDOTA-4AMP-F as a function of pH (37 °C, 1.4 T) in presence of 135 mM NaCl, 5 mM KCl, and 2.5 mM CaCl2 (filled diamonds), and in rabbit plasma (open circles). The chemical concentration required for MR contrast is orders of magnitude higher than for PET imaging. For this reason, F-19 and F-18 versions of the probe were prepared separately, and subsequently mixed to produce a low specific activity MR-PET agent. Simultaneous MR-PET imaging was performed on a series of samples with varying pH using a clinical 3T MRI with a MR-compatible human PET scanner insert.[21] Figure 2 shows simultaneous MR-PET images acquired on phantoms where the T1 varied (MR, 2A) but the probe concentration was constant (PET, 2B); or where T1 was constant (2C) but the probe concentration varied (2D). Figure 2 eloquently displays the limitations of using an MR responsive agent without independent knowledge of the agent concentration. Note that in both sets of phantoms, the pH is varied. The only way to obtain pH values from the images is to combine both the PET and MR datasets. Figure 2 T1-weighted MR images (A and C, T1 values (ms) listed) and PET images (B and D, PET intensities (a.u.) listed) of phantoms at pH 6.5 (tube 1), 6.8 (2), 7.1 (3), 7.4 (4), and 7.8 (5). Phantoms in images A and B have the same concentration (0.45 mM); phantoms ... Since the PET signal is linear with radiochemical concentration, the unknown agent concentration can be determined by comparing the PET images with a series of standards. For the MR data, the relationship between r1 and pH can be measured (see Fig 1) and this was repeated at 3T where a similar linear relationship between r1 and pH between pH 6 to 8.5 was obtained. From these two standard curves, the PET and MR imaging data can be analyzed to estimate the pH of the samples. Figure 3 shows the good correspondence between pH measured by electrode and pH calculated from the MR and PET images. Figure 3 pH obtained from PET-MR image analysis versus pH measured by a glass electrode. The solid line is a linear fit of the data, while the dotted line represents a 1:1 correspondence. In conclusion, this communication describes a smart MR-PET agent that can quantitatively and non-invasively report on pH. Imaging data were obtained on a commercial clinical MRI with a prototype human PET camera at agent concentrations routinely encountered in clinical MRI (0.1 – 1 mM). This augurs well for the application of GdDOTA-4AMP-F to image pH changes in vivo. The combination of PET for quantifying concentration and MR for quantifying T1 allows for the simultaneous determination of relaxivity. For smart MR probes where relaxivity is proportional to an environmental stimulus, this bimodal imaging approach enables direct quantification of the stimulus, pH in this case. We note that this bimodal MR-PET strategy is generally applicable to other smart MR probes.

Small-Animal Molecular Imaging Methods

The ability to trace or identify specific molecules within a specific anatomic location provides insight into metabolic pathways, tissue components, and tracing of solute transport mechanisms. With the increasing use of small animals for research, such imaging must have sufficiently high spatial resolution to allow anatomic localization as well as sufficient specificity and sensitivity to provide an accurate description of the molecular distribution and concentration. Methods: Imaging methods based on electromagnetic radiation, such as PET, SPECT, MRI, and CT, are increasingly applicable because of recent advances in novel scanner hardware and image reconstruction software and the availability of novel molecules that have enhanced sensitivity in these methodologies. Results: Small-animal PET has been advanced by the development of detector arrays that provide higher resolution and positron-emitting elements that allow new molecular tracers to be labeled. Micro-MRI has been improved in terms of spatial resolution and sensitivity through increased magnet field strength and the development of special-purpose coils and associated scan protocols. Of particular interest is the associated ability to image local mechanical function and solute transport processes, which can be directly related to the molecular information. This ability is further strengthened by the synergistic integration of PET with MRI. Micro-SPECT has been improved through the use of coded aperture imaging approaches as well as image reconstruction algorithms that can better deal with the photon-limited scan data. The limited spatial resolution can be partially overcome by integrating SPECT with CT. Micro-CT by itself provides exquisite spatial resolution of anatomy, but recent developments in high-spatial-resolution photon counting and spectrally sensitive imaging arrays, combined with x-ray optical devices, hold promise for actual molecular identification by virtue of the chemical bond lengths of molecules, especially biopolymers. Conclusion: Given the increasing use of small animals for evaluating new clinical imaging techniques and providing more insight into pathophysiologic phenomena as well as the availability of improved detection systems, scanning protocols, and associated software, the sensitivity and specificity of molecular imaging are increasing.

Nonrigid PET motion compensation in the lower abdomen using simultaneous tagged‐MRI and PET imaging

PURPOSE We propose a novel approach for PET respiratory motion correction using tagged-MRI and simultaneous PET-MRI acquisitions. METHODS We use a tagged-MRI acquisition followed by motion tracking in the phase domain to estimate the nonrigid deformation of biological tissues during breathing. In order to accurately estimate motion even in the presence of noise and susceptibility artifacts, we regularize the traditional HARP tracking strategy using a quadratic roughness penalty on neighboring displacement vectors (R-HARP). We then incorporate the motion fields estimated with R-HARP in the system matrix of an MLEM PET reconstruction algorithm formulated both for sinogram and list-mode data representations. This approach allows reconstruction of all detected coincidences in a single image while modeling the effect of motion both in the emission and the attenuation maps. At present, tagged-MRI does not allow estimation of motion in the lungs and our approach is therefore limited to motion correction in soft tissues. Since it is difficult to assess the accuracy of motion correction approaches in vivo, we evaluated the proposed approach in numerical simulations of simultaneous PET-MRI acquisitions using the NCAT phantom. We also assessed its practical feasibility in PET-MRI acquisitions of a small deformable phantom that mimics the complex deformation pattern of a lung that we imaged on a combined PET-MRI brain scanner. RESULTS Simulations showed that the R-HARP tracking strategy accurately estimated realistic respiratory motion fields for different levels of noise in the tagged-MRI simulation. In simulations of tumors exhibiting increased uptake, contrast estimation was 20% more accurate with motion correction than without. Signal-to-noise ratio (SNR) was more than 100% greater when performing motion-corrected reconstruction which included all counts, compared to when reconstructing only coincidences detected in the first of eight gated frames. These results were confirmed in our proof-of-principle PET-MRI acquisitions, indicating that our motion correction strategy is accurate, practically feasible, and is therefore ready to be tested in vivo. CONCLUSIONS This work shows that PET motion correction using motion fields measured with tagged-MRI in simultaneous PET-MRI acquisitions can be made practical for clinical application and that doing so has the potential to remove motion blur in whole-body PET studies of the torso.