Proceedings of the 17th International Meeting on Fully 3D Image Reconstruction in Radiology and Nuclear Medicine.

Contained within this volume are the scholarly contributions presented in both oral and poster formats at Fully3D 2023: The 17th International Meeting on Fully Three-Dimensional Image Reconstruction in Radiology and Nuclear Medicine. This conference convened from July 16-21, 2023, at Stony Brook University in New York. For ease of reference, all papers are organized alphabetically according to the last names of the primary authors. Our heartfelt appreciation goes out to all participants who took the time to submit, present, and revise their work for inclusion in these proceedings. Collectively, we would also like to express our profound gratitude to our generous sponsors, detailed in subsequent pages, who have played an instrumental role in offering awards and facilitating the various conference activities. Additionally, our thanks extend to the diligent reporter who collated invaluable feedback from attendees, which can be found in the pages that follow. September 7, 2023 Fully3D 2023 Co-Chairs: Jerome Liang, Paul Vaska, and Chuan Huang.

Quantitative functional imaging of the pigeon brain: implications for the evolution of avian powered flight.

The evolution of flight is a rare event in vertebrate history, and one that demands functional integration across multiple anatomical/physiological systems. The neuroanatomical basis for such integration and the role that brain evolution assumes in behavioural transformations remain poorly understood. We make progress by (i) generating a positron emission tomography (PET)-based map of brain activity for pigeons during rest and flight, (ii) using these maps in a functional analysis of the brain during flight, and (iii) interpreting these data within a macroevolutionary context shaped by non-avian dinosaurs. Although neural activity is generally conserved from rest to flight, we found significant increases in the cerebellum as a whole and optic flow pathways. Conserved activity suggests processing of self-movement and image stabilization are critical when a bird takes to the air, while increased visual and cerebellar activity reflects the importance of integrating multimodal sensory information for flight-related movements. A derived cerebellar capability likely arose at the base of maniraptoran dinosaurs, where volumetric expansion and possible folding directly preceded paravian flight. These data represent an important step toward establishing how the brain of modern birds supports their unique behavioural repertoire and provide novel insights into the neurobiology of the bird-like dinosaurs that first achieved powered flight.

Assessment of Alzheimer's Disease Imaging Biomarkers in World Trade Center Responders with Cognitive Impairment at Midlife.

Purpose Incidence of early onset neurocognitive dysfunction has been reported in World Trade Center (WTC) responders. Ongoing studies are investigating the underlying etiology, as we are concerned that an underlying risk of neurodegenerative dementia may be occurring because of their stressful and neurotoxic exposures to particulate matter when they responded to the search and rescue efforts on September 11, 2001. The purpose of this study is to report preliminary results from two ongoing positron emission tomography (PET)/magnetic resonance imaging (MRI) imaging studies investigating the presence of Alzheimer's disease (AD) biomarkers, such as ß-amyloid, tau, and neurodegeneration, and compare our findings to published norms. Methods We present findings on 12 WTC responders diagnosed with either cognitive impairment (CI) or mild cognitive impairment (MCI), now at midlife, who underwent PET/MRI brain imaging as part of ongoing studies. Six responders with CI received [ 18 F] florbetaben (FBB) to detect ß-amyloidosis and six separate responders with MCI received [ 18 F] flortaucipir (FTP) to detect tauopathy. All 12 responders underwent concomitant MRI scans for gray matter volume analysis of neurodegeneration. Results PET analysis revealed 50% FBB and 50% of FTP scans were clinically read as positive and that 50% of FTP scans identified as consistent with Braak's stage I or II. Furthermore, one responder identified as centiloid positive for AD. Gray matter volumes from MRI analyses were compared with age/sex-matched norms (Neuroquant), identifying abnormally low cortical volumes in the occipital and temporal lobes, as well as the inferior temporal gyri and the entorhinal cortex. Conclusion These preliminary results suggest that WTC responders with neurocognitive dysfunction may be at increased risk for a neurodegenerative dementia process as a result of their exposures at September 11, 2001.

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-compatible PET System.

In this study, we used a compact, high-resolution, and MRI-compatible PET camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

Reduced cerebellar cortical thickness in World Trade Center responders with cognitive impairment.

Prior research has demonstrated high levels of cognitive and physical functional impairments in World Trade Center (WTC) responders. A follow-up neuroimaging study identified changes to white matter connectivity within the cerebellum in responders with cognitive impairment (CI). In the first study to examine cerebellar cortical thickness in WTC responders with CI, we fielded a structural magnetic resonance imaging protocol. WTC responders (N = 99) participated in a structural magnetic resonance imaging (MRI) study, of whom 48 had CI. Participants with CI did not differ demographically or by intracranial volume when compared to cognitively unimpaired participants. MRIs were processed using the CERES imaging pipeline; bilateral cortical thickness in 12 cerebellar lobules was reported. Analyses were completed comparing mean cerebellar cortical thickness across groups. Lobules were examined to determine the location and functional correlates of reduced cerebellar cortical thickness. Multivariable-adjusted analyses accounted for the false discovery rate. Mean cerebellar cortical thickness was reduced by 0.17 mm in responders with CI. Decrements in cerebellar cortical thickness were symmetric and located in the Cerebellar Crus (I and II), and in Lobules IV, VI, VIIb, VIIIa, VIIIb, and IX. Cerebellar cortical thickness was associated with episodic memory, response speed, and tandem balance. WTC responders with CI had evidence of reduced cerebellar cortical thickness that was present across lobules in a pattern unique to this cohort.

Glymphatic Cerebrospinal Fluid and Solute Transport Quantified by MRI and PET Imaging.

Over the past decade there has been an enormous progress in our understanding of fluid and solute transport in the central nervous system (CNS). This is due to a number of factors, including important developments in whole brain imaging technology and computational fluid dynamics analysis employed for the elucidation of glymphatic transport function in the live animal and human brain. In this paper, we review the technical aspects of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in combination with administration of Gd-based tracers into the cerebrospinal fluid (CSF) for tracking glymphatic solute and fluid transport in the CNS as well as lymphatic drainage. Used in conjunction with advanced computational processing methods including optimal mass transport analysis, one gains new insights into the biophysical forces governing solute transport in the CNS which leads to intriguing new research directions. Considering drainage pathways, we review the novel T1 mapping technique for quantifying glymphatic transport and cervical lymph node drainage concurrently in the same subject. We provide an overview of knowledge gleaned from DCE-MRI studies of glymphatic transport and meningeal lymphatic drainage. Finally, we introduce positron emission tomography (PET) and CSF administration of radiotracers as an alternative method to explore other pharmacokinetic aspects of CSF transport into brain parenchyma as well as efflux pathways.

PET/MRI reveals ongoing metabolic activity in ACL grafts one year post-ACL reconstruction.

PURPOSE: To use serial PET/MRI imaging to radiographically evaluate the metabolic activity of the ACL graft over the first post-operative year. METHODS: Six patients undergoing primary ACL reconstruction were recruited in this prospective study in an inpatient university hospital. All patients underwent femoral and tibial suspensory cortical fixation with quadrupled semitendinosus autograft hamstring ACL reconstruction by an orthopaedic surgeon. Simultaneous 18F-FDG PET and MRI of both the operative and non-operative knee was performed at three, six, and 12 months post-operatively. Quantification of the mean standardized uptake value (SUV) within the whole-knee, as well as tibial tunnel, femoral tunnel, and intra-articular graft regions of interest (ROIs). RESULTS: PET whole-knee activity was increased at all time-points post-operatively compared to the control, non-operative knee. Activity decreased over time, yet considerable generalized activity remained 1 year post-operatively, with relative intensity 34% percent higher than control. When the operative knee was divided into three whole-regions, there was greater activity in the tibia at three than 12 months, the femur at six than 12 months, and in the tibia compared to the intra-articular region at 3 months. When they were separated into sub-regions, results demonstrated greater activity closer to the joint surface. CONCLUSIONS: PET/MRI evaluation of ACL graft reconstructions demonstrates evolving biologic activity within the graft and both tunnels. Focal areas of increased activity within the tunnels may indicate of ligamento-osseous morphologic changes. These data suggest that graft incorporation continues well beyond 1 year post-operatively. LEVEL OF EVIDENCE: Level IV.

Positron emission tomography-magnetic resonance liver parenchyma attenuation correction artifact in secondary hemochromatosis.

Positron emission tomography-magnetic resonance (PET-MR) hybrid imaging is a relatively new imaging modality combining the superb MR contrast capabilities among different soft-tissue structures with the high sensitivity of PET functional imaging. With the development of any new technology, a variety of limitations will be encountered including the introduction of new types of artifacts. In this case report, we present a restaging PET-MR scan for multiple myeloma that showed severely decreased fluorodeoxyglucose activity in the liver on the PET attenuated corrected images. Careful analysis showed the cause of the decreased activity to be the improper density assignment on the mu map caused by iron deposition within the liver. Follow-up imaging showed reversal of the phenomena following improvement of liver disease.

Evaluation of quantitative, efficient image reconstruction for VersaPET, a compact PET system.

PURPOSE: Previously we developed a high-resolution positron emission tomography (PET) system-VersaPET-characterized by a block geometry with relatively large axial and transaxial interblock gaps and a compact geometry susceptible to parallax blurring effects. In this work, we report the qualitative and quantitative evaluation of a graphic processing unit (GPU)-accelerated maximum-likelihood by expectation-maximization (MLEM) image reconstruction framework for VersaPET which features accurate system geometry and projection space point-spread-function (PSF) modeling. METHODS: We combined the ray-tracing module from software for tomographic image reconstruction (STIR), an open-source PET image reconstruction package, with VersaPET's exact block geometry for the geometric system matrix. Point-spread-function modeling of crystal penetration and scattering was achieved by a custom Monte-Carlo simulation for projection space blurring in all dimensions. We also parallelized the reconstruction in GPU taking advantage of the system's symmetry for PSF computation. To investigate the effects of PSF width, we generated and studied multiple kernels between one that reflects the true LYSO density in the MC simulation and another that reflects geometry only (no PSF). GATE simulations of hot and cold-sphere phantoms with spheres of different sizes, real microDerenzo phantom, and human blood vessel data were used to characterize the quantitative and qualitative performances of the reconstruction. RESULTS: Reconstruction with an accurate system geometry effectively improved image quality compared to STIR (version 3.0) which assumes an idealized system geometry. Reconstructions of GATE-simulated hot-sphere phantom data showed that all PSF kernels achieved superior performance in contrast recovery and bias reduction compared to using no PSF, but may introduce edge artifact and lumped background noise pattern depending on the width of PSF kernels. Cold-sphere phantom simulation results also indicated improvement in contrast recovery and quantification with PSF modeling (compared to no PSF) for 5 and 10 mm cold spheres. Real microDerenzo phantom images with the PSF kernel that reflects the true LYSO density showed degraded resolving power of small sectors that could be resolved more clearly by underestimated PSF kernels, which is consistent with recent literature despite differences in scanner geometries and in approaches to system model estimation. The human vessel results resemble those of the hot-sphere phantom simulation with the PSF kernel that reflects the true LYSO density achieving the highest peak in the time activity curve (TAC) and similar lumped noise pattern. CONCLUSIONS: We fully evaluated a practical MLEM reconstruction framework that we developed for VersaPET in terms of qualitative and quantitative performance. Different PSF kernels may be adopted for improving the results of specific imaging tasks but the underlying reasons for the variation in optimal kernel for the real and simulation studies requires further study.

Correction: MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia.

In the original version of this article, the name of the author "Kamesh Ayasolla" was incorrectly given as "Kamesh Ayyasola". This has now been corrected to "Kamesh Ayasolla" in both the PDF and HTML versions of the article.

Behavioral neuroimaging in birds using PET.

BACKGROUND: Birds comprise the most diverse group of terrestrial vertebrates. This success likely is related to the evolution of powered flight over 75 mya. Modern approaches for studying brain function, however, have yet to be fully adapted and applied to birds, especially as they relate to specific behaviors including flight. New method: We have developed a comprehensive set of in vivo experimental methods utilizing PET imaging with F-18 labeled fluorodeoxyglucose (FDG) to study regional changes in metabolism specifically related to flight, yet applicable to other behaviors as well. It incorporates approaches for selection of species, behavioral/imaging paradigm, animal preparation, radiotracer injection route, image quantification, and image analysis via an enhanced brain atlas. We also carried out preliminary modeling studies to better understand tracer kinetics. RESULTS: The methods were successful in identifying brain regions statistically associated with flight using only 8 animals. Peak brain uptake of FDG between birds and rodents is similar despite much higher blood glucose levels in birds. We also confirmed that brain uptake of FDG steadily decreases after the initial peak and provide evidence that it may be related to greater dephosphorylation of FDG phosphate than that observed in mammals. Comparison with existing methods: FDG PET has been used in only a few studies of the bird brain. We introduce a new species, more realistic flight behavior, paired (test/retest) design, and improved quantification and analysis approaches. CONCLUSIONS: The proposed imaging protocol is non-invasive yet sensitive to regional metabolic changes in the bird brain related to behavior.

MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN. We hypothesized that antenatal inhibition of MIF in CDH fetuses, would reduce vascular remodeling, and improve angiogenesis and lung development. METHODS: Pregnant rats were randomized into three groups: Control, nitrofen, and nitrofen + ISO-92. Lung volumes of pups were measured by CT scanning. Right ventricular systolic pressure (RVSP) and vascular wall thickness (VWT) were measured together with MIF concentration, angiogenesis markers, lung morphometry, and histology. RESULTS: Prenatal treatment with ISO-92, an MIF inhibitor, improved normalization of static lung volume, lung volume-to-body weight ratio, decreased alveolar septal thickness, RVSP and VWT and improved radial alveolar count as compared to the non-treated group. Expression of MIF was unaffected by ISO-92; however, ISO-92 increased p-eNOS and VEGF activities and reduced arginase 1, 2 and Sflt-1. CONCLUSION: Prenatal inhibition of MIF activity in CDH rat model improves angiogenesis and lung development. This selective intervention may be a future therapeutic strategy to reduce the morbidity and mortality of this devastating condition.

Simultaneous Preclinical Positron Emission Tomography-Magnetic Resonance Imaging Study of Lymphatic Drainage of Chelator-Free 64Cu-Labeled Nanoparticles.

BACKGROUND: Hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI) systems have been taken in use as new clinical diagnostic tools including detection and therapy planning of cancer. To reduce the amount of contrast agents injected in patients while fully benefitting both modalities, dual-modality probes are required. MATERIAL AND METHODS: This study was first aimed at developing a hybrid PET-MRI probe by labeling superparamagnetic iron oxide nanoparticles (SPIONs) with 64Cu using a fast and chelator-free conjugation method, and second, to demonstrate the ability of the agent to target sentinel lymph nodes (SLNs) in vivo using simultaneous PET-MRI imaging. RESULTS: High labeling efficiency of 97% produced within 10-15 min was demonstrated at room temperature. 64Cu-SPIONs were chemically stable in mouse serum for 24 h and after intradermal injection in the hind paw of C57BL/6J mice, demonstrated specific accumulation in the SLN. Simultaneous PET-MRI clearly demonstrated visualization of 64Cu-SPIONs, in dynamic and static imaging sequences up to 24 h after administration. CONCLUSION: The use of a single hybrid probe and simultaneous hybrid imaging provides an efficient, complementary integration of quantitation and is expected to improve preoperative planning and intraoperative guidance of cancer treatments.

Rapid 18F-FDG Uptake in Brain of Awake, Behaving Rat and Anesthetized Chicken has Implications for Behavioral PET Studies in Species With High Metabolisms.

Brain-behavior studies using 18F-FDG PET aim to reveal brain regions that become active during behavior. In standard protocols, 18F-FDG is injected, the behavior is executed during 30-60 min of tracer uptake, and then the animal is anesthetized and scanned. Hence, the uptake of 18F-FDG is not itself observed and could, in fact, be complete in very little time. This has implications for behavioral studies because uptake is assumed to reflect concurrent behavior. Here, we utilized a new, miniature PET scanner termed RatCAP to measure uptake simultaneously with behavior. We employed a novel injection protocol in which we administered 18F-FDG (i.v.) four times over two 2 h to allow for repeated measurements and the correlation of changes in uptake and behavioral activity. Furthermore, using standard PET methods, we explored the effects of injection route on uptake time in chickens, a model for avians, for which PET studies are just beginning. We found that in the awake, behaving rat most of the 18F-FDG uptake occurred within minutes and overlapped to a large extent with 18F-FDG data taken from longer uptake periods. By contrast, behavior which occurred within minutes of the 18F-FDG infusion differed markedly from the behavior that occurred during later uptake periods. Accordingly, we found that changes in 18F-FDG uptake in the striatum, motor cortex and cerebellum relative to different reference regions significantly predicted changes in behavioral activity during the scan, if the time bins used for correlation were near the injection times of 18F-FDG. However, when morphine was also injected during the scan, which completely abolished behavioral activity for over 50 min, a large proportion of the variance in behavioral activity was also explained by the uptake data from the entire scan. In anesthetized chickens, tracer uptake was complete in about 80 min with s.c. injection, but 8 min with i.v. injection. In conclusion, uptake time needs to be taken into account to more accurately correlate PET and behavioral data in mammals and avians. Additionally, RatCAP together with multiple, successive injections of 18F-FDG may be useful to explore changes in uptake over time in relation to changes in behavior.

Flying starlings, PET and the evolution of volant dinosaurs.

Birds have evolved behavioral and morphological adaptations for powered flight. Many aspects of this transition are unknown, including the neuroanatomical changes that made flight possible [1]. To understand how the avian brain drives this complex behavior, we utilized positron emission tomography (PET) scanning and the tracer (18)F-fluorodeoxyglucose (FDG) to document regional metabolic activity in the brain associated with a variety of locomotor behaviors. FDG studies are typically employed in rats [2] though the technology has been applied to birds [3]. We examined whole-brain function in European Starlings (Sturnus vulgaris), trained to fly in a wind tunnel while metabolizing the tracer. Drawing on predictions from early anatomical studies [4], we hypothesized increased metabolic activity in the Wulst and functionally related visual brain regions during flight. We found that flight behaviors correlated positively with entopallia and Wulst activity, but negatively with thalamic activity.

The state of instrumentation for combined positron emission tomography and magnetic resonance imaging.

Efforts at developing instrumentation for combined positron emission tomography and magnetic resonance imaging have gained considerable momentum in recent years, propelled in particular by new photosensor technologies. Small preclinical prototype systems developed in academia have been scaled up to full-scale small-animal imagers, and commercial whole-body clinical positron emission tomography-magnetic resonance imaging systems are now available. A wide variety of architectures are reviewed, from sequential to simultaneous and preclinical to clinical. Whereas scintillators retain their role for gamma-ray conversion, light guides, photosensors, and electronic readout methods vary widely. Common themes relating to the technical challenges are presented, including electromagnetic interference and shielding. Technological directions that will likely gain in importance in the future are discussed, such as the ability to measure time of flight and depth of interaction.

Integrating PET with behavioral neuroscience using RatCAP tomography.

Behavioral studies are an important part of neuroscience. They allow inferences about the functions of the brain and any internal states and processes it controls. Positron emission tomography (PET) is an in vivo imaging technique that provides insights into the mechanisms of neuronal communication. In this review, we focus on some of the contributions of PET to the field of behavioral neuroscience. Small animals typically require anesthesia to remain still during PET imaging, which places a burden on behavioral studies. Our approach integrates PET with behavioral observations using a miniature PET scanner that rats wear on the head, a mobility system to facilitate animal movement and ways to integrate the PET data with behavioral measures. We summarize our studies that assessed spontaneous, self-initiated behavioral activity and dopamine D2 receptor functions simultaneously.

Small animal simultaneous PET/MRI: initial experiences in a 9.4 T microMRI.

We developed a non-magnetic positron-emission tomography (PET) device based on the rat conscious animal PET that operates in a small-animal magnetic resonance imaging (MRI) scanner, thereby enabling us to carry out simultaneous PET/MRI studies. The PET detector comprises 12 detector blocks, each being a 4 × 8 array of lutetium oxyorthosilicate crystals (2.22 × 2.22 × 5 mm(3)) coupled to a matching non-magnetic avalanche photodiode array. The detector blocks, housed in a plastic case, form a 38 mm inner diameter ring with an 18 mm axial extent. Custom-built MRI coils fit inside the positron-emission tomography (PET) device, operating in transceiver mode. The PET insert is integrated with a Bruker 9.4 T 210 mm clear-bore diameter MRI scanner. We acquired simultaneous PET/MR images of phantoms, of in vivo rat brain, and of cardiac-gated mouse heart using [(11)C]raclopride and 2-deoxy-2-[(18)F]fluoro-D-glucose PET radiotracers. There was minor interference between the PET electronics and the MRI during simultaneous operation, and small effects on the signal-to-noise ratio in the MR images in the presence of the PET, but no noticeable visual artifacts. Gradient echo and high-duty-cycle spin echo radio frequency (RF) pulses resulted in a 7% and a 28% loss in PET counts, respectively, due to high PET counts during the RF pulses that had to be gated out. The calibration of the activity concentration of PET data during MR pulsing is reproducible within less than 6%. Our initial results demonstrate the feasibility of performing simultaneous PET and MRI studies in adult rats and mice using the same PET insert in a small-bore 9.4 T MRI.

Simultaneous assessment of rodent behavior and neurochemistry using a miniature positron emission tomograph.

Positron emission tomography (PET) neuroimaging and behavioral assays in rodents are widely used in neuroscience. PET gives insights into the molecular processes of neuronal communication, and behavioral methods analyze the actions that are associated with such processes. These methods have not been directly integrated, because PET studies in animals have until now required general anesthesia to immobilize the subject, which precludes behavioral studies. We present a method for imaging awake, behaving rats with PET that allows the simultaneous study of behavior. Key components include the 'rat conscious animal PET' or RatCAP, a miniature portable PET scanner that is mounted on the rat's head, a mobility system that allows considerable freedom of movement, radiotracer administration techniques and methods for quantifying behavior and correlating the two data sets. The simultaneity of the PET and behavioral data provides a multidimensional tool for studying the functions of different brain regions and their molecular constituents.