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The emergence of PET probes for amyloid plaques and neurofibrillary tangles, hallmarks of Alzheimer disease (AD), enables monitoring of pathology in AD mouse models. However, small-animal PET imaging is limited by coarse spatial resolution. We have installed a custom-fabricated PET insert into our small-animal MRI instrument and used PET/MRI hybrid imaging to define regions of amyloid vulnerability in 5xFAD mice. We compared fluorine-18 [ 18 F]-Florbetapir uptake in the 5xFAD brain by dedicated small-animal PET/MRI and PET/CT to validate the quantitative measurement of PET/MRI. Next, we used PET/MRI to define uptake in six brain regions. As expected, uptake was comparable to wild-type in the cerebellum and elevated in the cortex and hippocampus, regions implicated in AD. Interestingly, uptake was highest in the thalamus, a region often overlooked in AD studies. Development of small-animal PET/MRI enables tracking of brain region-specific pathology in mouse models, which may prove invaluable to understanding AD progression and therapeutic development.

We are building a high sensitivity preclinical PET/MRI insert using a highly multiplexed light sharing PET module. Each module incorporates four 19 × 19 arrays of 1 × 1 × 20 mm 3 LYSO crystals with dual-ended DOI encoding readout, requiring 32 readout channels for positioning and eight channels for timing. These constraints necessitate compact, robust electronics for digitization. We have characterized four linearized time-over-threshold circuits based on these detector requirements. The four circuits allow for high channel density and can digitize signals from highly multiplexed light sharing detectors. Each circuit digitizes one channel of a multiplexed SiPM array, yielding a binary output that interfaces directly with an FPGA. Using the optimal circuit, we have characterized the performance of a pair of PET modules. The four circuits were characterized based on linearity of the 22 Na photopeak positions and energy resolution at 511 keV, as well as separation of elements in a 10 × 10 array of 1.2 mm LYSO crystals coupled with a specular reflector. Practical measures of performance were comparable to those obtained with a DRS evaluation board, which served as a reference acquisition system. The ratio of the 22 Na photopeak positions was 2.0 for each circuit and the reference system, implying 20% saturation due to the SiPM. PET energy resolution of the optimal circuit was 11.8% FWHM for a single crystal versus 12.6% for the reference system, and crystals were equally well separated in all cases. PCBs implementing the optimal readout circuit were fabricated and used to construct two complete detector modules. Crystals in each of the four blocks in the module were well resolved, with a mean energy resolution of 24.4 ± 4.7%. Two modules operating in coincidence showed a single detector timing resolution of 3.0 ns, which is appropriate for preclinical applications.

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.

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics disturbance in affected cells. Diffusion weighted magnetic resonance imaging (MRI) identifies regions that are damaged, potentially irreversibly, by hypoxia-ischemia. Alterations in glucose utilization in the affected tissue may be detectable by positron emission tomography (PET) imaging of 2-deoxy-2-(18F)fluoro-ᴅ-glucose ([18F]FDG) uptake. Due to the rapid and variable nature of injury in this animal model, acquisition of both modes of data must be performed simultaneously in order to meaningfully correlate PET and MRI data. In addition, inter-animal variability in the hypoxic-ischemic injury due to vascular differences limits the ability to analyze multi-modal data and observe changes to a group-wise approach if data is not acquired simultaneously in individual subjects. The method presented here allows one to acquire both diffusion-weighted MRI and [18F]FDG uptake data in the same animal before, during, and after the hypoxic challenge in order to interrogate immediate physiological changes.

Positron emission tomography (PET) plays an increasingly important role in research and clinical applications, catalysed by remarkable technical advances and a growing appreciation of the need for reliable, sensitive biomarkers of human function in health and disease. Over the last 30 years, a large amount of the physics and engineering effort in PET has been motivated by the dominant clinical application during that period, oncology. This has led to important developments such as PET/CT, whole-body PET, 3D PET, accelerated statistical image reconstruction, and time-of-flight PET. Despite impressive improvements in image quality as a result of these advances, the emphasis on static, semi-quantitative 'hot spot' imaging for oncologic applications has meant that the capability of PET to quantify biologically relevant parameters based on tracer kinetics has not been fully exploited. More recent advances, such as PET/MR and total-body PET, have opened up the ability to address a vast range of new research questions, from which a future expansion of applications and radiotracers appears highly likely. Many of these new applications and tracers will, at least initially, require quantitative analyses that more fully exploit the exquisite sensitivity of PET and the tracer principle on which it is based. It is also expected that they will require more sophisticated quantitative analysis methods than those that are currently available. At the same time, artificial intelligence is revolutionizing data analysis and impacting the relationship between the statistical quality of the acquired data and the information we can extract from the data. In this roadmap, leaders of the key sub-disciplines of the field identify the challenges and opportunities to be addressed over the next ten years that will enable PET to realise its full quantitative potential, initially in research laboratories and, ultimately, in clinical practice.

Social bonds, especially attachment relationships, are crucial to our health and happiness. However, what we know about the neural substrates of these bonds is almost exclusively limited to rodent models and correlational experiments in humans. Here, we used socially monogamous non-human primates, titi monkeys (Callicebus cupreus) to experimentally examine changes in regional and global cerebral glucose metabolism (GCGM) during the formation and maintenance of pair bonds. Baseline positron emission tomography (PET) scans were taken of thirteen unpaired male titi monkeys. Seven males were then experimentally paired with females, scanned and compared, after one week, to six age-matched control males. Five of the six control males were then also paired and scanned after one week. Scans were repeated on all males after four months of pairing. PET scans were coregistered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. A primary finding was that paired males showed a significant increase in [18F]-fluorodeoxyglucose (FDG) uptake in whole brain following one week of pairing, which is maintained out to four months. Dopaminergic, motivational areas and those involved in social behavior showed the greatest change in glucose uptake. In contrast, control areas changed only marginally more than GCGM. These findings confirm the large effects of social bonds on GCGM. They also suggest that more studies should examine how social manipulations affect whole-brain FDG uptake, as opposed to assuming that it does not change across condition.

BackgroundAcute intoxication with organophosphorus (OP) cholinesterase inhibitors can trigger convulsions that progress to life-threatening status epilepticus. Survivors face long-term morbidity including mild-to-severe decline in memory. It is posited that neuroinflammation plays a key role in the pathogenesis of OP-induced neuropsychiatric deficits. Rigorous testing of this hypothesis requires preclinical models that recapitulate relevant phenotypic outcomes. Here, we describe a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) that exhibits persistent neuroinflammation and cognitive impairment.MethodsNeuroinflammation, neurodegeneration, and cognitive function were compared in adult male Sprague Dawley rats injected with an acutely toxic dose of DFP vs. vehicle controls at multiple time points up to 36 days post-exposure. Neuroinflammation was quantified using immunohistochemical biomarkers of microglia (ionized calcium-binding adapter molecule 1, IBA1) and activated astrocytes (glial fibrillary acidic protein, GFAP) and positron emission tomography (PET) imaging of [11C]-(R)-PK11195, a ligand for the 18-kDa mitochondrial membrane translocator protein (TSPO). FluoroJade-B staining was used to assess neurodegeneration; Pavlovian conditioning, to assess cognitive function.ResultsAnimals exhibited moderate-to-severe seizures within minutes of DFP injection that continued for up to 6 h post-injection. As indicated by IBA1 and GFAP immunoreactivity and by PET imaging of TSPO, acute DFP intoxication triggered neuroinflammation in the hippocampus and cortex during the first 3 days that peaked at 7 days and persisted to 21 days post-exposure in most animals. Neurodegeneration was detected in multiple brain regions from 1 to 14 days post-exposure. All DFP-intoxicated animals exhibited significant deficits in contextual fear conditioning at 9 and 20 days post-exposure compared to vehicle controls. Whole-brain TSPO labeling positively correlated with seizure severity score, but did not correlate with performance in the contextual fear-conditioning task.ConclusionsWe describe a preclinical model in which acute DFP intoxication causes seizures, persistent neuroinflammation, neurodegeneration, and memory impairment. The extent of the neuroinflammatory response is influenced by seizure severity. However, the observation that a subset of animals with moderate seizures and minimal TSPO labeling exhibited cognitive deficits comparable to those of animals with severe seizures and significant TSPO labeling suggests that DFP may impair learning and memory circuitry via mechanisms independent of seizures or neuroinflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]