Towards universal comparability of pericoronary adipose tissue attenuation: a coronary computed tomography angiography phantom study.

OBJECTIVES: Different computed tomography (CT) scanners, variations in acquisition protocols, and technical parameters employed for image reconstruction may introduce bias in the analysis of pericoronary adipose tissue (PCAT) attenuation derived from coronary computed tomography angiography (CCTA). Therefore, the aim of this study was to establish the effect of tube voltage, measured as kilovoltage peak (kVp), and iterative reconstruction on PCAT mean attenuation (PCATMA). METHODS: Twelve healthy ex vivo porcine hearts were injected with iodine-enriched agar-agar to allow for ex vivo CCTA imaging on a 256-slice CT and a dual-source CT system. Images were acquired at tube voltages of 80, 100, 120, and 140 kVp and reconstructed by using both filtered back projection and iterative reconstruction algorithms. PCATMA was measured semi-automatically on CCTA images in the proximal segment of coronary arteries. RESULTS: The tube voltage showed a significant effect on PCATMA measurements on both the 256-slice CT scanner (p < 0.001) and the dual-source CT system (p = 0.013), resulting in higher attenuation values with increasing tube voltage. Similarly, the use of iterative reconstructions was associated with a significant increase of PCATMA (256-slice CT: p < 0.001 and dual-source CT: p = 0.014). Averaged conversion factors to correct PCATMA measurements for tube voltage other than 120 kVp were 1.267, 1.080 and 0.947 for 80, 100, and 140 kVp, respectively. CONCLUSION: PCATMA values are significantly affected by acquisition and reconstruction parameters. The same tube voltage and reconstruction type are recommended when PCAT attenuation is used in multicenter and longitudinal studies. KEY POINTS: • The tube voltage used for CCTA acquisition affects pericoronary adipose tissue attenuation, resulting in higher attenuation values of fat with increasing tube voltage. • Conversion factors for pericoronary adipose tissue attenuation values could be used to adjust for differences in attenuation between scans performed at different tube voltages. • In longitudinal CCTA studies employing pericoronary adipose tissue attenuation as imaging endpoint, it is recommended to maintain tube voltage and image reconstruction type constant across serial scans.

Community Survey Results Show that Standardisation of Preclinical Imaging Techniques Remains a Challenge.

PURPOSE: To support acquisition of accurate, reproducible and high-quality preclinical imaging data, various standardisation resources have been developed over the years. However, it is unclear the impact of those efforts in current preclinical imaging practices. To better understand the status quo in the field of preclinical imaging standardisation, the STANDARD group of the European Society of Molecular Imaging (ESMI) put together a community survey and a forum for discussion at the European Molecular Imaging Meeting (EMIM) 2022. This paper reports on the results from the STANDARD survey and the forum discussions that took place at EMIM2022. PROCEDURES: The survey was delivered to the community by the ESMI office and was promoted through the Society channels, email lists and webpages. The survey contained seven sections organised as generic questions and imaging modality-specific questions. The generic questions focused on issues regarding data acquisition, data processing, data storage, publishing and community awareness of international guidelines for animal research. Specific questions on practices in optical imaging, PET, CT, SPECT, MRI and ultrasound were further included. RESULTS: Data from the STANDARD survey showed that 47% of survey participants do not have or do not know if they have QC/QA guidelines at their institutes. Additionally, a large variability exists in the ways data are acquired, processed and reported regarding general aspects as well as modality-specific aspects. Moreover, there is limited awareness of the existence of international guidelines on preclinical (imaging) research practices. CONCLUSIONS: Standardisation of preclinical imaging techniques remains a challenge and hinders the transformative potential of preclinical imaging to augment biomedical research pipelines by serving as an easy vehicle for translation of research findings to the clinic. Data collected in this project show that there is a need to promote and disseminate already available tools to standardise preclinical imaging practices.

Attenuation Correction Using Template PET Registration for Brain PET: A Proof-of-Concept Study.

NeuroLF is a dedicated brain PET system with an octagonal prism shape housed in a scanner head that can be positioned around a patient's head. Because it does not have MR or CT capabilities, attenuation correction based on an estimation of the attenuation map is a crucial feature. In this article, we demonstrate this method on [18F]FDG PET brain scans performed with a low-resolution proof of concept prototype of NeuroLF called BPET. We perform an affine registration of a template PET scan to the uncorrected emission image, and then apply the resulting transform to the corresponding template attenuation map. Using a whole-body PET/CT system as reference, we quantitively show that this method yields comparable image quality (0.893 average correlation to reference scan) to using the reference µ-map as obtained from the CT scan of the imaged patient (0.908 average correlation). We conclude from this initial study that attenuation correction using template registration instead of a patient CT delivers similar results and is an option for patients undergoing brain PET.

Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Imaging glutamate redistribution after acute N-acetylcysteine administration: A simultaneous PET/MR study.

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BPND) was assessed from PET data collected with [18F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [18F]PSS232 BPND were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [18F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation.

Multimodality imaging assessment of the deleterious role of the intraluminal thrombus on the growth of abdominal aortic aneurysm in a rat model.

OBJECTIVES: To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. METHODS: The post-induction growth of the AAA diameter was characterized using ultrasound in 22 rats. ILT was reported on 13 rats that underwent 14 magnetic resonance imaging (MRI) 2-18 days post-surgery, and on 10 rats that underwent 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET)/microcomputed tomography examinations 2-27 days post-surgery. Logistic regressions were used to establish the evolution with time of AAA length, diameter, ILT thickness, volume, stratification, MRI and FDG PET signalling properties, and histological assessment of inflammatory infiltrates. RESULTS: All of the following significantly increased with time post-induction (p < 0.001): AAA length, AAA diameter, ILT maximal thickness, ILT volume, ILT iron content and related MRI signalling changes, quantitative uptake on FDG PET, and the magnitude of inflammatory infiltrates on histology. However, the aneurysm growth peak followed occurrence of ILT approximately 6 days after elastase infusion. CONCLUSION: Our model emphasizes that occurrence of ILT precedes AAA peak growth. Aneurysm growth is associated with increasing levels of iron, signalling properties changes in both MRI and FDG PET, relating to its biological activities. KEY POINTS: • ILT occurrence in AAA is associated with increasing FDG uptake and growth. • MRI signalling changes in ILT reflect activities such as haemorrhage and RBC trapping. • Monitoring ILT activities using MRI may require no exogenous contrast agent.

Quantitative H2[(15)O]-PET in Pediatric Moyamoya Disease: Evaluating Perfusion before and after Cerebral Revascularization.

BACKGROUND: Moyamoya disease (MMD) is an idiopathic intracranial angiopathy with a progressive spontaneous occlusion of the circle of Willis resulting in repeated ischemia if not diagnosed and treated early, especially in children. Prevention of stroke is achieved by revascularization of the affected cerebral regions. Functional imaging techniques such as H2[(15)O]-Positron emission tomography (PET) allow quantification of cerebral perfusion/blood flow (CBF) and in particular cerebrovascular response after acetazolamide (AZA) challenge. The cerebrovascular reserve (CVR) can then be calculated and used to identify regions at risk of infarct, hence allowing surgery to be specifically targeted and personalized. METHODS: Pediatric patients with diagnosed MMD underwent initial H2[(15)O]-PET scans at baseline and after stimulation with AZA. Indication for surgery was then based collectively on the extent of disease observed clinically and on magnetic resonance imaging, on the arterial territories involved, as seen in angiography and the respective regional CVR observed in PET. Cerebral revascularization surgeries were subsequently performed, tailored to the individual patient. Postoperative assessment of clinical outcome was augmented with follow-up PET (median duration after surgery, 10.4 months). CBF at baseline, after AZA and CVR were compared between presurgery and postsurgery scans in the areas supplied by the major cerebral arteries. RESULTS: Parametric images reflecting CBF, response to AZA and CVR clearly showed deficits in cortical but not subcortical regions or cerebellum. AZA-CBF and CVR deficits were most clear in middle cerebral artery and anterior cerebral artery (ACA) regions. In addition to the clinical symptomatology, angiography, AZA-CBF, and CVR images allowed the laterality of deficits to be clearly visualized for tailored surgery and the indication for targeted ACA or posterior cerebral artery revascularization to be assessed. Comparison of baseline CBF, AZA-CBF, and CVR between presurgery and postsurgery scans in revascularized areas revealed a significant improvement in baseline and AZA-CBF after surgery. Although no significant differences in CVR after revascularization surgery were found, a clear improvement of the deficits apparent in AZA-CBF in revascularized regions was found. CONCLUSIONS: We demonstrate that quantitative H2[(15)O]-PET is a highly useful tool to direct surgical intervention in MMD. Detailed quantitative analysis of CBF changes and CVR after surgery supports a targeted surgical approach.

In vivo PET/CT in a human glioblastoma chicken chorioallantoic membrane model: a new tool for oncology and radiotracer development.

UNLABELLED: For many years the laboratory mouse has been used as the standard model for in vivo oncology research, particularly in the development of novel PET tracers, but the growth of tumors on chicken chorioallantoic membrane (CAM) provides a more rapid, low cost, and ethically sustainable alternative. For the first time, to our knowledge, we demonstrate the feasibility of in vivo PET and CT imaging in a U87 glioblastoma tumor model on chicken CAM, with the aim of applying this model for screening of novel PET tracers. METHODS: U87 glioblastoma cells were implanted on the CAM at day 11 after fertilization and imaged at day 18. A small-animal imaging cell was used to maintain incubation and allow anesthesia using isoflurane. Radiotracers were injected directly into the exposed CAM vasculature. Sodium (18)F-fluoride was used to validate the imaging protocol, demonstrating that image-degrading motion can be removed with anesthesia. Tumor glucose metabolism was imaged using (18)F-FDG, and tumor protein synthesis was imaged using 2-(18)F-fluoro-l-tyrosine. Anatomic images were obtained by contrast-enhanced CT, facilitating clear delineation of the tumor, delineation of tracer uptake in tumor versus embryo, and accurate volume measurements. RESULTS: PET imaging of tumor glucose metabolism and protein synthesis was successfully demonstrated in the CAM U87 glioblastoma model. Catheterization of CAM blood vessels facilitated dynamic imaging of glucose metabolism with (18)F-FDG and demonstrated the ability to study PET tracer uptake over time in individual tumors, and CT imaging improved the accuracy of tumor volume measurements. CONCLUSION: We describe the novel application of PET/CT in the CAM tumor model, with optimization of typical imaging protocols. PET imaging in this valuable tumor model could prove particularly useful for rapid, high-throughput screening of novel radiotracers.

Stress-induced decreases in local cerebral glucose utilization in specific regions of the mouse brain.

BACKGROUND: Restraint stress in rodents has been reported to activate the hypothalamic-pituitary-adrenocortical (HPA) axis and to increase c-fos expression in regions that express components of the corticotropin-releasing factor (CRF) system. We have previously reported that acute central administration of CRF increased a measure of relative local cerebral glucose utilization (LCGU), a measure of neuronal activity in specific brain regions, and activated the HPA axis in mice. It was hypothesized that the involvement of the CRF system in the stress response would lead to similar changes in relative LCGU after restraint stress. In the present studies the effect of restraint stress on relative LCGU and on the HPA axis in C57BL/6N mice were examined. FINDINGS: Restraint stress activated the HPA axis in a restraint-duration dependent manner, but in contrast to the reported effects of CRF, significantly decreased relative LCGU in frontal cortical, thalamic, hippocampal and temporal dissected regions. These findings support evidence that stressors enforcing limited physical activity reduce relative LCGU, in contrast to high activity stressors such as swim stress. CONCLUSIONS: In conclusion, the present studies do not support the hypothesis that stress-induced changes in relative LCGU are largely mediated by the CRF system. Further studies will help to delineate the role of the CRF system in the early phases of the relative LCGU response to stress and investigate the role of other neurotransmitter systems in this response.

Use of a beta microprobe system to measure arterial input function in PET via an arteriovenous shunt in rats.

BACKGROUND: Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The measurement of IF can be achieved through manual blood sampling, the use of small counting systems such as beta microprobes, or by derivation from PET images. Previous studies using beta microprobe systems to continuously measure IF have suffered from high background counts. METHODS: In the present study, a light-insensitive beta microprobe with a temporal resolution of up to 1 s was used in combination with a pump-driven femoral arteriovenous shunt to measure IF in rats. The shunt apparatus was designed such that the placement of the beta microprobe was highly reproducible. The probe-derived IF was compared to that obtained from manual sampling at 5-s intervals and IF derived from a left ventricle VOI in a dynamic PET image of the heart. RESULTS: Probe-derived IFs were very well matched to that obtained by "gold standard" manual blood sampling, but with an increased temporal resolution of up to 1 s. The area under the curve (AUC) ratio between probe- and manually derived IFs was 1.07 ± 0.05 with a coefficient of variation of 0.04. However, image-derived IFs were significantly underestimated compared to the manually sampled IFs, with an AUC ratio of 0.76 ± 0.24 with a coefficient of variation of 0.32. CONCLUSIONS: IF derived from the beta microprobe accurately represented the IF as measured by blood sampling, was reproducible, and was more accurate than an image-derived technique. The use of the shunt removed problems of tissue-background activity, and the use of a light-tight probe with minimal gamma sensitivity refined the system. The probe/shunt apparatus can be used in both microprobe and PET studies.

In vivo evidence for ligand-specific receptor activation in the central CRF system, as measured by local cerebral glucose utilization.

Corticotropin-releasing factor (CRF) is well known for its role in the hypothalamic-pituitary-adrenocortical (HPA) axis and its involvement in stress and anxiety. CRF acts via two main receptor subtypes, CRF(1) and CRF(2). Other endogenous CRF-related peptide ligands are the Urocortins 1 and 2 and Stresscopin. While CRF is thought to mediate its anxiogenic-like properties through CRF(1), the role of CRF(2) and its endogenous ligands Urocortin 2 and Stresscopin are less clear, with a suggested role in mediating the delayed effects of stress. Measurement of local cerebral glucose utilization (LCGU) provides an estimate of neuronal activity, and is of potential use as a translational tool in comparison to FDG PET. We hypothesized that comparison of the patterns of metabolic changes induced by CRF-related peptides could provide further information on their role in the brain. The present studies examined the effects of CRF-related peptides on LCGU, and the role of CRF(1) and CRF(2) in the CRF-induced LCGU response. CRF induced increases in LCGU in hypothalamic, thalamic, cerebellar and hippocampal regions, and further studies using antagonists or mutant mice lacking a functional CRF(1) receptor clearly suggested a role for CRF(2) in this effect. Urocortin 1 increased LCGU in a dissected hindbrain region. However, central administration of the CRF(2)-selective agonists Urocortin 2 and Stresscopin failed to affect LCGU, which may suggest ligand-dependent receptor activation within the CRF system. The present data supports a role for CRF(2) in the regulation of neuronal glucose metabolism.