Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Noninvasive In Vivo Thrombus Imaging in Patients With Ischemic Stroke or Transient Ischemic Attack-Brief Report.

BACKGROUND: 18F-GP1 is a novel positron-emitting radiotracer that is highly specific for activated platelets and thrombus. In a proof-of-concept study, we aimed to determine its potential clinical application in establishing the role and origin of thrombus in ischemic stroke. METHODS: Eleven patients with recent ischemic stroke (n=9) or transient ischemic attack (n=2) underwent 18F-GP1 positron emission tomography and computed tomography angiography at a median of 11 (range, 2-21) days from symptom onset. 18F-GP1 uptake (maximum target-to-background ratio) was assessed in the carotid arteries and brain. RESULTS: 18F-GP1 uptake was identified in 10 of 11 patients: 4 in the carotid arteries only, 3 in the brain only, and 3 in both the brain and carotid arteries. In those with carotid uptake, 4 participants had >50% stenosis and 3 had nonstenotic disease. One case had bilateral stenotic disease (>70%), but only the culprit carotid artery demonstrated 18F-GP1 uptake. The average uptake was higher in the culprit (median maximum target-to-background ratio, 1.55 [interquartile range, 1.26-1.82]) compared with the contralateral nonculprit carotid artery (maximum target-to-background ratio, 1.22 [1.19-1.6]). In those with brain 18F-GP1 uptake (maximum target-to-background ratio, 6.45 [4.89-7.65]), areas of acute infarction on computed tomography correlated with brain 18F-GP1 uptake in 6 cases. Ex vivo autoradiography of postmortem infarcted brain tissue showed focal uptake corresponding to intraluminal thrombus within the culprit vessel and downstream microvasculature. There was also evidence of diffuse uptake within some of the infarcted brain tissue reflecting parenchymal petechial hemorrhage. CONCLUSIONS: 18F-GP1 positron emission tomography and computed tomography angiography is a novel noninvasive method of identifying in vivo cerebrovascular thrombosis, which holds major promise in understanding the role and origin of thrombosis in stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03943966.

Microcalcification and Thoracic Aortopathy: A Window Into Disease Severity.

BACKGROUND: Patients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established. METHODS: One hundred one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathologic scores, immunohistochemistry, and nanoindentation (tissue elastic modulus) were compared with the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography. RESULTS: Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71-10.39]; P≤0.00010) or moderate histopathologic degeneration (n=30; 3.74 [0.87-11.80]; P<0.042) compared with control samples (n=18; 0.79 [0.36-1.90]). Alkaline phosphatase (n=26; P=0.0019) and OPN (osteopontin; n=26; P=0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathologic degeneration was related to reduced microcalcification (n=82; Spearman ρ, -0.51; P<0.0001)-a process closely linked with elastin loss (n=82; Spearman ρ, -0.43; P<0.0001) and lower tissue elastic modulus (n=28; Spearman ρ, 0.43; P=0.026).18F-sodium fluoride autoradiography demonstrated good correlation with histologically quantified microcalcification (n=66; r=0.76; P<0.001) and identified areas of focal weakness in vivo. CONCLUSIONS: Medial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification.18F-sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible noninvasive imaging modality for identifying aortic wall disruption with major translational promise.

18F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI and fluorine 18-labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed. Purpose To evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel. Results A total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12-1.82] vs 1.26 [IQR, 0.99-1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel. Conclusion Fluorine 18-labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome. Clinical trial registration no. NCT03215550 and NCT03215563 © RSNA, 2022 Online supplemental material is available for this article.

Organocatalytic Asymmetric Synthesis of SynVesT-1, a Synaptic Density Positron Emission Tomography Imaging Agent.

Heterocyclic nonacetamide ligands are used as positron emission tomography (PET) imaging agents of the synaptic vesicle glycoprotein 2A (SV2A), with potential applications in the diagnosis of various neuropsychiatric diseases. To date, the main synthetic strategy to access these optically active compounds has involved the racemic synthesis of a late-stage intermediate followed by the separation of the enantiomers. Here, we describe the use of iminium organocatalysis for the asymmetric synthesis of SynVesT-1, an important PET imaging agent of SV2A. The key step involved the conjugate addition of nitromethane with a cinnamaldehyde in the presence of the Jørgensen-Hayashi catalyst using the Merck dual acid cocatalyst system. Pinnick-type oxidation and esterification of the adduct was then followed by chemoselective nitro group reduction and cyclization using nickel borate. N-Alkylation of the resulting lactam then completed the seven-step synthesis of SynVesT-1. This approach was amenable for the synthesis of an organotin analogue, which following copper(II)-mediated fluoro-destannylation allowed rapid access to [18F]SynVesT-1.

Modelling [18F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain.

PURPOSE: To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [18F]LW223, kinetics in the heart and brain when using a simplified imaging approach. METHODS: Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [18F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (VT) and binding potential transfer corrected (BPTC) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40-120 min) were estimated. RESULTS: PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [18F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BPTC more stable in the heart and VT more stable in the brain. CONCLUSION: Modelling of [18F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging.

Automated Radiosynthesis of cis- and trans-4-[18F]Fluoro-l-proline Using [18F]Fluoride.

The positron emission tomography imaging agents cis- and trans-4-[18F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [18F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to deprotection methods that are performed manually, require multiple steps, or involve harsh conditions. Here we describe the development of two synthetic routes that allow access to precursors, which undergo highly selective radiofluorination reactions and rapid deprotection, under mild acidic conditions. These methods were found to be compatible with automation, avoiding manual handling of radioactive intermediates.

Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product.

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy.

Sexually dimorphic murine brain uptake of the 18†kDa translocator protein PET radiotracer [18F]LW223.

The 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with 18 kDa translocator protein radiotracers [11C]PBR28 in humans and [18F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [18F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs. Male and female C57Bl6/J mice (13.6 ± 5.4 weeks, 26.8 ± 5.4 g, mean ± SD) underwent 2 h PET scanning post-administration of [18F]LW223 (6.7 ± 3.6 MBq). Volume of interest and parametric analyses were performed using standard uptake values (90-120 min). Statistical differences were assessed by unpaired t-test or two-way ANOVA with Sidak's test (alpha = 0.05). The uptake of [18F]LW223 was significantly higher across multiple regions of the male mouse brain, with the most pronounced difference detected in hypothalamus (P < 0.0001). Males also exhibited significantly higher [18F]LW223 uptake in the heart when compared to females (P = 0.0107). Data support previous findings on sexually dimorphic 18 kDa translocator protein radiotracer uptake patterns in mice and highlight the need to conduct sex-controlled comparisons in 18 kDa translocator protein PET imaging studies.

Assessment of the alpha 7 nicotinic acetylcholine receptor as an imaging marker of cardiac repair-associated processes using NS14490.

BACKGROUND: Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context. We investigated this by assessing in vitro cellular expression of ɑ7nAChR, and by using a tritiated version of the PET radiotracer [18F]NS14490 in tissue autoradiography studies. RESULTS: ɑ7nAChR expression in human monocyte-derived macrophages and vascular cells showed the highest relative expression was within macrophages, but only endothelial cells exhibited a proliferation and hypoxia-driven increase in expression. Using a mouse model of inflammatory angiogenesis following sponge implantation, specific binding of [3H]NS14490 increased from 3.6 ± 0.2 µCi/g at day 3 post-implantation to 4.9 ± 0.2 µCi/g at day 7 (n = 4, P < 0.01), followed by a reduction at days 14 and 21. This peak matched the onset of vessel formation, macrophage infiltration and sponge fibrovascular encapsulation. In a rat MI model, specific binding of [3H]NS14490 was low in sham and remote MI myocardium. Specific binding within the infarct increased from day 14 post-MI (33.8 ± 14.1 µCi/g, P ≤ 0.01 versus sham), peaking at day 28 (48.9 ± 5.1 µCi/g, P ≤ 0.0001 versus sham). Histological and proteomic profiling of ɑ7nAChR positive tissue revealed strong associations between ɑ7nAChR and extracellular matrix deposition, and rat cardiac fibroblasts expressed ɑ7nAChR protein under normoxic and hypoxic conditions. CONCLUSION: ɑ7nAChR is highly expressed in human macrophages and showed proliferation and hypoxia-driven expression in human endothelial cells. While NS14490 imaging displays a pattern that coincides with vessel formation, macrophage infiltration and fibrovascular encapsulation in the sponge model, this is not the case in the MI model where the ɑ7nAChR imaging signal was strongly associated with extracellular matrix deposition which could be explained by ɑ7nAChR expression in fibroblasts. Overall, these findings support the involvement of ɑ7nAChR across several processes central to cardiac repair, with fibrosis most closely associated with ɑ7nAChR following MI.

In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation.

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterized over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.

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.

Noninvasive In Vivo Coronary Artery Thrombus Imaging.

BACKGROUND: The diagnosis and management of myocardial infarction are increasingly complex, and establishing the presence of intracoronary thrombosis has major implications for both the classification and treatment of myocardial infarction. OBJECTIVES: The aim of this study was to investigate whether positron emission tomographic (PET) and computed tomographic (CT) imaging could noninvasively detect in vivo thrombus formation in human coronary arteries using a novel glycoprotein IIb/IIIa receptor antagonist-based radiotracer, 18F-GP1. METHODS: In a single-center observational case-control study, patients with or without acute myocardial infarction underwent coronary 18F-GP1 PET/CT angiography. Coronary artery 18F-GP1 uptake was assessed visually and quantified using maximum target-to-background ratios. RESULTS: 18F-GP1 PET/CT angiography was performed in 49 patients with and 50 patients without acute myocardial infarction (mean age: 61 ± 9 years, 75% men). Coronary 18F-GP1 uptake was apparent in 39 of the 49 culprit lesions (80%) in patients with acute myocardial infarction. False negative results appeared to relate to time delays to scan performance and low thrombus burden in small-caliber distal arteries. On multivariable regression analysis, culprit vessel status was the only independent variable associated with higher 18F-GP1 uptake. Extracoronary cardiac 18F-GP1 findings included a high frequency of infarct-related intramyocardial uptake (35%) as well as left ventricular (8%) or left atrial (2%) thrombus. CONCLUSIONS: Coronary 18F-GP1 PET/CT angiography is the first noninvasive selective technique to identify in vivo coronary thrombosis in patients with acute myocardial infarction. This novel approach can further define the role and location of thrombosis within the heart and has the potential to inform the diagnosis, management, and treatment of patients with acute myocardial infarction. (In-Vivo Thrombus Imaging With 18F-GP1, a Novel Platelet PET Radiotracer [iThrombus]; NCT03943966).

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent.

Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females. Females' resistance to fat loss was associated with decreased lipolysis, energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis, compared to males. The sex differences in glucose homeostasis were not associated with differential glucose uptake but with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity and higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis similarly in both sexes. Finally, in a cohort of overweight and obese humans, CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR's metabolic benefits. These findings have important implications for understanding the interplay between diet and health, and for maximising the benefits of CR in humans.

Assessing the impact of different penalty factors of the Bayesian reconstruction algorithm Q.Clear on in vivo low count kinetic analysis of [11C]PHNO brain PET-MR studies.

INTRODUCTION: Q.Clear is a Bayesian penalised likelihood (BPL) reconstruction algorithm available on General Electric (GE) Positron Emission Tomography (PET)-Computed Tomography (CT) and PET-Magnetic Resonance (MR) scanners. This algorithm is regulated by a ß value which acts as a noise penalisation factor and yields improvements in signal to noise ratio (SNR) in clinical scans, and in contrast recovery and spatial resolution in phantom studies. However, its performance in human brain imaging studies remains to be evaluated in depth. This pilot study aims to investigate the impact of Q.Clear reconstruction methods using different ß value versus ordered subset expectation maximization (OSEM) on brain kinetic modelling analysis of low count brain images acquired in the PET-MR. METHODS: Six [11C]PHNO PET-MR brain datasets were reconstructed with Q.Clear with ß100-1000 (in increments of 100) and OSEM. The binding potential relative to non-displaceable volume (BPND) were obtained for the Substantia Nigra (SN), Striatum (St), Globus Pallidus (GP), Thalamus (Th), Caudate (Cd) and Putamen (Pt), using the MIAKAT™ software. Intraclass correlation coefficients (ICC), repeatability coefficients (RC), coefficients of variation (CV) and bias from Bland-Altman plots were reported. Statistical analysis was conducted using a 2-way ANOVA model with correction for multiple comparisons. RESULTS: When comparing a standard OSEM reconstruction of 6 iterations/16 subsets and 5 mm filter with Q.Clear with different ß values under low counts, the bias and RC were lower for Q.Clear with ß100 for the SN (RC = 2.17), Th (RC = 0.08) and GP (RC = 0.22) and with ß200 for the St (RC = 0.14), Cd (RC = 0.18)and Pt (RC = 0.10). The p-values in the 2-way ANOVA model corroborate these findings. ICC values obtained for Th, St, GP, Pt and Cd demonstrate good reliability (0.87, 0.99, 0.96, 0.99 and 0.96, respectively). For the SN, ICC values demonstrate poor reliability (0.43). CONCLUSION: BPND results obtained from quantitative low count brain PET studies using [11C]PHNO and reconstructed with Q.Clear with ß < 400, which is the value used for clinical [18F]FDG whole-body studies, demonstrate the lowest bias versus the typical iterative reconstruction method OSEM.

Bypass Grafting and Native Coronary Artery Disease Activity.

OBJECTIVES: The aim of this study was to describe the potential of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) to identify graft vasculopathy and to investigate the influence of coronary artery bypass graft (CABG) surgery on native coronary artery disease activity and progression. BACKGROUND: As well as developing graft vasculopathy, CABGs have been proposed to accelerate native coronary atherosclerosis. METHODS: Patients with established coronary artery disease underwent baseline 18F-NaF PET, coronary artery calcium scoring, coronary computed tomographic angiography, and 1-year repeat coronary artery calcium scoring. Whole-vessel coronary microcalcification activity (CMA) on 18F-NaF PET and change in calcium scores were quantified in patients with and without CABG surgery. RESULTS: Among 293 participants (mean age 65 ± 9 years, 84% men), 48 (16%) underwent CABG surgery 2.7 years [IQR: 1.4-10.4 years] previously. Although all arterial and the majority (120 of 128 [94%]) of vein grafts showed no 18F-NaF uptake, 8 saphenous vein grafts in 7 subjects had detectable CMA. Bypassed native coronary arteries had 3 times higher CMA values (2.1 [IQR: 0.4-7.5] vs 0.6 [IQR: 0-2.7]; P < 0.001) and greater progression of 1-year calcium scores (118 Agatston unit [IQR: 48-194 Agatston unit] vs 69 [IQR: 21-142 Agatston unit]; P = 0.01) compared with patients who had not undergone CABG, an effect confined largely to native coronary plaques proximal to the graft anastomosis. In sensitivity analysis, bypassed native coronary arteries had higher CMA (2.0 [IQR: 0.4-7.5] vs 0.8 [IQR: 0.3-3.2]; P < 0.001) and faster disease progression (24% [IQR: 16%-43%] vs 8% [IQR: 0%-24%]; P = 0.002) than matched patients (n = 48) with comparable burdens of coronary artery disease and cardiovascular comorbidities in the absence of bypass grafting. CONCLUSIONS: Native coronary arteries that have been bypassed demonstrate increased disease activity and more rapid disease progression than nonbypassed arteries, an observation that appears independent of baseline atherosclerotic plaque burden. Microcalcification activity is not a dominant feature of graft vasculopathy.

Performance evaluation of the Q.Clear reconstruction framework versus conventional reconstruction algorithms for quantitative brain PET-MR studies.

BACKGROUND: Q.Clear is a Bayesian penalized likelihood (BPL) reconstruction algorithm that presents improvements in signal-to-noise ratio (SNR) in clinical positron emission tomography (PET) scans. Brain studies in research require a reconstruction that provides a good spatial resolution and accentuates contrast features however, filtered back-projection (FBP) reconstruction is not available on GE SIGNA PET-Magnetic Resonance (PET-MR) and studies have been reconstructed with an ordered subset expectation maximization (OSEM) algorithm. This study aims to propose a strategy to approximate brain PET quantitative outcomes obtained from images reconstructed with Q.Clear versus traditional FBP and OSEM. METHODS: Contrast recovery and background variability were investigated with the National Electrical Manufacturers Association (NEMA) Image Quality (IQ) phantom. Resolution, axial uniformity and SNR were investigated using the Hoffman phantom. Both phantoms were scanned on a Siemens Biograph 6 TruePoint PET-Computed Tomography (CT) and a General Electric SIGNA PET-MR, for FBP, OSEM and Q.Clear. Differences between the metrics obtained with Q.Clear with different ß values and FBP obtained on the PET-CT were determined. RESULTS: For in plane and axial resolution, Q.Clear with low ß values presented the best results, whereas for SNR Q.Clear with higher ß gave the best results. The uniformity results are greatly impacted by the ß value, where ß < 600 can yield worse uniformity results compared with the FBP reconstruction. CONCLUSION: This study shows that Q.Clear improves contrast recovery and provides better resolution and SNR, in comparison to OSEM, on the PET-MR. When using low ß values, Q.Clear can provide similar results to the ones obtained with traditional FBP reconstruction, suggesting it can be used for quantitative brain PET kinetic modelling studies.

Effects of administration route on uptake kinetics of 18F-sodium fluoride positron emission tomography in mice.

18F-sodium fluoride (18F-NaF) is a positron emission tomography (PET) radiotracer widely used in skeletal imaging and has also been proposed as a biomarker of active calcification in atherosclerosis. Like most PET radiotracers, 18F-NaF is typically administered intravenously. However in small animal research intravenous administrations can be challenging, because partial paravenous injection is common due to the small calibre of the superficial tail veins and repeat administrations via tail veins can lead to tissue injury therefore limiting the total number of longitudinal scanning points. In this paper, the feasibility of using intra-peritoneal route of injection of 8F-NaF to study calcification in mice was studied by looking at the kinetic and uptake profiles of normal soft tissues and bones versus intra-vascular injections. Dynamic PET was performed for 60 min on nineteen isoflurane-anesthetized male Swiss mice after femoral artery (n = 7), femoral vein (n = 6) or intraperitoneal (n = 6) injection of 8F-NaF. PET data were reconstructed and the standardised uptake value (SUV) and standardised uptake value ratio (SUVr) were estimated from the last three frames between 45- and 60-min and 8F-NaF uptake constant (Ki) was derived by Patlak graphical analysis. In soft tissue, the 18F-NaF perfusion phase changes depending on the type on injection route, whereas the uptake phase is similar regardless of the administration route. In bone tissue SUV, SUVr and Ki measures were not significantly different between the three administration routes. Comparison between PET and CT measures showed that bones that had the highest CT density displayed the lowest PET activity and conversely, bones where CT units were low had high 8F-NaF uptake. Intraperitoneal injection is a valid and practical alternative to the intra-vascular injections in small-animal 18F-NaF PET imaging providing equivalent pharmacokinetic data. CT outcome measures report on sites of stablished calcification whereas PET measures sites of higher complexity and active calcification.