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Abstract Background Attenuation correction is crucial in quantitative positron emission tomography-magnetic resonance (PET-MRI) imaging. We evaluated three methods to improve the segmentation and modelling of the attenuation coefficients in the nasal sinus region. Two methods (cuboid and template method) included a MRI-CT conversion model for assigning the attenuation coefficients in the nasal sinus region, whereas one used fixed attenuation coefficient assignment (bulk method). Methods The study population consisted of data of 10 subjects which had undergone PET-CT and PET-MRI. PET images were reconstructed with and without time-of-flight (TOF) using CT-based attenuation correction (CTAC) as reference. Comparison was done visually, using DICE coefficients, correlation, analyzing attenuation coefficients, and quantitative analysis of PET and bias atlas images. Results The median DICE coefficients were 0.824, 0.853, 0.849 for the bulk, cuboid and template method, respectively. The median attenuation coefficients were 0.0841 cm−1, 0.0876 cm−1, 0.0861 cm−1 and 0.0852 cm−1, for CTAC, bulk, cuboid and template method, respectively. The cuboid and template methods showed error of less than 2.5% in attenuation coefficients. An increased correlation to CTAC was shown with the cuboid and template methods. In the regional analysis, improvement in at least 49% and 80% of VOI was seen with non-TOF and TOF imaging. All methods showed errors less than 2.5% in non-TOF and less than 2% in TOF reconstructions. Conclusions We evaluated two proof-of-concept methods for improving quantitative accuracy in PET/MRI imaging and showed that bias can be further reduced by inclusion of TOF. Largest improvements were seen in the regions of olfactory bulb, Heschl's gyri, lingual gyrus and cerebellar vermis. However, the overall effect of inclusion of the sinus region as separate class in MRAC to PET quantification in the brain was considered modest.

Abstract Background Folate receptor-β (FR-β) is a cell surface receptor that is significantly upregulated on activated macrophages during inflammation and provides a potential target for folate-based therapeutic and diagnostic agents. FR-β expression in central nervous system inflammation remains relatively unexplored. Therefore, we used focally induced acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) to study patterns of FR-β expression and evaluated its potential as an in vivo imaging target. Methods Focal EAE was induced in rats using heat-killed Bacillus Calmette-Guérin followed by activation with complete Freund’s adjuvant supplemented with Mycobacterium tuberculosis. The rats were assessed with magnetic resonance imaging and positron emission tomography/computed tomography (PET/CT) at acute (14 days) and chronic (90 days) phases of inflammation. The animals were finally sacrificed for ex vivo autoradiography of their brains. PET studies were performed using FR-β-targeting aluminum [18F]fluoride-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate ([18F]AlF-NOTA-folate, 18F-FOL) and 18 kDa translocator protein (TSPO)-targeting N-acetyl-N-(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine (11C-PBR28). Post-mortem immunohistochemistry was performed using anti-FR-β, anti-cluster of differentiation 68 (anti-CD68), anti-inducible nitric oxide synthase (anti-iNOS), and anti-mannose receptor C-type 1 (anti-MRC-1) antibodies. The specificity of 18F-FOL binding was verified using in vitro brain sections with folate glucosamine used as a blocking agent. Results Immunohistochemical evaluation of focal EAE lesions demonstrated anti-FR-β positive cells at the lesion border in both acute and chronic phases of inflammation. We found that anti-FR-β correlated with anti-CD68 and anti-MRC-1 immunohistochemistry; for MRC-1, the correlation was most prominent in the chronic phase of inflammation. Both 18F-FOL and 11C-PBR28 radiotracers bound to the EAE lesions. Autoradiography studies verified that this binding took place in areas of anti-FR-β positivity. A blocking assay using folate glucosamine further verified the tracer’s specificity. In the chronic phase of EAE, the lesion-to-background ratio of 18F-FOL was significantly higher than that of 11C-PBR28 (P = 0.016). Conclusion Our EAE results imply that FR-β may be a useful target for in vivo imaging of multiple sclerosis-related immunopathology. FR-β-targeted PET imaging with 18F-FOL may facilitate the monitoring of lesion development and complement the information obtained from TSPO imaging by bringing more specificity to the PET imaging armamentarium for neuroinflammation.

Abstract Background The reliable quantification of myocardial blood flow (MBF) with MRI, necessitates the correction of errors in arterial input function (AIF) caused by the T1 saturation effect. The aim of this study was to compare MBF determined by a traditional dual bolus method against a modified dual bolus approach and to evaluate both methods against PET in a porcine model of myocardial ischemia. Methods Local myocardial ischemia was induced in five pigs, which were subsequently examined with contrast enhanced MRI (gadoteric acid) and PET (O-15 water). In the determination of MBF, the initial high concentration AIF was corrected using the ratio of low and high contrast AIF areas, normalized according to the corresponding heart rates. MBF was determined from the MRI, during stress and at rest, using the dual bolus and the modified dual bolus methods in 24 segments of the myocardium (total of 240 segments, five pigs in stress and rest). Due to image artifacts and technical problems 53% of the segments had to be rejected from further analyses. These two estimates were later compared against respective rest and stress PET-based MBF measurements. Results Values of MBF were determined for 112/240 regions. Correlations for MBF between the modified dual bolus method and PET was r s = 0.84, and between the traditional dual bolus method and PET r s = 0.79. The intraclass correlation was very good (ICC = 0.85) between the modified dual bolus method and PET, but poor between the traditional dual bolus method and PET (ICC = 0.07). Conclusions The modified dual bolus method showed a better agreement with PET than the traditional dual bolus method. The modified dual bolus method was found to be more reliable than the traditional dual bolus method, especially when there was variation in the heart rate. However, the difference between the MBF values estimated with either of the two MRI-based dual-bolus methods and those estimated with the gold-standard PET method were statistically significant.

Abstract Background Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial cell molecule and primary amine oxidase that mediates leukocyte entry to sites of inflammation. However, there is limited knowledge of the inflammation-related expression of VAP-1 in the central nervous system (CNS). Therefore, we investigated the expression of VAP-1 within the CNS vasculature in two focal rat models of experimental autoimmune encephalomyelitis (EAE) mimicking multiple sclerosis (MS). Methods EAE was induced either with Bacillus Calmette-Guérin, resulting in a delayed-type hypersensitivity-like pathogenesis (fDTH-EAE), or with myelin oligodendrocyte glycoprotein (fMOG-EAE). A subgroup of fMOG-EAE rats were treated daily with a selective VAP-1 inhibitor (LJP1586; 5 mg/kg). On 3 and 14 days after lesion activation, rat brains were assessed using magnetic resonance imaging (MRI), and ex vivo autoradiography was conducted to evaluate the binding of Gallium-68-labelled VAP-1 ligand. Histology and immunohistochemistry (OX-42, VAP-1, intercellular adhesion protein-1 [ICAM-1], P-selectin) supported the ex vivo autoradiography. Results EAE lesions showed MRI-detectable signal changes and binding of the VAP-1-targeting radiotracer in both rat models. Some of the VAP-1 positive vessels showed morphological features typical for high endothelial-like venules at sites of inflammation. Inhibition of VAP-1 activity with small molecule inhibitor, LJP1586, decreased lymphocyte density in the acute inflammatory phase of fMOG-EAE lesions (day 3, P = 0.026 vs. untreated), but not in the remission phase (day 14, P = 0.70 vs. untreated), and had no effect on the amount of OX-42-positive cells in either phase. LJP1586 treatment reduced VAP-1 and ICAM-1 expression in the acute inflammatory phase, whereas P-selectin remained not detectable at all studied stages of the disease. Conclusions Our results revealed that VAP-1 is expressed and functionally active in vasculature within the induced focal EAE lesions during the acute phase of inflammation and remains expressed after the acute inflammation has subsided. The study indicates that VAP-1 is actively involved in the development of inflammatory CNS lesions. During this process, the endothelial cell lesion-related vasculature seem to undergo a structural transformation from regular flat-walled endothelium to HEV-like endothelium.

Abstract Background Radiolabeled RGD peptides detect αvβ3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvβ3 integrin is expressed in viable ischemic or injured myocardium. Methods We studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology. Results Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvβ3 integrin that was expressed in the injured myocardial areas. Conclusions Cardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvβ3 integrin expression associated with repair of recent myocardial injury.