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Kobayashi, Masato, Teresa Jiang, Sanjay Telu, et al. "11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195." Journal of Cerebral Blood Flow & Metabolism 38, no. 3 (2017): 393–403. http://dx.doi.org/10.1177/0271678x17699223.
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Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the “signal to background” ratio (assessed as binding potential ( BPND)) of 11C-( R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-( R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30–90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-( R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-( R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-( R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.
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Alfaifi, B., E. Agushi, R. Hinz, A. Jackson, D. Lewis, and D. Coope. "P15.10.A USE OF DUAL TRACERS PET AS A PREDICTIVE BIOMARKER OF THE SITE OF RECURRENCE IN HIGH GRADE GLIOMA." Neuro-Oncology 25, Supplement_2 (2023): ii111—ii112. http://dx.doi.org/10.1093/neuonc/noad137.374.
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Abstract BACKGROUND High grade glioma has poor survival rate and tumour recurrence occurs despite current treatments. Positron emission tomography (PET) with [11C](R)PK11195 can evaluate translocator protein (TSPO) and [11C]methionine can assess amino acid transport. PET imaging might have the potential to detect tumour regions at baseline that will later develop as the site of recurrence. We compare TSPO measured using [11C](R)PK11195 and amino acid transport using [11C]methionine at baseline and investigate to what extend the two tracers can predict the site of tumour recurrence. MATERIAL AND METHODS Twelve patients with newly diagnosed high grade glioma underwent multimodal imaging studies. Preoperative MRI, [11C](R)PK11195 PET, [11C]methionine PET and postoperative (follow-up) MRI were co-registered. [11C](R)PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model with grey matter cerebellar time-activity curve as tissue input function. [11C]methionine uptake was calculated as tumour to background ratio (TBR). Contrast enhancing volumes of interest (VOI) were defined on T1W post contrast. The VOI of [11C]methionine high uptake was standardized as TBR>1.7. For [11C](R)PK11195 VOI, the mean BPND + SD of grey matter voxels was calculated from individual maps of healthy control (HC; n = 50). Afterward, 95% confidence interval threshold (HC mean + 1.96 × SD) was used to describe high voxel activity in tumour (BPND>0.35). Tumour recurrence VOI was defined as contrast enhancement on the follow-up images. RESULTS The mean percentage overlap between high [11C](R)PK11195 BPND and [11C]methionine uptake was 48±17%. The mean percentage of each VOI showing exclusively high [11C](R)PK11195 BPND or exclusively high [11C]methionine was 25±21 or 27±22 respectively. The mean percentage overlap between high [11C](R)PK11195 and contrast enhancement is 36±14. The mean percentage of exclusively hight [11C](R)PK11195 or exclusively contrast enhancement were 38±18 or 26±25 respectively. The mean percentage overlap between high [11C]methionine and contrast enhancement were 47±12. The mean percentage of exclusively [11C]methionine or contrast enhancement were 36±20 or 17±17 respectively. The percentage volume overlap between contrast enhancing regions at recurrence and baseline [11C](R)PK11195 or [11C]methionine was 20±13 or 25±13 respectively. CONCLUSION The two PET tracers have high overlap although some regions are specific for high TSPO binding without high methionine uptake which could reflect an inflammatory component within the tumour microenvironment. The common regions between methionine and contrast enhancement is larger than TSPO binding which could represent that TSPO binding is less effected by disrupted blood-brain barrier. The mean percentage overlap with VOI representing tumour recurrence were similar.
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Bitker, Laurent, Nicolas Costes, Didier Le Bars, et al. "Noninvasive quantification of macrophagic lung recruitment during experimental ventilation-induced lung injury." Journal of Applied Physiology 127, no. 2 (2019): 546–58. http://dx.doi.org/10.1152/japplphysiol.00825.2018.
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Macrophagic lung infiltration is pivotal in the development of lung biotrauma because of ventilation-induced lung injury (VILI). We assessed the performance of [11C](R)-PK11195, a positron emission tomography (PET) radiotracer binding the translocator protein, to quantify macrophage lung recruitment during experimental VILI. Pigs ( n = 6) were mechanically ventilated under general anesthesia, using protective ventilation settings (baseline). Experimental VILI was performed by titrating tidal volume to reach a transpulmonary end-inspiratory pressure (∆PL) of 35–40 cmH2O. We acquired PET/computed tomography (CT) lung images at baseline and after 4 h of VILI. Lung macrophages were quantified in vivo by the standardized uptake value (SUV) of [11C](R)-PK11195 measured in PET on the whole lung and in six lung regions and ex vivo on lung pathology at the end of experiment. Lung mechanics were extracted from CT images to assess their association with the PET signal. ∆PL increased from 9 ± 1 cmH2O under protective ventilation, to 36 ± 6 cmH2O during experimental VILI. Compared with baseline, whole-lung [11C](R)-PK11195 SUV significantly increased from 1.8 ± 0.5 to 2.9 ± 0.5 after experimental VILI. Regional [11C](R)-PK11195 SUV was positively associated with the magnitude of macrophage recruitment in pathology ( P = 0.03). Compared with baseline, whole-lung CT-derived dynamic strain and tidal hyperinflation increased significantly after experimental VILI, from 0.6 ± 0 to 2.0 ± 0.4, and 1 ± 1 to 43 ± 19%, respectively. On multivariate analysis, both were significantly associated with regional [11C](R)-PK11195 SUV. [11C](R)-PK11195 lung uptake (a proxy of lung inflammation) was increased by experimental VILI and was associated with the magnitude of dynamic strain and tidal hyperinflation. NEW & NOTEWORTHY We assessed the performance of [11C](R)-PK11195, a translocator protein-specific positron emission tomography (PET) radiotracer, to quantify macrophage lung recruitment during experimental ventilation-induced lung injury (VILI). In this proof-of-concept study, we showed that the in vivo quantification of [11C](R)-PK11195 lung uptake in PET reflected the magnitude of macrophage lung recruitment after VILI. Furthermore, increased [11C](R)-PK11195 lung uptake was associated with harmful levels of dynamic strain and tidal hyperinflation applied to the lungs.
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de Souza, Aline Morais, Caroline Cristiano Real, Mara de Souza Junqueira, et al. "Potential of [11C](R)-PK11195 PET Imaging for Evaluating Tumor Inflammation: A Murine Mammary Tumor Model." Pharmaceutics 14, no. 12 (2022): 2715. http://dx.doi.org/10.3390/pharmaceutics14122715.
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Background: Breast tumor inflammation is an immunological process that occurs mainly by mediation of Tumor-Associated Macrophages (TAM). Aiming for a specific measurement of tumor inflammation, the current study evaluated the potential of Positron Emission Tomography (PET) imaging with [11C](R)-PK11195 to evaluate tumor inflammation in a mammary tumor animal model. Methods: Female Balb/C mice were inoculated with 4T1 cells. The PET imaging with [11C](R)-PK11195 and [18F]FDG was acquired 3 days, 1 week, and 2 weeks after cell inoculation. Results: The [11C](R)-PK11195 tumor uptake increased from 3 days to 1 week, and decreased at 2 weeks after cell inoculation, as opposed to the [18F]FDG uptake, which showed a slight decrease in uptake at 1 week and increased uptake at 2 weeks. In the control group, no significant differences occurred in tracer uptake over time. Tumor uptake of both radiopharmaceuticals is more expressed in tumor edge regions, with greater intensity at 2 weeks, as demonstrated by [11C](R)-PK11195 autoradiography and immunofluorescence with TSPO antibodies and CD86 pro-inflammatory phenotype. Conclusion: The [11C](R)-PK11195 was able to identify heterogeneous tumor inflammation in a murine model of breast cancer and the uptake varied according to tumor size. Together with the glycolytic marker [18F]FDG, molecular imaging with [11C](R)-PK11195 may provide a better characterization of inflammatory responses in cancer.
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Su, Zhangjie, Federico Roncaroli, Pascal F. Durrenberger, et al. "The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: A 11C-(R)PK11195 PET Imaging and Neuropathology Study." Journal of Nuclear Medicine 56, no. 4 (2015): 512–7. https://doi.org/10.2967/jnumed.114.151621.
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The 18-kDa mitochondrial translocator protein (TSPO) is up-regulated in high grade astrocytomas and can be imaged by positron emission tomography (PET) using the selective radiotracer 11C-(R)PK11195. We investigated 11C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma associated microglia/macrophages within the tumors. METHODS: Twenty-two glioma patients underwent dynamic 11C-(R)PK11195 PET scans and perfusion MRI acquisition. Parametric maps of 11C-(R)PK11195 binding potential (BPND) were generated. Co-registered MR/PET images were used to guide tumor biopsy. The tumor tissue was quantitatively assessed for TSPO expression and infiltration of glioma associated microglia/macrophages (GAMs) using immunohistochemistry and double immunofluorescence. The imaging and histopathologic parameters were compared among different histotypes and grades, and correlated with each other. RESULTS: BPND of 11C-(R)PK11195 in high-grade gliomas were significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated positively with BPND in the tumors. Glioma associated microglia/macrophages only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BPND. CONCLUSION: PET with 11C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients that are suitable for TSPO targeted treatment.
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Yokokura, Masamichi, Tatsuhiro Terada, Tomoyasu Bunai, et al. "Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195." Journal of Cerebral Blood Flow & Metabolism 37, no. 3 (2016): 877–89. http://dx.doi.org/10.1177/0271678x16646788.
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The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [11C]( R)PK11195 and a second-generation tracer [11C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer’s disease (AD) and were correlated with clinical scores. An analysis of variance showed category-dependent elevation in levels of [11C]DPA713 BPND in all brain regions and showed a significant increase in the AD group, whereas no significant changes among groups were found when [11C]( R)PK11195 BPND was used. Cognito-mnemonic scores were significantly correlated with [11C]DPA713 BPND levels in many brain regions, whereas [11C]( R)PK11195 BPND failed to correlate with the scores. As mentioned elsewhere, the present results confirmed that the second-generation TSPO tracer [11C]DPA713 has a greater sensitivity to TSPO in both aging and neuronal degeneration than [11C]( R)PK11195. Positron emission tomography with [11C]DPA713 is suitable for the delineation of in vivo microglial activation occurring globally over the cerebral cortex irrespective of aging and degeneration.
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Schuck, Phelipi Nunes, Caroline Machado Dartora, and Ana Maria Marques da Silva. "Geração de Imagens PET Estáticas com [11C]-(R)-PK11195: Definição do Intervalo Temporal." Revista Brasileira de Física Médica 11, no. 2 (2017): 25. http://dx.doi.org/10.29384/rbfm.2017.v11.n2.p25-29.
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O radiotraçador [11C]-(R)-PK11195 mostra afinidade com a microglia em imagens PET in vivo e vem sendo utilizado como indicador de doença inflamatória cerebral, como a esclerose múltipla (EM). Atualmente, não há consenso sobre o intervalo temporal adequado para gerar imagens PET estáticas com [11C]-(R)-PK11195. O objetivo deste trabalho é determinar o intervalo temporal mais adequado para a geração de imagens PET cerebrais estáticas adquiridas com [11C]-(R)-PK11195 para a quantificação. Foram geradas imagens PET estáticas com [11C]-(R)-PK11195 nos intervalos de: 0-60min, 5-20min, 5-30min, 10-60min, 30-60min e 40-60min. Para quantificação das imagens foi utilizado o método da razão entre a média do SUV (Standard Uptake Value) nas regiões justacortical e periventricular e na substância branca, denominado SUVRWM. Os resultados mostram grande variação do SUVRWM nos intervalos que incluem o período de perfusão do radiotraçador. Existe uma maior estabilidade do SUVRWM nos últimos intervalos avaliados (30-60min e 40-60min), tanto para o grupo controle, como para os pacientes com EM. Conclui-se que o melhor intervalo para aquisição da imagem PET estática para quantificação é de 40 a 60 minutos após a administração, o que significa uma imagem adquirida 40 min após a injeção do radiotraçador [11C]-(R)-PK11195, por um período de 20 min.
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Boutin, Hervé, Katie Murray, Jesus Pradillo, et al. "[18F]GE-180: a novel TSPO radiotracer compared to [11C]PK11195 in a preclinical model of stroke." Eur J Nucl Med Mol Imaging 42, no. 3 (2014): 503–11. https://doi.org/10.1007/s00259-014-2939-8.
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PURPOSE: Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer 11C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer 18F-GE-180 in a rat model of stroke. METHODS: Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with 11C-R-PK11195 and 18F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of 18F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). RESULTS: 18F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of 11C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BPND = 3.5 ± 0.4 and 2.4 ± 0.5 for 18F-GE-180 and 11C-R-PK11195, respectively, with R 1 = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of 18F-GE-180 significantly displaced 18F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. CONCLUSION: The in vivo binding characteristics of 18F-GE-180 demonstrate a better signal to noise ratio than 11C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that 18F-GE-180 is a strong candidate to replace 11C-R-PK11195.
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Gent, Yoony Y. J., Nazanin Ahmadi, Alexandre E. Voskuyl, et al. "Detection of Subclinical Synovitis with Macrophage Targeting and Positron Emission Tomography in Patients with Rheumatoid Arthritis without Clinical Arthritis." Journal of Rheumatology 41, no. 11 (2014): 2145–52. http://dx.doi.org/10.3899/jrheum.140059.
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Objective.To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure.Methods.(R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0–3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0–66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (> 1) were summed to obtain a cumulative MRI score (range 0–288). Occurrence of flare was determined during 3-year followup.Results.Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (> 6, n = 3) corresponded with highest cumulative MRI scores (> 39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0–4.5) vs 0 (0–1), p < 0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare.Conclusion.(R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R)-11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years.
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Rapic, Sara, Heiko Backes, Thomas Viel, et al. "Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease." Neurobiology of Aging 34, no. 11 (2012): 351–4. https://doi.org/10.1016/j.neurobiolaging.2012.04.016.
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In Alzheimer’s disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13- to 15-month-old AD mice using [11C]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks’ treatment, 5-week wash-out period). [11C]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [11C]-(R)-PK11195 PET could not demonstrate genotype- or treatment-dependent differences in the 13- to 14-month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method.
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Kropholler, Marc A., Ronald Boellaard, Alie Schuitemaker, et al. "Development of a Tracer Kinetic Plasma Input Model for (R)-[11C]PK11195 Brain Studies." Journal of Cerebral Blood Flow & Metabolism 25, no. 7 (2005): 842–51. http://dx.doi.org/10.1038/sj.jcbfm.9600092.
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(R)-[11C]PK11195 ([1-(2-chlorophenyl)- N-methyl- N-(1-methylpropyl]-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor, which, in the brain, is mainly expressed on activated microglia. Using both clinical studies and Monte Carlo simulations, the aim of this study was to determine which tracer kinetic plasma input model best describes (R)-[11C]PK11195 kinetics. Dynamic positron emission tomography (PET) scans were performed on 13 subjects while radioactivity in arterial blood was monitored online. Discrete blood samples were taken to generate a metabolite corrected plasma input function. One-tissue, two-tissue irreversible, and two-tissue reversible compartment models, with and without fixing K1/ k2 ratio, k4 or blood volume to whole cortex values, were fitted to the data. The effects of fixing parameters to incorrect values were investigated by varying them over a physiologic range and determining accuracy and reproducibility of binding potential and volume of distribution using Monte Carlo simulations. Clinical data showed that a two-tissue reversible compartment model was optimal for analyzing (R)-[11C]PK11195 PET brain studies. Simulations showed that fixing the K1/ k2 ratio of this model provided the optimal trade-off between accuracy and reproducibility. It was concluded that a two-tissue reversible compartment model with K1/ k2 fixed to whole cortex value is optimal for analyzing (R)-[11C]PK11195 PET brain studies.
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Rizzo, Gaia, Mattia Veronese, Matteo Tonietto, et al. "Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities." Journal of Cerebral Blood Flow & Metabolism 39, no. 5 (2017): 874–85. http://dx.doi.org/10.1177/0271678x17742004.
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The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [11C]PBR28, [18F]DPA714 and [11C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [11C]-R-PK11195 data from six healthy subjects. Then, we compared the [11C]-R-PK11195 vascular binding estimates with previously published values for [18F]DPA714 and [11C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [11C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.
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Kitade, Makoto, Hideaki Nakajima, Tetsuya Tsujikawa, et al. "Evaluation of (R)-[11C]PK11195 PET/MRI for Spinal Cord-Related Neuropathic Pain in Patients with Cervical Spinal Disorders." Journal of Clinical Medicine 12, no. 1 (2022): 116. http://dx.doi.org/10.3390/jcm12010116.
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Activated microglia are involved in secondary injury after acute spinal cord injury (SCI) and in development of spinal cord-related neuropathic pain (NeP). The aim of the study was to assess expression of translocator protein 18 kDa (TSPO) as an indicator of microglial activation and to investigate visualization of the dynamics of activated microglia in the injured spinal cord using PET imaging with (R)-[11C]PK11195, a specific ligand for TSPO. In SCI chimeric animal models, TSPO was expressed mainly in activated microglia. Accumulation of (R)-[3H]PK11195 was confirmed in autoradiography and its dynamics in the injured spinal cord were visualized by (R)-[11C]PK11195 PET imaging in the acute phase after SCI. In clinical application of (R)-[11C]PK11195 PET/MRI of the cervical spinal cord in patients with NeP related to cervical disorders, uptake was found in cases up to 10 months after injury or surgery. No uptake could be visualized in the injured spinal cord in patients with chronic NeP at more than 1 year after injury or surgery, regardless of the degree of NeP. However, a positive correlation was found between standardized uptake value ratio and the severity of NeP, suggesting the potential of clinical application for objective evaluation of chronic NeP.
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Schuitemaker, Alie, Bart NM van Berckel, Marc A. Kropholler, et al. "Evaluation of Methods for Generating Parametric (R)-[11C]PK11195 Binding Images." Journal of Cerebral Blood Flow & Metabolism 27, no. 9 (2007): 1603–15. http://dx.doi.org/10.1038/sj.jcbfm.9600459.
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Activated microglia can be visualised using ( R)-[11C]PK11195 (1-[2-chlorophenyl]- N-methyl- N-[1-methyl-propyl]-3-isoquinoline carboxamide) and positron emission tomography (PET). In previous studies, various methods have been used to quantify ( R)-[11C]PK11195 binding. The purpose of this study was to determine which parametric method would be best suited for quantifying ( R)-[11C]PK11195 binding at the voxel level. Dynamic ( R)-[11C]PK11195 scans with arterial blood sampling were performed in 20 healthy and 9 Alzheimer's disease subjects. Parametric images of both volume of distribution ( Vd) and binding potential ( BP) were obtained using Logan graphical analysis with plasma input. In addition, BP images were generated using two versions of the basis function implementation of the simplified reference tissue model, two versions of Ichise linearisations, and Logan graphical analysis with reference tissue input. Results of the parametric methods were compared with results of full compartmental analysis using nonlinear regression. Simulations were performed to assess accuracy and precision of each method. It was concluded that Logan graphical analysis with arterial input function is an accurate method for generating parametric images of Vd. Basis function methods, one of the Ichise linearisations and Logan graphical analysis with reference tissue input provided reasonably accurate and precise estimates of BP. In pathological conditions with reduced flow rates or large variations in blood volume, the basis function method is preferred because it produces less bias and is more precise.
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Raijmakers, Ruud, Megan Roerink, Stephan Keijmel, et al. "No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [11C]-PK11195." Neurology - Neuroimmunology Neuroinflammation 9, no. 1 (2021): e1113. http://dx.doi.org/10.1212/nxi.0000000000001113.
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Background and ObjectivesThe pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide ([11C]-PK11195).MethodsThe study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [11C]-PK11195 PET scan, and the [11C]-PK11195 binding potential (BPND) was calculated.ResultsNo statistically significant differences in BPND were found for patients with CFS or patients with QFS compared with HSs. BPND of [11C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS.DiscussionIn contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS.Trial Registration InformationEudraCT number 2014-004448-37.
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Myers, R., R. B. Banati, T. Jones, and V. J. Cunningham. "Quantification of [11C](R)-PK11195 in Clinical PET." NeuroImage 7, no. 4 (1998): A37. http://dx.doi.org/10.1016/s1053-8119(18)31906-2.
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Kim, *Jong-Hoon, Yo-Han Joo, Jeong-Hee Kim, and Young-Don Son. "ALTERED PATTERNS OF ASSOCIATION BETWEEN TSPO BINDING AND MGLUR5 AVAILABILITY IN VIVO IN DRUG-NAIVE PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A PRELIMINARY DUAL-TRACER PET STUDY." International Journal of Neuropsychopharmacology 28, Supplement_1 (2025): i137—i138. https://doi.org/10.1093/ijnp/pyae059.238.
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Abstract Background Based on the monoamine theory of major depressive disorder (MDD), symptoms are derived from a deficiency or imbalance in monoaminergic neurotransmission. The limitation of such a model (1) may highlight the need for alternative neurobiological constructs. Accumulating data indicate that neuroinflammation and its interactions with glutamatergic signaling may present a compelling alternative model for understanding the pathophysiology of MDD and its therapeutic approaches (2-4); however, the patterns of interregional correlations between neuroinflammation and glutamatergic signaling in MDD has not been directly investigated using in vivo positron emission tomography (PET) imaging. Aims & Objectives In this preliminary dual-tracer PET study, we tested for altered spatial associations between availability of ligands for the neuroinflammation marker, translocator protein (TSPO), and the metabotropic glutamate receptor-5 (mGluR5) marker in a group of MDD patients compared with matched healthy controls (HCs). Method Ten drug-naï ve non-smoking MDD patients without comorbidity and eight matched non-smoking HCs underwent PET scanning with the TSPO ligand [11C]PK11195 and the mGluR5 ligand [11C]ABP688. For TSPO availability, we quantified [11C]PK11195 binding potential (BPND) using a reference tissue model (5) based on the supervised cluster analysis (SVCA4) algorithm (6). For mGluR5 availability, [11 C]ABP688 BPND was obtained using the simplified reference tissue model (7) with cerebellar gray matter as a reference region. Regional BPND values were obtained from limbic brain regions that are pivotal in emotion and its regulation: prefrontal cortex, anterior cingulate cortex, parietal cortex, temporal cortex, insula, hippocampus, and amygdala. We calculated the interregional correlation coefficients between regional [11C]PK11195 BPND and [11C]ABP688 BPND values, and compared group differences in the correlation matrices using Fisher’ s z-transformation statistics. The level of statistical significance was defined as two-tailed p &lt;0.05. Results Regional [11C]PK11195 BPND and [11C]ABP688 BPND values showed widespread positive correlations in the HC group, but negative and attenuated positive correlations in the hippocampus and amygdala in the MDD group. The between-group comparisons of the interregional correlation coefficients showed significant differences between the [11C]PK11195 BPND in the left hippocampus and [11C]ABP688 BPND in the bilateral parietal and left temporal cortices, between the [11C]PK11195 BPND in the right hippocampus and [11C]ABP688 BPND in the bilateral prefrontal cortex, bilateral anterior cingulate cortex, bilateral parietal cortex, bilateral temporal cortex, insula, and right amygdala, and between the [11C]PK11195 BPND in the bilateral amygdala and [11C]ABP688 BPND in the right parietal cortex. Discussion & Conclusion Our preliminary dual-tracer PET study shows substantially different patterns of interregional correlations between the availability of TSPO and mGluR5 in MDD patients compared to HCs. The results are in line with a mechanism whereby neuroinflammation may provoke a down-regulation of a post-synaptic marker of glutamatergic transmission in limbic-cortical regions in MDD. These results call for examination in larger groups, aiming to accommodate the heterogeneity of MDD pathophysiology. References 1.Moncrieff, J., Cooper, R.E., Stockmann, T., Amendola, S., Hengartner, M.P., Horowitz, M.A., 2022. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 1–14. https://doi.org/10.1038/s41380-022-01661-0 2.Moylan, S., Maes, M., Wray, N.R., Berk, M., 2013. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 18, 595–606. https://doi.org/10.1038/mp.2012.33 3.Enache, D., Pariante, C.M., Mondelli, V., 2019. Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun 81, 24–40. https://doi.org/10.1016/j.bbi.2019.06.015 4.Osimo, E.F., Pillinger, T., Rodriguez, I.M., Khandaker, G.M., Pariante, C.M., Howes, O.D., 2020. Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav Immun 87, 901–909. https://doi.org/10.1016/j.bbi.2020.02.010 5.Yaqub, M., Tolboom, N., van Berckel, B.N.M., Scheltens, P., Lammertsma, A.A., Boellaard, R., 2010. Simplified parametric methods for [18F]FDDNP studies. NeuroImage 49, 433–441. https://doi.org/10.1016/j.neuroimage.2009.07.046 6.Yaqub, M., van Berckel, B.N., Schuitemaker, A., Hinz, R., Turkheimer, F.E., Tomasi, G., Lammertsma, A.A., Boellaard, R., 2012. Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C]PK11195 brain PET studies. J Cereb Blood Flow Metab 32, 1600–1608. https://doi.org/10.1038/jcbfm.2012.59 7.Wu, Y., Carson, R.E., 2002. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab 22, 1440–1452. https://doi.org/10.1097/01.WCB.0000033967.83623.34
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Yankam Njiwa, J., N. Costes, C. Bouillot, et al. "Quantitative longitudinal imaging of activated microglia as a marker of inflammation in the pilocarpine rat model of epilepsy using [11C]-(R)-PK11195 PET and MRI." Journal of Cerebral Blood Flow & Metabolism 37, no. 4 (2016): 1251–63. http://dx.doi.org/10.1177/0271678x16653615.
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Inflammation may play a role in the development of epilepsy after brain insults. [11C]-( R)-PK11195 binds to TSPO, expressed by activated microglia. We quantified [11C]-( R)-PK11195 binding during epileptogenesis after pilocarpine-induced status epilepticus (SE), a model of temporal lobe epilepsy. Nine male rats were studied thrice (D0-1, D0 + 6, D0 + 35, D0 = SE induction). In the same session, 7T T2-weighted images and DTI for mean diffusivity (MD) and fractional anisotropy (FA) maps were acquired, followed by dynamic PET/CT. On D0 + 35, femoral arterial blood was sampled for rat-specific metabolite-corrected arterial plasma input functions (AIFs). In multiple MR-derived ROIs, we assessed four kinetic models (two with AIFs; two using a reference region), standard uptake values (SUVs), and a model with a mean AIF. All models showed large (up to two-fold) and significant TSPO binding increases in regions expected to be affected, and comparatively little change in the brainstem, at D0 + 6. Some individuals showed increases at D0 + 35. AIF models yielded more consistent increases at D0 + 6. FA values were decreased at D0 + 6 and had recovered by D0 + 35. MD was increased at D0 + 6 and more so at D0 + 35. [11C]-( R)-PK11195 PET binding and MR biomarker changes could be detected with only nine rats, highlighting the potential of longitudinal imaging studies.
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Mantovani, Dimitri B. A., Milena S. Pitombeira, Phelipi N. Schuck, et al. "Evaluation of Non-Invasive Methods for (R)-[11C]PK11195 PET Image Quantification in Multiple Sclerosis." Journal of Imaging 10, no. 2 (2024): 39. http://dx.doi.org/10.3390/jimaging10020039.
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This study aims to evaluate non-invasive PET quantification methods for (R)-[11C]PK11195 uptake measurement in multiple sclerosis (MS) patients and healthy controls (HC) in comparison with arterial input function (AIF) using dynamic (R)-[11C]PK11195 PET and magnetic resonance images. The total volume of distribution (VT) and distribution volume ratio (DVR) were measured in the gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, cerebellum, and brainstem using AIF, the image-derived input function (IDIF) from the carotid arteries, and pseudo-reference regions from supervised clustering analysis (SVCA). Uptake differences between MS and HC groups were tested using statistical tests adjusted for age and sex, and correlations between the results from the different quantification methods were also analyzed. Significant DVR differences were observed in the gray matter, white matter, putamen, pallidum, thalamus, and brainstem of MS patients when compared to the HC group. Also, strong correlations were found in DVR values between non-invasive methods and AIF (0.928 for IDIF and 0.975 for SVCA, p < 0.0001). On the other hand, (R)-[11C]PK11195 uptake could not be differentiated between MS patients and HC using VT values, and a weak correlation (0.356, p < 0.0001) was found between VTAIF and VTIDIF. Our study shows that the best alternative for AIF is using SVCA for reference region modeling, in addition to a cautious and appropriate methodology.
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Narciso, Lucas Diovani Lopes, Phelipi Nunes Schuck, Caroline Machado Dartora, Cristina Sebastião Matushita, Jefferson Becker, and Ana Maria Marques da Silva. "Semiquantification Study of [11C]-(R)-PK11195 PET Brain Images in Multiple Sclerosis." Revista Brasileira de Física Médica 10, no. 2 (2016): 39. http://dx.doi.org/10.29384/rbfm.2016.v10.n2.p39-43.
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PET brain images with [11C]-(R)-PK11195 are being widely used to visualize microglial activation in vivo in neurodegenerative diseases, such as multiple sclerosis (MS). The aim of this study is to investigate the uptake behavior in juxtacortical and periventricular regions of [11C]-(R)-PK11195 PET brain images reformatted in different time intervals by applying three methods, seeking method and time interval that significantly differentiate MS patients from healthy controls. Semiquantitative SUV and SUVR methods were applied to PET images from different time intervals acquired from 10 patients with MS and 5 healthy controls. The results show significant difference between groups for SUV (p = 0.01) in 40 to 60 min interval, and SUVR with white matter as reference (p < 0.01) in 10 to 60 min interval, measured in the juxtacortical and periventricular regions.
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Seo, Seongho, Ye-Ha Jung, Dasom Lee, et al. "Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET." PLOS ONE 16, no. 2 (2021): e0246152. http://dx.doi.org/10.1371/journal.pone.0246152.
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Purpose Fibromyalgia (FM) and complex regional pain syndrome (CRPS) share many pathological mechanisms related to chronic pain and neuroinflammation, which may contribute to the multifactorial pathological mechanisms in both FM and CRPS. The aim of this study was to assess neuroinflammation in FM patients compared with that in patients with CRPS and healthy controls. Methods Neuroinflammation was measured as the distribution volume ratio (DVR) of [11C]-(R)-PK11195 positron emission tomography (PET) in 12 FM patients, 11 patients with CRPS and 15 healthy controls. Results Neuroinflammation in FM patients was significantly higher in the left pre (primary motor cortex) and post (primary somatosensory cortex) central gyri (p < 0.001), right postcentral gyrus (p < 0.005), left superior parietal and superior frontal gyri (p < 0.005), left precuneus (p < 0.01), and left medial frontal gyrus (p = 0.036) compared with healthy controls. Furthermore, the DVR of [11C]-(R)-PK11195 in FM patients demonstrated decreased neuroinflammation in the medulla (p < 0.005), left superior temporal gyrus (p < 0.005), and left amygdala (p = 0.020) compared with healthy controls. Conclusions To the authors’ knowledge, this report is the first to describe abnormal neuroinflammation levels in the brains of FM patients compared with that in patients with CRPS using [11C]-(R)-PK11195 PET. The results suggested that abnormal neuroinflammation can be an important pathological factor in FM. In addition, the identification of common and different critical regions related to abnormal neuroinflammation in FM, compared with patients with CRPS and healthy controls, may contribute to improved diagnosis and the development of effective medical treatment for patients with FM.
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Molthoff, Carla F. M., Hedy Folkersma, Jessica C. Foster-Dingley, et al. "Combined microdialysis and longitudinal (R)-[11C]PK11195 PET study." NeuroImage 52 (August 2010): S35. http://dx.doi.org/10.1016/j.neuroimage.2010.04.217.
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Kropholler, M. A., R. Boellaard, E. H. Elzinga, et al. "Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis." European Journal of Nuclear Medicine and Molecular Imaging 36, no. 4 (2008): 624–31. http://dx.doi.org/10.1007/s00259-008-0987-7.
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Tondo, Giacomo, Cecilia Boccalini, Silvia Paola Caminiti, et al. "Brain Metabolism and Microglia Activation in Mild Cognitive Impairment: A Combined [18F]FDG and [11C]-(R)-PK11195 PET Study." Journal of Alzheimer's Disease 80, no. 1 (2021): 433–45. http://dx.doi.org/10.3233/jad-201351.
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Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. Objective: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. Methods: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson’s correlation at single subject level. Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer’s disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β = –0.804; p = 0.016). Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.
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Alfaifi, Bandar, Alan Jackson, Rainer Hinz, Daniel Lewis, and David Coope. "DUAL PET IMAGING OF NEOPLASTIC AND INflAMMATORY BIOMARKERS IN HIGH GRADE GLIOMA." Neuro-Oncology 25, Supplement_3 (2023): iii2. http://dx.doi.org/10.1093/neuonc/noad147.006.
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Abstract AIMS To characterize spatial distributions of 18kDa translocator protein (TSPO) and amino acid uptake as measured through dynamic [11C] (R)-PK11195 and [11C]-methionine PET in high-grade glioma. METHOD Twelve patients with newly diagnosed high-grade glioma underwent dual PET studies. [11C] (R)-PK11195 binding potential (BPND) maps were generated using simplified reference tissue model with grey-matter cerebellar time- activity-curve as tissue input-function. [11C]-methionine uptake was calculated as tumour-to-background ratio (TBR). Volumes of interest (VOIs) were defined on T1W post-contrast MRI as contrast-enhancing (CE) tumour and a ‘peritumoural’ region 5mm from the CE edge. Voxel-wise comparison of the tracers used Pearson’s correlation coeffcient. VOIs were furthermore subdivided into higher/lower TSPO (BPND &gt; 0.17) and higher/lower methionine (TBR &gt; 1.7). RESULTS Within the CE, voxel-wise comparison showed a strong correlation (r &gt; 0.7) in eight subjects, moderate correlation (r &gt; 0.5) in three subjects and weak correlation (r &lt; 0.5) in one subject. Volume (mm3) with high BPND/high TBR accounted for 62±29% whereas high BPND/low TBR accounted for 13±16%. Within the peritumoral area, there was a small reduction in the proportion of subjects in the strong correlation group (6/12) but the pro- portion of voxels with higher TSPO binding and lower methionine uptake was substantially greater (35±16%). CONCLUSIONS Within high-grade glioma, there is a strong overall correlation between TSPO expression and amino acid uptake. However, in the peritumoural region there are areas of elevated TSPO expression without increased methionine uptake which could represent an inflammatory component or a discrete neoplastic cell population that may not be adequately defined with standard imaging biomarkers.
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Visi, Eszter, Rainer Hinz, Martin Punter, Arshad Majid, Alexander Gerhard, and Karl Herholz. "Positron emission tomography to image cerebral neuroinflammation in ischaemic stroke: a pilot study." Efficacy and Mechanism Evaluation 7, no. 1 (2020): 1–26. http://dx.doi.org/10.3310/eme07010.
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Background Activated microglia play a complex role in neuroinflammation associated with acute ischaemic stroke. As a potential target for anti-inflammatory therapy, it is crucial to understand the association between intensity, extent and the clinical outcome of a stroke. The 18-kDa translocator protein is a marker of cerebral microglial activation and of macrophage infiltration after damage to the brain. It can be imaged by positron emission tomography. Therefore, the recently developed radiopharmaceutical [18F]-GE180 was used in patients after a mild to moderate stroke and compared with [11C]-(R)-PK11195, which has already been established in research but cannot be used in routine clinical settings because of its very short half-life. Objectives Objectives for phase 1 were to evaluate the tolerability of positron emission tomography scanning, to assess the technical feasibility of imaging the 18-kDa translocator protein using [18F]-GE180 as radiopharmaceutical, to compare [18F]-GE180 with [11C]-(R)-PK11195 as reference. Objectives for phase 2 were examining the relation of positron emission tomography imaging with clinical outcome, magnetic resonance imaging and systemic inflammation. However, the study was ended after phase 1 because of the results obtained in that phase and did not enter phase 2. Methods Ten participants (aged 24–89 years, median 68 years) (eight male and two female) with a history of recent ischaemic stroke of mild to moderate severity (modified Rankin scale score of 2–3) in the middle cerebral artery territory were scanned 18 to 63 days (median 34.5 days) after the stroke by magnetic resonance imaging (Philips 1.5 T; Philips, Amsterdam, the Netherlands), [18F]-GE180 (200 MBq, 30-minute dynamic scan) and [11C]-(R)-PK11195 (740 MBq, 60-minute dynamic scan) positron emission tomography (Siemens HRRT; Siemens, Munich, Germany). The two positron emission tomography scans were performed on 2 separate days (mean 3.4 days apart). Five patients were randomised to receive the [18F]-GE180 scan at the first session and five patients were randomised to receive it at the second session. Participants were genotyped for the rs6971 18-kDa translocator protein polymorphism, which is known to affect binding of [18F]-GE180 but not of [11C]-(R)-PK11195. All positron emission tomography and magnetic resonance data sets were co-registered with T1-weighted magnetic resonance image scans. Binding of [18F]-GE180 was compared with [11C]-(R)-PK11195 for the infarct and contralateral reference regions. Spearman’s rank-order correlation was used to compare tracers, t-tests to compare patient subgroups. Results Tolerability of scans was rated as 4.36 (range 4–5) out of a maximum of 5 by participants, and there were no serious adverse events. There was a close correlation between [18F]-GE180 and [11C]-(R)-PK11195 (r = 0.79 to 0.84). The 18-kDa translocator protein polymorphism had a significant impact on the uptake of [18F]-GE180, which was very low in normal cortex. Ischaemic lesions with contrast enhancement on magnetic resonance as an indicator of blood–brain barrier damage showed a significantly higher uptake of [18F]-GE180 than the lesions without enhancement, even in low-affinity binders. Conclusions [18F]-GE180 was safe and well tolerated. However, strong dependency of uptake on blood–brain barrier damage and a genetic 18-kDa translocator protein polymorphism, as well as a high contribution of vascular signal to the uptake and evidence of non-specific binding in ischaemic lesions with blood–brain barrier damage, limits the clinical applicability of [18F]-GE180 as a diagnostic marker of neuroinflammation. Limitations As the study was ended after phase 1, this was only a small pilot trial. Further studies are warranted to fully understand the influence of blood–brain barrier damage on positron emission tomography microglia imaging. Trial registration Registered as a clinical trial with EudraCT 2014-000591-26. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 1. See the NIHR Journals Library website for further information. It was also supported by GE Healthcare (Chicago, IL, USA) by free production and delivery of [18F]-GE180 and by supply of regulatory documents (Investigational Medical Product Dossier, Investigator’s Brochure). There was partial support by the European Commission (INMiND, grant #278850) and the NIHR Sheffield Biomedical Research Centre.
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Chandrupatla, Durga M. S. H., Karin Weijers, Yoony Y. J. Gent, et al. "Sustained Macrophage Infiltration upon Multiple Intra-Articular Injections: An Improved Rat Model of Rheumatoid Arthritis for PET Guided Therapy Evaluation." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/509295.
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To widen the therapeutic window for PET guided evaluation of novel anti-RA agents, modifications were made in a rat model of rheumatoid arthritis (RA). Arthritis was induced in the right knee of Wistar rats with repeated boosting to prolong articular inflammation. The contralateral knee served as control. After immunization with methylated bovine serum albumin (mBSA) in complete Freund’s adjuvant and custom Bordetella pertussis antigen, one or more intra-articular (i.a.) mBSA injections were given over time in the right knee. Serum anti-mBSA antibodies, DTH response, knee thickness, motion, and synovial macrophages were analyzed and [18F]FDG(-general inflammation) and (R)-[11C]PK11195 (macrophages-)PET was performed followed byex vivotissue distribution. Significant anti-mBSA levels, DTH, swelling of arthritic knee, and sustained and prolonged macrophage infiltration in synovial tissue were found, especially using multiple i.a. injections. Increased [18F]FDG and (R)-[11C]PK11195 accumulation was demonstrated in arthritic knees as compared to contralateral knees, which was confirmed inex vivotissue distribution studies. Boosting proved advantageous for achieving a chronic model without remission. The model will offer excellent opportunities for repeated PET studies to monitor progression of disease and efficacy of novel therapeutic agents for RA in the same animal.
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Kropholler, Marc A., Bart N. M. van Berckel, Alie Schuitemaker, et al. "Evaluation of reference tissue models for analysing [11C](R)-PK11195 studies." Journal of Cerebral Blood Flow & Metabolism 25, no. 1_suppl (2005): S642. http://dx.doi.org/10.1038/sj.jcbfm.9591524.0642.
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Walterfang, Mark, Maria A. Di Biase, Vanessa L. Cropley, et al. "Imaging of neuroinflammation in adult Niemann-Pick type C disease." Neurology 94, no. 16 (2020): e1716-e1725. http://dx.doi.org/10.1212/wnl.0000000000009287.
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ObjectiveTo test the hypothesis that neuroinflammation is a key process in adult Niemann-Pick type C (NPC) disease, we undertook PET scanning utilizing a ligand binding activated microglia on 9 patients and 9 age- and sex-matched controls.MethodWe scanned all participants with the PET radioligand 11C-(R)-PK-11195 and undertook structural MRI to measure gray matter volume and white matter fractional anisotropy (FA).ResultsWe found increased binding of 11C-(R)-PK-11195 in total white matter compared to controls (p < 0.01), but not in gray matter regions, and this did not correlate with illness severity or duration. Gray matter was reduced in the thalamus (p < 0.0001) in patients, who also showed widespread reductions in FA across the brain compared to controls (p < 0.001). A significant correlation between 11C-(R)-PK11195 binding and FA was shown (p = 0.002), driven by the NPC patient group.ConclusionsOur findings suggest that neuroinflammation—particularly in white matter—may underpin some structural and degenerative changes in patients with NPC.
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Rissanen, Eero, Jouni Tuisku, Tero Vahlberg, et al. "Microglial activation, white matter tract damage, and disability in MS." Neurology - Neuroimmunology Neuroinflammation 5, no. 3 (2018): e443. http://dx.doi.org/10.1212/nxi.0000000000000443.
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ObjectiveTo investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS.MethodsPatients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [11C](R)-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison.Results[11C](R)-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.ConclusionsPET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.
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Cumming, Paul, Bjorn Burgher, Omkar Patkar, et al. "Sifting through the surfeit of neuroinflammation tracers." Journal of Cerebral Blood Flow & Metabolism 38, no. 2 (2017): 204–24. http://dx.doi.org/10.1177/0271678x17748786.
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The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [11C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [11C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.
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Yaqub, Maqsood, Bart NM van Berckel, Alie Schuitemaker, et al. "Optimization of Supervised Cluster Analysis for Extracting Reference Tissue Input Curves in (R)-[11C]PK11195 Brain PET Studies." Journal of Cerebral Blood Flow & Metabolism 32, no. 8 (2012): 1600–1608. http://dx.doi.org/10.1038/jcbfm.2012.59.
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Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer's disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPM V b). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions ( V b) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of V b in RPM improved both parametric images and binding potential contrast between groups. Incorporation of V b within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies.
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Verweij, N. J. F., M. Ter Wee, J. De Jongh, et al. "SAT0551 WHOLE BODY MACROPHAGE PET IMAGING THAT INCLUDES THE FEET CAN PROVIDE ADDITIONAL INFORMATION TO CLINICAL ASSESSMENT IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1233.2–1233. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4380.
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Background:Clinical assessment of arthritis is the cornerstone in the diagnosis and treatment of rheumatoid arthritis (RA). Nevertheless, reliable determination of (sub)clinical arthritis can be difficult, especially in the feet. Advanced imaging techniques may contribute to early diagnosis and therapy monitoring through sensitive detection and (quantitative) monitoring of synovitis. Previously, it has been demonstrated that macrophage imaging using (R)-[11C]PK11195 positron emission tomography (PET) allows for highly sensitive and specific imaging of RA disease activity in the hands.(1,2)Whole body macrophage PET imaging that includes the feet has not yet been evaluated in RA.Objectives:To compare whole body macrophage PET imaging to clinical assessment of arthritis activity in clinically active, early RA patients.Methods:Thirty-five previously untreated RA patients (age 54 ± 12, 51% male) with at least two clinically inflamed joints were included. They underwent a whole body (R)-[11C]PK11195 PET/computed tomography (CT) scan in addition to standard clinical assessment of number of tender and swollen joints (TJC and SJC, respectively). Two readers blinded to clinical assessment (GZ and CvdL) visually scored intensity of uptake in joints on a 0 to 3 scale. A PET positive joint score was defined at ≥ 1. Additionally, (R)-[11C]PK11195 uptake in joints was assessed quantitatively as standardized uptake values (SUV). Visual parameters were compared to clinical parameters using Cohen’s kappa, and quantitative parameters were analyzed using an independent T-test.Results:All patients showed enhanced tracer uptake in one or more joints (Figure 1). A total of 168 joints were visually PET positive, with the following distribution: 16% in the wrists, 14% in the metacarpophalangeal joints, 25% in the proximal interphalangeal joints, 4% in the ankles, 37% in the metatarsophalangeal joints. Positivity in other large joints was rare (4%). The number of discrepant findings between PET and clinical outcome (TJC and/or SJC) varied based on anatomic localization; more joints were clinically active in the hands, and more joints were active on the PET scan in the feet. Consequently, agreement between visual PET positivity and clinical activity was low, with only moderate agreement found in the ankles (κ = 0.46 and 0.41 for SJC and TJC respectively). Quantitative PET data showed a trend towards higher SUV values in joints that were clinically tender and/or swollen, reaching a significant difference in the feet (ankles + MTPs) versus SJC (Figure 2; 0.7 vs 1.0,p< 0.001). However, parts of the clinically non-affected joints also depicted moderately increased SUV values, and vice versa.Figure 1.Visual PET uptake in the left MTP5-joint.Figure 2.(R)-[11C]PK11195 (SUV) in both clinically affected and non-affected feet joints (defined as swollen yes or no).Conclusion:Whole body macrophage PET imaging showed clear uptake of (R)-[11C]PK11195 in several joints of clinically active, early RA patients, especially in MTP-joints. The best correlation between quantitative PET data and clinical assessment of swelling was observed in the feet. In general, however, PET also provided distinct information from clinical assessment, which may provide a means for detecting subclinical synovitis. We are performing longitudinal studies to further assess the value of macrophage PET in RA.References:[1]Elzinga EH, et al. J Nucl Med. 2011; 52(1): 77-80.[2]Gent YY, et al. J Rheumatology. 2014; 41: 2145-52Acknowledgments:We thank ReumaNederland and Pfizer for financial support of this investigator initiated study.Disclosure of Interests:Nicki J.F. Verweij: None declared, Marieke ter Wee: None declared, Jerney de Jongh: None declared, Gerben C.J. Zwezerijnen: None declared, Maqsood Yaqub: None declared, Maarten Boers: None declared, Alexandre Voskuyl: None declared, Adriaan A. Lammertsma: None declared, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Conny J. van der Laken: None declared
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Hardwick, Matthew J., Ming-Kai Chen, Kwamena Baidoo, Martin G. Pomper, and Tomás R. Guilarte. "In Vivo Imaging of Peripheral Benzodiazepine Receptors in Mouse Lungs: A Biomarker of Inflammation." Molecular Imaging 4, no. 4 (2005): 7290.2005.05133. http://dx.doi.org/10.2310/7290.2005.05133.
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The ability to visualize the immune response with radioligands targeted to immune cells will enhance our understanding of cellular responses in inflammatory diseases. Peripheral benzodiazepine receptors (PBR) are present in monocytes and neutrophils as well as in lung tissue. We used lipopolysaccharide (LPS) as a model of inflammation to assess whether the PBR could be used as a noninvasive marker of inflammation in the lungs. Planar imaging of mice administrated 10 or 30 mg/kg LPS showed increased [123I]-( R)-PK11195 radioactivity in the thorax 2 days after LPS treatment relative to control. Following imaging, lungs from control and LPS-treated mice were harvested for ex vivo gamma counting and showed significantly increased radioactivity above control levels. The specificity of the PBR response was determined using a blocking dose of nonradioactive PK11195 given 30 min prior to radiotracer injection. Static planar images of the thorax of nonradioactive PK11195 pretreated animals showed a significantly lower level of radiotracer accumulation in control and in LPS-treated animals ( p < .05). These data show that LPS induces specific increases in PBR ligand binding in the lungs. We also used in vivo small-animal PET studies to demonstrate increased [11C]-( R)-PK11195 accumulation in the lungs of LPS-treated mice. This study suggests that measuring PBR expression using in vivo imaging techniques may be a useful biomarker to image lung inflammation.
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Agushi, E., D. Coope, R. Hinz, A. Jackson, and F. Roncaroli. "P04.01 [11C]-(R)PK11195 PET imaging and Dynamic MRI in Transforming Gliomas." Neuro-Oncology 19, suppl_3 (2017): iii39. http://dx.doi.org/10.1093/neuonc/nox036.141.
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Gerhard, A., R. B. Banati, G. B. Goerres, et al. "[11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy." Neurology 61, no. 5 (2003): 686–89. http://dx.doi.org/10.1212/01.wnl.0000078192.95645.e6.
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Hunter, H. J. A., R. Hinz, A. Gerhard, et al. "Brain inflammation and psoriasis: a [11C]-(R)-PK11195 positron emission tomography study." British Journal of Dermatology 175, no. 5 (2016): 1082–84. http://dx.doi.org/10.1111/bjd.13788.
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van Berckel, Bart N. M., M. G. Bossong, R. Boellaard, et al. "Microglia activation in recent onset schizophrenia: A quantitative (R)-[11C]PK11195 study." NeuroImage 41 (January 2008): T119. http://dx.doi.org/10.1016/j.neuroimage.2008.04.087.
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Haarman, Bartholomeus C. M. (Benno), Rixt F. Riemersma-Van der Lek, Jan Cees de Groot, et al. "Neuroinflammation in bipolar disorder – A [11C]-(R)-PK11195 positron emission tomography study." Brain, Behavior, and Immunity 40 (August 2014): 219–25. http://dx.doi.org/10.1016/j.bbi.2014.03.016.
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van Berckel, Bart N. M., Ronald Boellaard, Marc A. Kropholler, et al. "Assessment of microglia activation in schizophrenia using [11C](R)-PK11195 and PET." Journal of Cerebral Blood Flow & Metabolism 25, no. 1_suppl (2005): S391. http://dx.doi.org/10.1038/sj.jcbfm.9591524.0391.
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Hammoud, Dima A., Christopher J. Endres, Ankit R. Chander, et al. "Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS." Journal of Neurovirology 11, no. 4 (2005): 346–55. http://dx.doi.org/10.1080/13550280500187351.
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Parente, A., P. K. Feltes, D. Vallez Garcia, et al. "Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195." Journal of Nuclear Medicine 57, no. 5 (2016): 785–91. http://dx.doi.org/10.2967/jnumed.115.165019.
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Edison, Paul, Hilary A. Archer, Alexander Gerhard, et al. "Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study." Neurobiology of Disease 32, no. 3 (2008): 412–19. http://dx.doi.org/10.1016/j.nbd.2008.08.001.
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van, der Doef Thalia F., Witte Lot D. de, Arjen L. Sutterland, et al. "In vivo (R)-[11C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis." NPJ Schizophrenia 2 (August 31, 2016): 16031. https://doi.org/10.1038/npjschz.2016.31.
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Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various <em>in vivo</em> and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer <em>(R)</em>-[<sup>11</sup>C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis <em>in vivo</em> at an early stage of the disease. <em>(R)</em>-[<sup>11</sup>C]PK11195 binding potential (BP<sub>ND</sub>) was measured in 19 patients with recent onset psychosis and 17 age and gender-matched healthy controls. Total gray matter, as well as five gray matter regions of interest (frontal cortex, temporal cortex, parietal cortex, striatum, and thalamus) were defined <em>a priori</em>. PET data were analysed using a reference tissue approach and a supervised cluster analysis algorithm to identify the reference region. No significant difference in <em>(R)</em>-[<sup>11</sup>C]PK11195 BP<sub>ND</sub> between patients and controls was found in total gray matter, nor one of the regions of interest. These findings suggest that microglia activation is not present in recent onset psychosis or that it is a subtle phenomenon that could not be detected using the design of the present study.
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Lamare, F., R. Hinz, O. Gaemperli, et al. "Detection and Quantification of Large-Vessel Inflammation with 11C-(R)-PK11195 PET/CT." Journal of Nuclear Medicine 52, no. 1 (2010): 33–39. http://dx.doi.org/10.2967/jnumed.110.079038.
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Folkersma, H., R. Boellaard, M. Yaqub, et al. "Widespread and Prolonged Increase in (R)-11C-PK11195 Binding After Traumatic Brain Injury." Journal of Nuclear Medicine 52, no. 8 (2011): 1235–39. http://dx.doi.org/10.2967/jnumed.110.084061.
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Goerres, Gerhard W., Thomas Revesz, John Duncan, and Richard B. Banati. "Imaging Cerebral Vasculitis in Refractory Epilepsy Using [11C] (R)-PK11195 Positron Emission Tomography." American Journal of Roentgenology 176, no. 4 (2001): 1016–18. http://dx.doi.org/10.2214/ajr.176.4.1761016.
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Jeon, So Yeon, Seongho Seo, Jae Sung Lee, et al. "[11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome." Medicine 96, no. 1 (2017): e5735. http://dx.doi.org/10.1097/md.0000000000005735.
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Schuitemaker, Alie, Marc A. Kropholler, Ronald Boellaard, et al. "Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study." Neurobiology of Aging 34, no. 1 (2013): 128–36. http://dx.doi.org/10.1016/j.neurobiolaging.2012.04.021.
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Turkheimer, Ferico E., P. Edison, N. Pavese, et al. "Supervised reference region extraction for the quantification of [11C]-(R)-PK11195 brain studies." NeuroImage 31 (January 2006): T18. http://dx.doi.org/10.1016/j.neuroimage.2006.04.009.
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