Publications by authors named "Rudi A J O Dierckx"

180 Publications

FDG-PET/CT in intensive care patients with bloodstream infection.

Crit Care 2021 04 7;25(1):133. Epub 2021 Apr 7.

Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is an advanced imaging technique that can be used to examine the whole body for an infection focus in a single examination in patients with bloodstream infection (BSI) of unknown origin. However, literature on the use of this technique in intensive care patients is scarce. The purpose of this study was to evaluate the diagnostic yield of FDG-PET/CT in intensive care patients with BSI.

Methods: In this retrospective cohort study, all intensive care patients from our Dutch university medical center who had culture-proven BSI between 2010 and 2020 and underwent FDG-PET/CT to find the focus of infection were included. Diagnostic performance was calculated and logistic regression analysis was performed to evaluate the association between FDG-PET/CT outcome and C-reactive protein level (CRP), leukocyte count, duration of antibiotic treatment, duration of ICU stay, quality of FDG-PET/CT, and dependency on mechanical ventilation. In addition, the impact of FDG-PET/CT on clinical treatment was evaluated.

Results: 30 intensive care patients with BSI were included. In 21 patients, an infection focus was found on FDG-PET/CT which led to changes in clinical management in 14 patients. FDG-PET/CT achieved a sensitivity of 90.9% and specificity of 87.5% for identifying the focus of infection. Poor quality of the FDG-PET images significantly decreased the likelihood of finding an infection focus as compared to reasonable or good image quality (OR 0.16, P = 0.034). No other variables were significantly associated with FDG-PET/CT outcome. No adverse events during the FDG-PET/CT procedure were reported.

Conclusion: FDG-PET/CT has a high diagnostic yield for detecting the infection focus in patients with BSI admitted to intensive care. Poor PET image quality was significantly associated with a decreased likelihood of finding the infection focus in patients with BSI. This could be improved by adequate dietary preparation and cessation of intravenous glucose and glucose-regulating drugs. Recent advances in PET/CT technology enable higher image quality with shorter imaging time and may contribute to routinely performing FDG-PET/CT in intensive care patients with BSI of unknown origin.
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http://dx.doi.org/10.1186/s13054-021-03557-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028784PMC
April 2021

PET/CT Imaging and Physiology of Mice on High Protein Diet.

Int J Mol Sci 2021 Mar 22;22(6). Epub 2021 Mar 22.

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands.

Background: High protein (HP) diets have been proposed to reduce body weight in humans. The diets are known to alter energy metabolism, which can affect the quality of [F]FDG PET heart images. In this preclinical study, we therefore explore the impact of a prolonged HP diet on myocardial [F]FDG uptake.

Methods: C57BL/6J (Black six (Bl6)) and apolipoprotein E-deficient () mice were fed chow, a HP diet, or a low protein (LP) diet for 12 weeks. At baseline and after treatment, the animals were injected with 33.0 MBq of [F]FDG and a 30 min PET/CT scan was made. Myocardial volume and [F]FDG uptake were quantified using PET and the % of body fat was calculated from CT.

Results: Myocardial [F]FDG uptake was similar for all diets at the follow-up scan but an increase between baseline and follow-up scans was noticed in the LP groups. Myocardial volume was significantly smaller in the C57BL HP group compared to the other Bl6 groups. Body weight increased less in the two HP groups compared to the chow and LP groups. Body fat percentage was significantly higher in the LP groups. This effect was stronger in C57BL mice (28.7%) compared to mice (15.1%).

Conclusions: Myocardial uptake of [F]FDG in mice is not affected by increased protein intake but [F]FDG uptake increases when the amount of protein is lowered. A lower body weight and percentage of body fat were noticed when applying a HP diet.
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http://dx.doi.org/10.3390/ijms22063236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004865PMC
March 2021

PET/CT Imaging and Physiology of Mice on High Protein Diet.

Int J Mol Sci 2021 Mar 22;22(6). Epub 2021 Mar 22.

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands.

Background: High protein (HP) diets have been proposed to reduce body weight in humans. The diets are known to alter energy metabolism, which can affect the quality of [F]FDG PET heart images. In this preclinical study, we therefore explore the impact of a prolonged HP diet on myocardial [F]FDG uptake.

Methods: C57BL/6J (Black six (Bl6)) and apolipoprotein E-deficient () mice were fed chow, a HP diet, or a low protein (LP) diet for 12 weeks. At baseline and after treatment, the animals were injected with 33.0 MBq of [F]FDG and a 30 min PET/CT scan was made. Myocardial volume and [F]FDG uptake were quantified using PET and the % of body fat was calculated from CT.

Results: Myocardial [F]FDG uptake was similar for all diets at the follow-up scan but an increase between baseline and follow-up scans was noticed in the LP groups. Myocardial volume was significantly smaller in the C57BL HP group compared to the other Bl6 groups. Body weight increased less in the two HP groups compared to the chow and LP groups. Body fat percentage was significantly higher in the LP groups. This effect was stronger in C57BL mice (28.7%) compared to mice (15.1%).

Conclusions: Myocardial uptake of [F]FDG in mice is not affected by increased protein intake but [F]FDG uptake increases when the amount of protein is lowered. A lower body weight and percentage of body fat were noticed when applying a HP diet.
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http://dx.doi.org/10.3390/ijms22063236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004865PMC
March 2021

Feasibility of pharmacokinetic parametric PET images in scaled subprofile modelling using principal component analysis.

Neuroimage Clin 2021 Mar 13;30:102625. Epub 2021 Mar 13.

University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, The Netherlands.

Scaled subprofile model using principal component analysis (SSM/PCA) is a multivariate analysis technique used, mainly in [F]-2-fluoro-2-deoxy-d-glucose (FDG) PET studies, for the generation of disease-specific metabolic patterns (DP) that may aid with the classification of subjects with neurological disorders, like Alzheimer's disease (AD). The aim of this study was to explore the feasibility of using quantitative parametric images for this type of analysis, with dynamic [C]-labelled Pittsburgh Compound B (PIB) PET data as an example. Therefore, 15 AD patients and 15 healthy control subjects were included in an SSM/PCA analysis to generate four AD-DPs using relative cerebral blood flow (R), binding potential (BP) and SUVR images derived from dynamic PIB and static FDG-PET studies. Furthermore, 49 new subjects with a variety of neurodegenerative cognitive disorders were tested against these DPs. The AD-DP was characterized by a reduction in the frontal, parietal, and temporal lobes voxel values for R and SUVR-FDG DPs; and by a general increase of values in cortical areas for BP and SUVR-PIB DPs. In conclusion, the results suggest that the combination of parametric images derived from a single dynamic scan might be a good alternative for subject classification instead of using 2 independent PET studies.
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http://dx.doi.org/10.1016/j.nicl.2021.102625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020472PMC
March 2021

The new integrated nuclear medicine and radiology residency program in the Netherlands: why do residents choose to subspecialize in nuclear medicine and why not?

J Nucl Med 2021 Mar 12. Epub 2021 Mar 12.

Medical Imaging Center, University Medical Center Groningen, Netherlands.

To explore reasons that influence a resident's choice for the nuclear medicine subspecialty in the integrated nuclear medicine and radiology residency program in the Netherlands. A web questionnaire was developed and distributed among residents in the Dutch integrated nuclear medicine and radiology training. A total of 114 residents were included. The survey results revealed four categories of incentives to choose the nuclear medicine subspecialty: 1) Expertise of nuclear medicine physicians and their quality of supervision in the training hospital, 2) Opportunities to do scientific research during and after residency, 3) Diversity of pathology, radiotracers, examinations and therapies in the training hospital, and 4) The expectation that the role of hybrid imaging will increase in the future. They also revealed four groups of disincentives to choose the nuclear medicine subspecialty: 1) Lack of collaboration and integration between nuclear medicine and radiology in some training hospitals, 2) Imbalance between nuclear medicine and radiology during the first 2.5 years of basic training during residency at the expense of nuclear medicine, 3) Uncertainty regarding the international recognition of the nuclear medicine subspecialty training, and 4) Uncertain future of nuclear medicine regarding the chances of employment and the ratio of work activities of nuclear medicine to radiology. This study provided insight into residents' motives to pursue or refrain from nuclear medicine subspecialization in an integrated nuclear medicine and radiology residency program. Medical imaging specialists in training hospitals and developers of curricula for nuclear medicine and radiology training should take these motives into account to ensure a sufficient outflow of newly graduated nuclear medicine specialists.
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http://dx.doi.org/10.2967/jnumed.120.261503DOI Listing
March 2021

Amyloid burden quantification depends on PET and MR image processing methodology.

PLoS One 2021 5;16(3):e0248122. Epub 2021 Mar 5.

Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Quantification of amyloid load with positron emission tomography can be useful to assess Alzheimer's Disease in-vivo. However, quantification can be affected by the image processing methodology applied. This study's goal was to address how amyloid quantification is influenced by different semi-automatic image processing pipelines. Images were analysed in their Native Space and Standard Space; non-rigid spatial transformation methods based on maximum a posteriori approaches and tissue probability maps (TPM) for regularisation were explored. Furthermore, grey matter tissue segmentations were defined before and after spatial normalisation, and also using a population-based template. Five quantification metrics were analysed: two intensity-based, two volumetric-based, and one multi-parametric feature. Intensity-related metrics were not substantially affected by spatial normalisation and did not significantly depend on the grey matter segmentation method, with an impact similar to that expected from test-retest studies (≤10%). Yet, volumetric and multi-parametric features were sensitive to the image processing methodology, with an overall variability up to 45%. Therefore, the analysis should be carried out in Native Space avoiding non-rigid spatial transformations. For analyses in Standard Space, spatial normalisation regularised by TPM is preferred. Volumetric-based measurements should be done in Native Space, while intensity-based metrics are more robust against differences in image processing pipelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248122PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935288PMC
March 2021

Requests for radiologic imaging: Prevalence and determinants of inadequate quality according to RI-RADS.

Eur J Radiol 2021 Apr 25;137:109615. Epub 2021 Feb 25.

Medical Imaging Center, Department of Radiology, Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address:

Purpose: To determine the prevalence and determinants of radiologic imaging requests that are of inadequate quality according to the Reason for exam Imaging Reporting and Data System (RI-RADS).

Methods: This study included a random sample of 673 radiologic examinations performed at a tertiary care center. The quality of each imaging request was graded according to RI-RADS. Ordinal regression analysis was performed to determine the association of RI-RADS grade with patient age, gender, and hospital status, indication for imaging, requesting specialty, imaging modality, body region, time of examination, and relationship with previous imaging within the past one year.

Results: RI-RADS grades A (adequate request), B (barely adequate request), C (considerably limited request), and D (deficient request) were assigned to 159 (23.6 %), 166 (24.7 %), 214 (31.8 %), and 134 (19.9 %) of cases, respectively. Indication for imaging, requesting specialty, and body region were independently significantly associated with RI-RADS grades. Specifically, routine preoperative imaging (odds ratio [OR]: 3.422, P = 0.030) and transplantation imaging requests (OR: 8.710, P = 0.000) had a higher risk of poorer RI-RADS grades, whereas infection/inflammation as indication for imaging (OR: 0.411, P = 0.002), pediatrics as requesting specialty (OR: 0.400, P = 0.007), and head (OR: 0.384, P = 0.017), spine (OR: 0.346, P = 0.016), and upper extremity (OR: 0.208, P = 0.000) as body regions had a lower risk of poorer RI-RADS grades.

Conclusion: The quality of radiologic imaging requests is inadequate in >75 % of cases, and is affected by several factors. The data from this study can be used as a baseline and benchmark for further investigation and improvement.
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http://dx.doi.org/10.1016/j.ejrad.2021.109615DOI Listing
April 2021

Allosteric Interactions between Adenosine A and Dopamine D Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging.

Int J Mol Sci 2021 Feb 9;22(4). Epub 2021 Feb 9.

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands.

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A and dopamine D receptors (R). Stimulation of AR inhibits and blockade of AR enhances DR-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of DR via its interaction with AR. Reciprocal AR/DR interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. AR and DR co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor-receptor interactions within AR/DR heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson's disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting AR/DR heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.
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http://dx.doi.org/10.3390/ijms22041719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915359PMC
February 2021

Use of population input functions for reduced scan duration whole-body Patlak F-FDG PET imaging.

EJNMMI Phys 2021 Feb 5;8(1):11. Epub 2021 Feb 5.

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Whole-body Patlak images can be obtained from an acquisition of first 6 min of dynamic imaging over the heart to obtain the arterial input function (IF), followed by multiple whole-body sweeps up to 60 min pi. The use of a population-averaged IF (PIF) could exclude the first dynamic scan and minimize whole-body sweeps to 30-60 min pi. Here, the effects of (incorrect) PIFs on the accuracy of the proposed Patlak method were assessed. In addition, the extent of mitigating these biases through rescaling of the PIF to image-derived IF values at 30-60 min pi was evaluated.

Methods: Using a representative IF and rate constants from the literature, various tumour time-activity curves (TACs) were simulated. Variations included multiplication of the IF with a positive and negative gradual linear bias over 60 min of 5, 10, 15, 20, and 25% (generating TACs using an IF different from the PIF); use of rate constants (K, k, and both K and k) multiplied by 2, 1.5, and 0.75; and addition of noise (μ = 0 and σ = 5, 10 and 15%). Subsequent Patlak analysis using the original IF (representing the PIF) was used to obtain the influx constant (K) for the differently simulated TACs. Next, the PIF was scaled towards the (simulated) IF value using the 30-60-min pi time interval, simulating scaling of the PIF to image-derived values. Influence of variabilities in IF and rate constants, and rescaling the PIF on bias in K was evaluated.

Results: Percentage bias in K observed using simulated modified IFs varied from - 16 to 16% depending on the simulated amplitude and direction of the IF modifications. Subsequent scaling of the PIF reduced these K biases in most cases (287 out of 290) to < 5%.

Conclusions: Simulations suggest that scaling of a (possibly incorrect) PIF to IF values seen in whole-body dynamic imaging from 30 to 60 min pi can provide accurate Ki estimates. Consequently, dynamic Patlak imaging protocols may be performed for 30-60 min pi making whole-body Patlak imaging clinically feasible.
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http://dx.doi.org/10.1186/s40658-021-00357-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865035PMC
February 2021

PET Agents in Dementia: An Overview.

Semin Nucl Med 2021 May 23;51(3):196-229. Epub 2021 Jan 23.

University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, the Netherlands; Ghent University, Ghent, Belgium.

This article presents an overview of imaging agents for PET that have been applied for research and diagnostic purposes in patients affected by dementia. Classified by the target which the agents visualize, seven groups of tracers can be distinguished, namely radiopharmaceuticals for: (1) Misfolded proteins (ß-amyloid, tau, α-synuclein), (2) Neuroinflammation (overexpression of translocator protein), (3) Elements of the cholinergic system, (4) Elements of monoamine neurotransmitter systems, (5) Synaptic density, (6) Cerebral energy metabolism (glucose transport/ hexokinase), and (7) Various other proteins. This last category contains proteins involved in mechanisms underlying neuroinflammation or cognitive impairment, which may also be potential therapeutic targets. Many receptors belong to this category: AMPA, cannabinoid, colony stimulating factor 1, metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), opioid (kappa, mu), purinergic (P2X7, P2Y12), sigma-1, sigma-2, receptor for advanced glycation endproducts, and triggering receptor expressed on myeloid cells-1, besides several enzymes: cyclooxygenase-1 and 2 (COX-1, COX-2), phosphodiesterase-5 and 10 (PDE5, PDE10), and tropomyosin receptor kinase. Significant advances in neuroimaging have been made in the last 15 years. The use of 2-[F]-fluoro-2-deoxy-D-glucose (FDG) for quantification of regional cerebral glucose metabolism is well-established. Three tracers for ß-amyloid plaques have been approved by the Food and Drug Administration and European Medicines Agency. Several tracers for tau neurofibrillary tangles are already applied in clinical research. Since many novel agents are in the preclinical or experimental stage of development, further advances in nuclear medicine imaging can be expected in the near future. PET studies with established tracers and tracers for novel targets may result in early diagnosis and better classification of neurodegenerative disorders and in accurate monitoring of therapy trials which involve these targets. PET data have prognostic value and may be used to assess the response of the human brain to interventions, or to select the appropriate treatment strategy for an individual patient.
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http://dx.doi.org/10.1053/j.semnuclmed.2020.12.008DOI Listing
May 2021

The Added Value of [F]FDG PET/CT in the Management of Invasive Fungal Infections.

Diagnostics (Basel) 2021 Jan 17;11(1). Epub 2021 Jan 17.

Medical Imaging Center, University of Groningen, University Medical Center Groningen, 9700 AC Groningen, The Netherlands.

Anatomy-based imaging methods are the usual imaging methods used in assessing invasive fungal infections (IFIs). [F]FDG PET/CT has also been used in the evaluation of IFIs. We assessed the added value of [F]FDG PET/CT when added to the most frequently used anatomy-based studies in the evaluation of IFIs. The study was conducted in two University Medical Centers in the Netherlands. Reports of [F]FDG PET/CT and anatomy-based imaging performed within two weeks of the [F]FDG PET/CT scan were retrieved, and the presence and sites of IFI lesions were documented for each procedure. We included 155 [F]FDG PET/CT scans performed in 73 patients. A total of 216 anatomy-based studies including 80 chest X-rays, 89 computed tomography studies, 14 magnetic resonance imaging studies, and 33 ultrasound imaging studies were studied. The anatomy-based studies were concordant with the [F]FDG PET/CT for 94.4% of the scans performed. [F]FDG PET/CT detected IFI lesions outside of the areas imaged by the anatomy-based studies in 48.6% of the scans. In 74% of the patients, [F]FDG PET/CT added value in the management of the IFIs.
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http://dx.doi.org/10.3390/diagnostics11010137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830875PMC
January 2021

Medical knowledge and clinical productivity: independently correlated metrics during radiology residency.

Eur Radiol 2021 Jan 15. Epub 2021 Jan 15.

Department of Radiology, Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700, RB, Groningen, The Netherlands.

Objective: To determine the association between medical knowledge relevant to radiology practice (as measured by the Dutch radiology progress test [DRPT]) and clinical productivity during radiology residency.

Methods: This study analyzed the results of 6 DRPTs and time period-matched clinical production points of radiology residents affiliated to a tertiary care academic medical center between 2013 and 2016. The Spearman correlation analysis was performed to determine the association between DRPT percentile scores and average daily clinical production points. Linear regression analyses were performed to determine the association of DRPT percentile scores with average daily clinical production points, adjusted for age and gender of the radiology resident, and postgraduate year.

Results: Eighty-four DRPTs with time period-matched clinical production points were included. These 84 DRPTs were made by 29 radiology residents (18 males and 11 females) with a median age of 31 years (range: 26-38 years). The Spearman correlation coefficient between DRPT percentile scores and average daily clinical production points was 0.550 (95% confidence interval: 0.381-0.694) (p < 0.001), indicating a significant moderate positive association. On multivariate analysis, average daily clinical production points (β coefficient of 0.035, p = 0.003), female gender of the radiology resident (β coefficient of 12.690, p = 0.001), and postgraduate year (β coefficient of 10.179, p < 0.001) were significantly associated with DRPT percentile scores. These three independent variables achieved an adjusted R of 0.527.

Conclusion: Clinical productivity is independently associated with medical knowledge relevant to radiology practice during radiology residency. These findings indicate that clinical productivity of a resident could be a potentially relevant metric in a radiology training program.

Key Points: • There is a significant moderate correlation between medical knowledge relevant to radiology practice and clinical productivity during radiology residency. • Medical knowledge relevant to radiology practice remains independently associated with clinical productivity during radiology residency after adjustment for postgraduate year and gender. • Clinical productivity of a resident may be regarded as a potentially relevant metric in a radiology training program.
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http://dx.doi.org/10.1007/s00330-020-07646-3DOI Listing
January 2021

Non-adherence to consensus guidelines on preoperative imaging in surgery for primary hyperparathyroidism.

Laryngoscope Investig Otolaryngol 2020 Dec 8;5(6):1247-1253. Epub 2020 Oct 8.

University of Groningen, University Medical Center Groningen, Surgical Oncology Groningen The Netherlands.

Objective: The aim of this study was to determine the adherence to consensus guidelines on preoperative imaging of patients with primary hyperparathyroidism (pHPT) in real local practice.

Methods: This was a retrospective multicenter cohort study of 411 patients undergoing parathyroidectomy for pHPT from 2007 to 2017 in three referral centers.

Results: In 286/411 patients (69%) the preoperative imaging workup adhered to guidelines (utilizing ultrasound and parathyroid scintigraphy). In patients in whom guidelines were followed 63% were discharged within one day versus 37% in whom guidelines were not followed ( < .0005). The use of a bimodality imaging workup, starting with ultrasound and parathyroid scintigraphy followed by imaging upscaling aiming for anatomical and functional concordance, was a predictor for the performance of a minimally invasive parathyroidectomy (OR 4.098, 95% CI 2.296-7.315, < .0005).

Conclusion: The level of compliance to preoperative imaging guidelines is suboptimal in this population. Patients in whom adherence was achieved showed a shorter length of stay. More education of physicians is required regarding the appropriate preoperative imaging workup in pHPT.

Level Of Evidence: 2b (individual cohort study).
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http://dx.doi.org/10.1002/lio2.464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752066PMC
December 2020

Pharmacokinetic Modeling of ()-[C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates.

Mol Pharm 2021 01 14;18(1):416-428. Epub 2020 Dec 14.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, Groningen 9713 GZ, The Netherlands.

()-[C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of ()-[C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of ()-[C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish ()-[C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of ()-[C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The ()-[C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the ()-[C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution () and the efflux constant estimations were affected by the evaluated scan durations, whereas the influx constant estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain increased significantly up to 208% ( < 0.001) and up to 159% ( < 0.001) compared with baseline scans. The values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of , calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788571PMC
January 2021

Skeletal muscle mass and sarcopenia can be determined with 1.5-T and 3-T neck MRI scans, in the event that no neck CT scan is performed.

Eur Radiol 2020 Nov 21. Epub 2020 Nov 21.

Department of Radiology, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: Cross-sectional area (CSA) measurements of the neck musculature at the level of third cervical vertebra (C3) on CT scans are used to diagnose radiological sarcopenia, which is related to multiple adverse outcomes in head and neck cancer (HNC) patients. Alternatively, these assessments are performed with neck MRI, which has not been validated so far. For that, the objective was to evaluate whether skeletal muscle mass and sarcopenia can be assessed on neck MRI scans.

Methods: HNC patients were included between November 2014 and November 2018 from a prospective data-biobank. CSAs of the neck musculature at the C3 level were measured on CT (n = 125) and MRI neck scans (n = 92 on 1.5-T, n = 33 on 3-T). Measurements were converted into skeletal muscle index (SMI), and sarcopenia was defined (SMI < 43.2 cm/m). Pearson correlation coefficients, Bland-Altman plots, McNemar test, Cohen's kappa coefficients, and interclass correlation coefficients (ICCs) were estimated.

Results: CT and MRI correlated highly on CSA and SMI (r = 0.958-0.998, p < 0.001). The Bland-Altman plots showed a nihil mean ΔSMI (- 0.13-0.44 cm/m). There was no significant difference between CT and MRI in diagnosing sarcopenia (McNemar, p = 0.5-1.0). Agreement on sarcopenia diagnosis was good with κ = 0.956-0.978 and κ = 0.870-0.933, for 1.5-T and 3-T respectively. Observer ICCs in MRI were excellent. In general, T2-weighted images had the best correlation and agreement with CT.

Conclusions: Skeletal muscle mass and sarcopenia can interchangeably be assessed on CT and 1.5-T and 3-T MRI neck scans. This allows future clinical outcome assessment during treatment irrespective of used modality.

Key Points: • Screening for low amount of skeletal muscle mass is usually measured on neck CT scans and is highly clinical relevant as it is related to multiple adverse outcomes in head and neck cancer patients. • We found that skeletal muscle mass and sarcopenia determined on CT and 1.5-T and 3-T MRI neck scans at the C3 level can be used interchangeably. • When CT imaging of the neck is missing for skeletal muscle mass analysis, patients can be assessed with 1.5-T or 3-T neck MRIs.
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http://dx.doi.org/10.1007/s00330-020-07440-1DOI Listing
November 2020

Myelin quantification with MRI: A systematic review of accuracy and reproducibility.

Neuroimage 2021 02 12;226:117561. Epub 2020 Nov 12.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Electronic address:

Objectives: Currently, multiple sclerosis is treated with anti-inflammatory therapies, but these treatments lack efficacy in progressive disease. New treatment strategies aim to repair myelin damage and efficacy evaluation of such new therapies would benefit from validated myelin imaging techniques. Several MRI methods for quantification of myelin density are available now. This systematic review aims to analyse the performance of these MRI methods.

Methods: Studies comparing myelin quantification by MRI with histology, the current gold standard, or assessing reproducibility were retrieved from PubMed/MEDLINE and Embase (until December 2019). Included studies assessed both myelin histology and MRI quantitatively. Correlation or variance measurements were extracted from the studies. Non-parametric tests were used to analyse differences in study methodologies.

Results: The search yielded 1348 unique articles. Twenty-two animal studies and 13 human studies correlated myelin MRI with histology. Eighteen clinical studies analysed the reproducibility. Overall bias risk was low or unclear. All MRI methods performed comparably, with a mean correlation between MRI and histology of R=0.54 (SD=0.30) for animal studies, and R=0.54 (SD=0.18) for human studies. Reproducibility for the MRI methods was good (ICC=0.75-0.93, R=0.90-0.98, COV=1.3-27%), except for MTR (ICC=0.05-0.51).

Conclusions: Overall, MRI-based myelin imaging methods show a fairly good correlation with histology and a good reproducibility. However, the amount of validation data is too limited and the variability in performance between studies is too large to select the optimal MRI method for myelin quantification yet.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117561DOI Listing
February 2021

A Photocleavable Contrast Agent for Light-Responsive MRI.

Pharmaceuticals (Basel) 2020 Oct 8;13(10). Epub 2020 Oct 8.

Department of Radiology, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands.

Thanks to its innocuousness and high spatiotemporal resolution, light is used in several established and emerging applications in biomedicine. Among them is the modulation of magnetic resonance imaging (MRI) contrast agents' relaxivity with the aim to increase the sensitivity, selectivity and amount of functional information obtained from this outstanding whole-body medical imaging technique. This approach requires the development of molecular contrast agents that show high relaxivity and strongly pronounced photo-responsiveness. To this end, we report here the design and synthesis of a light-activated MRI contrast agent, together with its evaluation using UV-vis spectroscopy, Fast Field Cycling (FFC) relaxometry and relaxometric measurements on clinical MRI scanners. The high relaxivity of the reported agent changes substantially upon irradiation with light, showing a 17% decrease in relaxivity at 0.23T upon irradiation with λ = 400 nm (violet) light for 60 min. On clinical MRI scanners (1.5T and 3.0T), irradiation leads to a decrease in relaxivity of 9% and 19% after 3 and 60 min, respectively. The molecular design presents an important blueprint for the development of light-activatable MRI contrast agents.
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http://dx.doi.org/10.3390/ph13100296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599822PMC
October 2020

Pharmacokinetic Modeling of [F]MC225 for Quantification of the P-Glycoprotein Function at the Blood-Brain Barrier in Non-Human Primates with PET.

Mol Pharm 2020 09 17;17(9):3477-3486. Epub 2020 Aug 17.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, Groningen 9713 GZ, the Netherlands.

[F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood-brain barrier with positron emission tomography. This study evaluates [F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant increased by 40.7% and the volume of distribution () by 30.4% after P-gp inhibition, while the efflux constant did not change significantly. Similar changes were found for all evaluated scan durations. did not depend on scan duration (10 min- = 0.2191 vs 91 min- = 0.2258), while and did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using obtained with 1-TCM. For the 91-min scan, and can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482398PMC
September 2020

Patient safety in nuclear medicine: identification of key strategic areas for vigilance and improvement.

Nucl Med Commun 2020 Nov;41(11):1111-1116

Medical Imaging Center, Department of Radiology, Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands.

Objective: To determine the types of patient safety incidents and associated harm in nuclear medicine practice.

Methods: This study included 147 patient safety incidents related to nuclear medicine practice and submitted to the incident reporting system of a tertiary care nuclear medicine department between 2014 and 2019.

Results: The top-three incident types according to the International Classification for Patient Safety (ICPS) were medication/IV fluids (36/147, 24.5%), clinical administration (28/147, 19.0%), and clinical process/procedure (27/147, 18.4%), altogether comprising 61.9% of incidents. Within the medication/IV fluids domain, half of incident subtypes were attributable to supply/ordering, omitted medicine or dose, and wrong dose/strength of frequency. Within the clinical administration domain, appointment and wrong patient represented the majority of incident subtypes. Within the clinical process/procedure domain, the majority of incident subtypes fell in the categories: specimens/results and incomplete/inadequate. There was no patient harm in 145 (98.6%) of cases, mild patient harm in 1 (0.7%) case, and in 1 (0.7%) case, it remained unclear if there was patient harm. In 4 (2.7%) cases, a Prevention Recovery Information System for Monitoring and Analysis evaluation was performed because of the high risk of reoccurrence and patient harm.

Conclusions: The majority of patient safety incidents in nuclear medicine occur in three main ICPS categories (medication/IV fluids, clinical administration, and clinical process/procedure, in order of decreasing frequency). These can be considered as key strategic areas for incident prevention and patient safety improvement. Nevertheless, the rate of actual patient harm was very low in our series.
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http://dx.doi.org/10.1097/MNM.0000000000001262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556244PMC
November 2020

Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study.

Int J Radiat Biol 2020 Sep 16;96(9):1135-1143. Epub 2020 Jul 16.

Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Purpose: Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation.

Materials And Methods: Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, F-fluorodeoxyglucose (F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-C-methyl-4,4'-diaminostilbene (C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes.

Results: Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced F-FDG uptake on day 94. C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and C-MeDAS uptake was observed in irradiated rats.

Conclusions: Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats.
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http://dx.doi.org/10.1080/09553002.2020.1787542DOI Listing
September 2020

Focused ultrasound for opening blood-brain barrier and drug delivery monitored with positron emission tomography.

J Control Release 2020 08 16;324:303-316. Epub 2020 May 16.

University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Electronic address:

Focused ultrasound (FUS) is a minimally-invasive technology used for treatment of many diseases, including diseases related to the colon, uterus, prostate, and brain. Although it has been mainly used for ablative procedures, the ability of FUS to open the blood-brain barrier (BBB) presents a promising new application. However, the mechanism of BBB opening by FUS remains unclear. This review focuses on the use of FUS to open the BBB for enhancing drug delivery and investigating how Positron Emission Tomography (PET) provides insight into the underlying mechanism.
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http://dx.doi.org/10.1016/j.jconrel.2020.05.020DOI Listing
August 2020

The Crisis After the Crisis: The Time Is Now to Prepare Your Radiology Department.

J Am Coll Radiol 2020 06 22;17(6):749-751. Epub 2020 Apr 22.

Medical Imaging Center, Department of Radiology, Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands.

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http://dx.doi.org/10.1016/j.jacr.2020.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174155PMC
June 2020

Effect of muscle depletion on survival in peripheral arterial occlusive disease: Quality over quantity.

J Vasc Surg 2020 12 21;72(6):2006-2016.e1. Epub 2020 Apr 21.

Department of Radiology, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address:

Objective: Patients with peripheral arterial occlusive disease (PAOD) have a poor prognosis and a high prevalence of comorbidity. This study investigated whether sarcopenia and/or myosteatosis negatively affect long-term survival in patients with PAOD.

Methods: This was a single-center, retrospective cohort study of 686 consecutive patients diagnosed and treated for PAOD and who underwent computed tomography scanning. Cross-sectional muscle measurements were obtained at the level of the third lumbar vertebra. Optimal stratification was used to define sex-specific and body mass index-specific cutoff values for sarcopenia and myosteatosis, respectively. The Cox proportional hazards model was used to determine the effect of sarcopenia and myosteatosis on overall survival.

Results: Sarcopenia was associated with age, body mass index, myosteatosis, malignancy, congestive heart failure, hemodialysis, and Fontaine 4 classification. Myosteatosis was associated with age, sarcopenia, type 2 diabetes mellitus, hypertension, chronic obstructive pulmonary disease, malignancy, congestive heart failure, ischemic stroke, and Fontaine 4 classification. Sarcopenia (hazard ratio [HR], 2.82; 95% confidence interval [CI], 2.05-3.86; P < .001) and myosteatosis (HR, 4.13; 95% CI, 3.03-5.63; P < .001) were both associated with reduced survival in univariable analysis. When adjusted for other prognostic markers, myosteatosis (HR, 2.09; 95% CI, 1.46-2.99; P < .001) was still associated with lower overall survival in the multivariable model, but sarcopenia (HR, 1.40; 95% CI, 0.97-2.01; P = .073) was not.

Conclusions: Muscle depletion is independently associated with a poorer overall survival in patients with PAOD. Myosteatosis is a stronger predictor than sarcopenia, which indicates that quality is more important than quantity. Results should be interpreted with caution owing to missing data on medication usage.
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http://dx.doi.org/10.1016/j.jvs.2020.03.050DOI Listing
December 2020

Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats.

Psychopharmacology (Berl) 2020 Jun 22;237(6):1595-1606. Epub 2020 Feb 22.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands.

Introduction: Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression.

Aim: The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress.

Material And Methods: Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA.

Results: RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment.

Discussion: Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.
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http://dx.doi.org/10.1007/s00213-020-05483-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239822PMC
June 2020

The Acute and Early Effects of Whole-Brain Irradiation on Glial Activation, Brain Metabolism, and Behavior: a Positron Emission Tomography Study.

Mol Imaging Biol 2020 08;22(4):1012-1020

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Purpose: Radiotherapy is a frequently applied treatment modality for brain tumors. Concomitant irradiation of normal brain tissue can induce various physiological responses. The aim of this study was to investigate whether acute and early-delayed effects of brain irradiation on glial activation and brain metabolism can be detected with positron emission tomography (PET) and whether these effects are correlated with behavioral changes.

Procedures: Rats underwent 0-, 10-, or 25-Gy whole-brain irradiation. At 3 and 31 days post irradiation, 1-(2-chlorophenyl)-N-[C]methyl-(1-methylpropyl)-3-isoquinoline carboxamide ([C]PK11195) and 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) PET scans were acquired to detect changes in glial activation (neuroinflammation) and glucose metabolism, respectively. The open-field test (OFT) was performed on days 6 and 27 to assess behavioral changes.

Results: Twenty-five-gray-irradiated rats showed higher [C]PK11195 uptake in most brain regions than controls on day 3 (striatum, hypothalamus, accumbens, septum p < 0.05), although some brain regions had lower uptake (cerebellum, parietal association/retrosplenial visual cortex, frontal association/motor cortex, somatosensory cortex, p < 0.05). On day 31, several brain regions in 25-Gy-irradiated rats still showed significantly higher [C]PK11195 uptake than controls and 10-Gy-irradiated group (p < 0.05). Within-group analysis showed that [C]PK11195 uptake in individual brain regions of 25-Gy treated rats remained stable or slightly increased between days 3 and 31. In contrast, a significant reduction (p < 0.05) in tracer uptake between days 3 and 31 was found in all brain areas of controls and 10-Gy-irradiated animals. Moreover, 10-Gy treatment led to a significantly higher [F]FDG uptake on day 3 (p < 0.05). [F]FDG uptake decreased between days 3 and 31 in all groups; no significant differences between groups were observed anymore on day 31, except for increased uptake in the hypothalamus in the 10-Gy group. The OFT did not show any significant differences between groups.

Conclusions: Non-invasive PET imaging indicated that brain irradiation induces neuroinflammation and a metabolic flare, without causing acute or early-delayed behavioral changes.
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http://dx.doi.org/10.1007/s11307-020-01483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343765PMC
August 2020

Effect of Dopamine D Receptor Antagonists on [F]-FEOBV Binding.

Mol Pharm 2020 03 17;17(3):865-872. Epub 2020 Feb 17.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, 9700RB, The Netherlands.

The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D receptor antagonists were used to assess changes in [F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate () was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted > 0.07, Cohen's 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [F]-FEOBV was significantly higher after haloperidol treatment (adjusted = 0.022, Cohen's = 2.51) than in controls. Compared to controls, the AUC of [F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted = 0.4, Cohen's = 1.77) and raclopride (adjusted = 0.052, Cohen's = 1.49) treatment, respectively. No changes in the AUC of [F]-FEOBV were found in the cerebellum (Cohen's 0.63-0.74). Raclopride treatment nonsignificantly increased in the striatum 1.3-fold compared to control rats (adjusted = 0.1, Cohen's = 1.1) while it reduced in the cerebellum by 28% (adjusted = 0.0004, Cohen's = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in in the striatum (10%, adjusted = 1, Cohen's = 0.44) and a 40-50% lower than controls in all other brain regions (adjusted < 0.0005, Cohen's = 3.3-4.7). The changes in induced by the selective D receptor antagonist raclopride can in part be quantified using [F]-FEOBV PET imaging. Haloperidol, a nonselective D/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054895PMC
March 2020

F-FDG PET/CT in the Diagnostic and Treatment Evaluation of Pediatric Posttransplant Lymphoproliferative Disorders.

J Nucl Med 2020 09 31;61(9):1307-1313. Epub 2020 Jan 31.

Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

We aimed to evaluate the diagnostic performance of F-FDG PET/CT for the detection of posttransplantation lymphoproliferative disorder (PTLD) in a pediatric population and explore its feasibility during response assessment. This retrospective study included 28 pediatric transplant recipients who underwent a total of 32 F-FDG PET/CT scans due to clinical suspicion of PTLD within an 8-y period. Pathology reports and 2 y of follow-up were used as the reference standard. Twenty-one response assessment F-FDG PET/CT scans were reevaluated according to the Lugano criteria. The diagnosis of PTLD was established in 14 patients (49%). Sensitivity, specificity, positive predictive value, and negative predictive value of F-FDG PET/CT for the detection of PTLD in children with a clinical suspicion of this disease were 50% (7/14), 100% (18/18), 100% (7/7), and 72% (18/25), respectively. False-negative results occurred in patients with PTLD in the Waldeyer's ring, cervical lymph nodes, or small bowel with either nondestructive or polymorphic PTLD. Two of 5 interim F-FDG PET/CT scans and 3 of 9 end-of-treatment F-FDG PET/CT scans were false-positive. F-FDG PET/CT had good specificity and positive predictive value but low to moderate sensitivity and negative predictive value for the detection of PTLD in a 28-pediatric-patient cohort with a clinical suspicion of this disease. False-negative results were confirmed in the Waldeyer's ring, cervical lymph nodes, and small bowel with either nondestructive or polymorphic PTLD subtypes. F-FDG PET/CT appears to have a limited role in the response assessment setting of pediatric PTLD, given the observed high proportions of false-positives both at interim and at end-of-treatment evaluations.
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http://dx.doi.org/10.2967/jnumed.119.239624DOI Listing
September 2020

Intrastriatal gradient analyses of 18F-FDOPA PET scans for differentiation of Parkinsonian disorders.

Neuroimage Clin 2020 3;25:102161. Epub 2020 Jan 3.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands.

Aim: L -3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA PET may be used to distinguish subjects with Parkinsonism from those with symptoms not originating from impaired dopaminergic transmission. However, it is not routinely utilized to discriminate Idiopathic Parkinson's disease (IPD) from Atypical Parkinsonian Disorders (APD). We investigated the potential of FDOPA PET to discriminate between IPD and APD, with a focus on the anterior-to-posterior decline in het striatum, considered to be more specific for IPD.

Materials And Methods: 18F-DOPA PET data from a total of 58 subjects were retrospectively analyzed. 28 subjects had idiopathic Parkinson's disease (14 male, 14 female; age at scan 61 +- 11,5), 13 atypical Parkinsonian disease (7 male, 6 females; age at scan: 69,6 +- 6,4) and 17 were controls (6 male, 11 female; age at scan 65,3 +-8,6). Regional striatal-to-occipital ratio's (RSOR's) were calculated, as well as multiple in-line VOI's from the caudate nucleus to the posterior part of the putamen. The linearity of anteroposterior decline was determined by a linear regression fit and associated R squared values. ROC curves were calculated to assess the diagnostic performance of these measurements. Data contralateral to the clinically most affected side were used for analysis.

Results: ROC curve analysis for differentiation between controls and Parkinsonism patients showed the highest AUC for the caudate nucleus-to-posterior putamen ratio (AUC = 0.930; p < 0.00) and for the R squared value for the linear regression fit (AUC = 0.948; p = 0.006). For discrimating IPD from APD, the highest AUC was found for the caudate nucleus-to-anterior putamen ratio (0.824; p < 0.001) CONCLUSIONS: Subregional analysis of the striatum in F-DOPA PET scans may provide additional diagnostic information in patients screened for a  presynaptic dopaminergic deficit. A more linear decrease from the head of the caudate nucleus to the posterior putamen was  present in patients with IPD, although this feature did not have additional diagnostic value over the RSOR analysis.
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http://dx.doi.org/10.1016/j.nicl.2019.102161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976972PMC
January 2021

Test-Retest Repeatability of [F]MC225-PET in Rodents: A Tracer for Imaging of P-gp Function.

ACS Chem Neurosci 2020 02 3;11(4):648-658. Epub 2020 Feb 3.

Department of Nuclear Medicine and Molecular Imaging , University of Groningen, University Medical Center Groningen , Hanzeplein 1 , P.O. Box 30001, 9713 GZ Groningen , The Netherlands.

In longitudinal PET studies, animals are repeatedly anesthetized which may affect the repeatability of PET measurements. The aim of this study was to assess the effect of anesthesia on the P-gp function as well as the reproducibility of [F]MC225 PET scans. Thus, dynamic PET scans with blood sampling were conducted in 13 Wistar rats. Seven animals were exposed to isoflurane anesthesia 1 week before the PET scan ("Anesthesia-exposed" PET). A second group of six animals was used to evaluate the reproducibility of measurements of P-gp function at the blood-brain barrier (BBB) with [F]MC225. In this group, two PET scans were made with a 1 week interval ("Test" and "Retest" PET). Pharmacokinetic parameters were calculated using compartmental models and metabolite-corrected plasma as an input function. "Anesthesia-exposed" animals showed a 28% decrease in whole-brain volume of distribution () ( < 0.001) compared to "Test", where the animals were not previously anesthetized. The at "Retest" also decreased (19%) compared to "Test" ( < 0.001). The values in whole-brain were significantly increased by 18% in "Anesthesia-exposed" ( = 0.005) and by 15% in "Retest" ( = 0.008) compared to "Test". However, no significant differences were found in the influx rate constant , which is considered as the best parameter to measure the P-gp function. Moreover, Western Blot analysis did not find significant differences in the P-gp expression of animals not pre-exposed to anesthesia ("Test") or pre-exposed animals ("Retest"). To conclude, anesthesia may affect the brain distribution of [F]MC225 but it does not affect the P-gp expression or function.
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http://dx.doi.org/10.1021/acschemneuro.9b00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034080PMC
February 2020

Modeling of [F]FEOBV Pharmacokinetics in Rat Brain.

Mol Imaging Biol 2020 08;22(4):931-939

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, P.O Box 30.001, Groningen, 9700RB, The Netherlands.

Purpose: [F]Fluoroethoxybenzovesamicol ([F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated the quantification of [F]FEOBV in rats in control conditions and after partial saturation of VAChT using plasma and reference tissue input models and test-retest reliability.

Procedure: Ninety-minute dynamic [F]FEOBV PET scans with arterial blood sampling were performed in control rats and rats pretreated with 10 μg/kg FEOBV. Kinetic analyses were performed using one- (1TCM) and two-tissue compartmental models (2TCM), Logan and Patlak graphical analyses with metabolite-corrected plasma input, reference tissue Patlak with cerebellum as reference tissue, standard uptake value (SUV) and SUV ratio (SUVR) using 60- or 90-min acquisition. To assess test-retest reliability, two dynamic [F]FEOBV scans were performed 1 week apart.

Results: The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate K showed a lower coefficient of variation (COV, 14-24 %) than the volume of distribution V (16-108 %). Patlak graphical analysis showed a good fit to the data for both acquisition times with a COV (12-27 %) comparable to the irreversible 2TCM. For 60 min, Logan analysis performed comparably to both irreversible models (COV 14-32 %) but showed lower sensitivity to VAChT saturation. Partial saturation of VAChT did not affect model selection when using plasma input. However, poor correlations were found between irreversible 2TCM and SUV and SUVR in partially saturated VAChT states. Test-retest reliability and intraclass correlation for SUV were good.

Conclusion: [F]FEOBV is best modeled using the irreversible 2TCM or Patlak graphical analysis. SUV should only be used if blood sampling is not possible.
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http://dx.doi.org/10.1007/s11307-019-01466-8DOI Listing
August 2020