| 1. |
- Bahce, Idris, et al.
(author)
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Development of [11C]erlotinib Positron Emission Tomography for In Vivo Evaluation of EGF Receptor Mutational Status
- 2013
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 183-193
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Journal article (peer-reviewed)abstract
- PURPOSE: To evaluate whether, in patients with non-small cell lung carcinoma (NSCLC), tumor uptake of [(11)C]erlotinib can be quantified and imaged using positron emission tomography and to assess whether the level of tracer uptake corresponds with the presence of activating tumor EGF receptor (EGFR) mutations.EXPERIMENTAL DESIGN: Ten patients with NSCLCs, five with an EGFR exon 19 deletion, and five without were scanned twice (test retest) on the same day with an interval of at least 4 hours. Each scanning procedure included a low-dose computed tomographic scan, a 10-minute dynamic [(15)O]H(2)O scan, and a 1-hour dynamic [(11)C]erlotinib scan. Data were analyzed using full tracer kinetic modeling. EGFR expression was evaluated using immunohistochemistry.RESULTS: The quantitative measure of [(11)C]erlotinib uptake, that is, volume of distribution (V(T)), was significantly higher in tumors with activating mutations, that is, all with exon 19 deletions (median V(T), 1.76; range, 1.25-2.93), than in those without activating mutations (median V(T), 1.06; range, 0.67-1.22) for both test and retest data (P = 0.014 and P = 0.009, respectively). Good reproducibility of [(11)C]erlotinib V(T) was seen (intraclass correlation coefficient = 0.88). Intergroup differences in [(11)C]erlotinib uptake were not correlated with EGFR expression levels, nor tumor blood flow.CONCLUSION: [(11)C]erlotinib V(T) was significantly higher in NSCLCs tumors with EGFR exon 19 deletions.
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| 2. |
- Chen, Weena J Y, et al.
(author)
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Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men
- 2011
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In: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 10, s. 67-
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Journal article (peer-reviewed)abstract
- BACKGROUND:Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM.METHODS:We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma.RESULTS:T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist.CONCLUSIONS:OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities.TRIAL REGISTRATION:Current Controlled Trials ISRCTN53177482.
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| 3. |
- Mansor, Syahir, et al.
(author)
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Parametric Methods for Dynamic (11)C-Phenytoin PET Studies.
- 2017
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:3, s. 479-483
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Journal article (peer-reviewed)abstract
- In this study, the performance of various methods for generating quantitative parametric images of dynamic (11)C-phenytoin PET studies was evaluated. Methods: Double-baseline 60-min dynamic (11)C-phenytoin PET studies, including online arterial sampling, were acquired for 6 healthy subjects. Parametric images were generated using Logan plot analysis, a basis function method, and spectral analysis. Parametric distribution volume (VT) and influx rate (K1) were compared with those obtained from nonlinear regression analysis of time-activity curves. In addition, global and regional test-retest (TRT) variability was determined for parametric K1 and VT values. Results: Biases in VT observed with all parametric methods were less than 5%. For K1, spectral analysis showed a negative bias of 16%. The mean TRT variabilities of VT and K1 were less than 10% for all methods. Shortening the scan duration to 45 min provided similar VT and K1 with comparable TRT performance compared with 60-min data. Conclusion: Among the various parametric methods tested, the basis function method provided parametric VT and K1 values with the least bias compared with nonlinear regression data and showed TRT variabilities lower than 5%, also for smaller volume-of-interest sizes (i.e., higher noise levels) and shorter scan duration.
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| 4. |
- Rijzewijk, Luuk J, et al.
(author)
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Liver fat content in type 2 diabetes : relationship with hepatic perfusion and substrate metabolism.
- 2010
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:11, s. 2747-2754
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Journal article (peer-reviewed)abstract
- OBJECTIVE:Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content.RESEARCH DESIGN AND METHODS:Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%.RESULTS:Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = -0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = -0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = -0.329, P = 0.004).CONCLUSIONS:In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat on hepatic physiology.
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| 5. |
- Timmer, Stefan A J, et al.
(author)
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Carriers of the hypertrophic cardiomyopathy MYBPC3 mutation are characterized by reduced myocardial efficiency in the absence of hypertrophy and microvascular dysfunction
- 2011
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 13:12, s. 1283-1289
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Journal article (peer-reviewed)abstract
- AIMS:Next to left ventricular (LV) hypertrophy, hypertrophic cardiomyopathy (HCM) is characterized by microvascular dysfunction and reduced myocardial external efficiency (MEE). Insights into the presence of these abnormalities as early markers of disease are of clinical importance in risk stratification, and development of therapeutic approaches. Therefore, the aim was to investigate myocardial perfusion and energetics in genotype-positive, phenotype-negative HCM subjects (carriers).METHODS AND RESULTS:Fifteen carriers of an MYBPC3 mutation underwent [15O]water positron emission tomography (PET) to assess myocardial blood flow (MBF). [11C]acetate PET was performed to obtain myocardial oxygen consumption (MVO2). By use of cardiovascular magnetic resonance imaging, LV volumes and mass were defined to calculate MEE, i.e. the ratio between external work and MVO2. Eleven healthy, genotype-negative, family relatives underwent similar scanning protocols to serve as a control group. Left ventricular mass was comparable between carriers and controls (93 ± 25 vs. 99 ± 21 g, P= 0.85), as was MBF at rest (1.19 ± 0.34 vs. 1.18 ± 0.32 mL min−1 g−1, P= 0.92), and during hyperaemia (3.87 ± 0.75 vs. 3.96 ± 0.86 mL min−1 g−1, P= 0.77). Myocardial oxygen consumption averaged 0.137 ± 0.057 mL min−1 g−1 in carriers and was not significantly different from controls (0.125 ± 0.043 mL min−1 g−1, P= 0.29). Cardiac work, however, was slightly reduced in carriers (7398 ± 1384 vs. 9139 ± 2484 mmHg mL in controls, P= 0.08). As a consequence, MEE was significantly decreased in carriers (27 ± 10 vs. 36 ± 8% in controls, P= 0.02).CONCLUSION:Carriers display reduced myocardial work generation in relation to oxygen consumption, in the absence of hypertrophy and flow abnormalities. Hence, impaired myocardial energetics may constitute a primary component of HCM pathogenesis.
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| 6. |
- Timmer, Stefan A J, et al.
(author)
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Effects of alcohol septal ablation on coronary microvascular function and myocardial energetics in hypertrophic obstructive cardiomyopathy
- 2011
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In: American Journal of Physiology. Heart and Circulatory Physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 301:1, s. H129-H137
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Journal article (peer-reviewed)abstract
- This study investigated the effects of alcohol septal ablation (ASA) on microcirculatory function and myocardial energetics in patients with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract (LVOT) obstruction. In 15 HCM patients who underwent ASA, echocardiography was performed before and 6 mo after the procedure to assess the LVOT gradient (LVOTG). Additionally, [15O]water PET was performed to obtain resting myocardial blood flow (MBF) and coronary vasodilator reserve (CVR). Changes in LV mass (LVM) and volumes were assessed by cardiovascular magnetic resonance imaging. Myocardial oxygen consumption (MVVo2) was evaluated by [11C]acetate PET in a subset of seven patients to calculate myocardial external efficiency (MEE). After ASA, peak LVOTG decreased from 41 ± 32 to 23 ± 19 mmHg (P = 0.04), as well as LVM (215 ± 74 to 169 ± 63 g; P < 0.001). MBF remained unchanged (0.94 ± 0.23 to 0.98 ± 0.15 ml·min−1·g−1; P = 0.45), whereas CVR increased (2.55 ± 1.23 to 3.05 ± 1.24; P = 0.05). Preoperatively, the endo-to-epicardial MBF ratio was lower during hyperemia compared with rest (0.80 ± 0.18 vs. 1.18 ± 0.15; P < 0.001). After ASA, the endo-to-epicardial hyperemic (h)MBF ratio increased to 1.03 ± 0.26 (P = 0.02). ΔCVR was correlated to ΔLVOTG (r = −0.82; P < 0.001) and ΔLVM (r = −0.54; P = 0.04). MEE increased from 15 ± 6 to 20 ± 9% (P = 0.04). Coronary microvascular dysfunction in obstructive HCM is at least in part reversible by relief of LVOT obstruction. After ASA, hMBF and CVR increased predominantly in the subendocardium. The improvement in CVR was closely correlated to the absolute reduction in peak LVOTG, suggesting a pronounced effect of LV loading conditions on microvascular function of the subendocardium. Furthermore, ASA has favorable effects on myocardial energetics.
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| 7. |
- Timmer, S A J, et al.
(author)
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Right ventricular energetics in patients with hypertrophic cardiomyopathy and the effect of alcohol septal ablation
- 2011
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In: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 17:10, s. 827-831
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Journal article (peer-reviewed)abstract
- BACKGROUND:Diastolic dysfunction in hypertrophic cardiomyopathy (HCM) is accompanied by augmented left ventricular (LV) end-diastolic pressure, above all in the presence of LV outflow tract (LVOT) obstruction. Increased back-pressure may augment right ventricular (RV) afterload and induce an oxidative metabolic imbalance between the 2 ventricles. The aim was to study right-to-left ventricular oxidative metabolism in HCM and the effects of alcohol septal ablation (ASA).METHODS AND RESULTS:Twenty-one HCM patients were enrolled. Eleven healthy subjects served as a control group. Subjects underwent 2-dimensional echocardiography to assess LVOT gradient, left atrial size, and diastolic function. [11C]Acetate positron-emission tomography (PET) was performed to determine RVk2 and LVk2, as a noninvasive index of oxidative metabolism. Seven HCM patients with LVOT obstruction, scheduled to undergo ASA, were also studied 6 months after the procedure. RVk2 was higher in HCM patients than i control subjects (0.081 ± 0.021 min−1 vs. 0.061 ± 0.017 min−1; P = .05), whereas LVk2 was similar between groups. Consequently, RVk2/LVk2 was increased in the patients (0.85 ± 0.19 vs 0.59 ± 0.13; P = .004). In patients with obstructive HCM, ASA reduced RVk2 (0.085 ± 0.021 min−1 to 0.072 ± 0.022 min−1; P = .001). Inasmuch as LVk2 remained unaffected by the procedure, RVk2/LVk2 was decreased after ASA (0.66 ± 0.18; P = .03). The absolute change in LVOT gradient was related to the absolute change in RVk2 (r = 0.77; P = .044).CONCLUSIONS:In HCM patients, RV oxygen consumption is increased in relation to the LV. ASA reduces RV oxygen consumption in HCM patients with LVOT obstruction, suggesting that increased LV loading conditions and diastolic dysfunction play a predominant role in augmenting RV workload in these patients.
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| 8. |
- Bogdanović, Renée Marie, et al.
(author)
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(R)-[(11)C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance : Evaluation in a rat epilepsy model
- 2014
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In: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 85, s. 104-112
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Journal article (peer-reviewed)abstract
- Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[(11)C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[(11)C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.
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| 9. |
- Danad, Ibrahim, et al.
(author)
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Quantitative Assessment of Myocardial Perfusion in the Detection of Significant Coronary Artery Disease Cutoff Values and Diagnostic Accuracy of Quantitative [O-15]H2O PET Imaging
- 2014
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 64:14, s. 1464-1475
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Journal article (peer-reviewed)abstract
- BACKGROUND Recent studies have demonstrated improved diagnostic accuracy for detecting coronary artery disease (CAD) when myocardial blood flow (MBF) is quantified in absolute terms, but there are no uniformly accepted cutoff values for hemodynamically significant CAD. OBJECTIVES The goal of this study was to determine cutoff values for absolute MBF and to evaluate the diagnostic accuracy of quantitative [O-15]H2O positron emission tomography (PET). METHODS A total of 330 patients underwent both quantitative [O-15]H2O PET imaging and invasive coronary angiography in conjunction with fractional flow reserve measurements. A stenosis >90% and/or fractional flow reserve <= 0.80 was considered obstructive; a stenosis <30% and/or fractional flow reserve >0.80 was nonobstructive. RESULTS Hemodynamically significant CAD was diagnosed in 116 (41%) of 281 patients who fulfilled study criteria for CAD. Resting perfusion was 1.00 +/- 0.25 and 0.92 +/- 0.23 ml/min/g in regions supplied by nonstenotic and significantly stenosed vessels, respectively (p < 0.001). During stress, perfusion increased to 3.26 +/- 1.04 ml/min/g and 1.73 +/- 0.67 ml/min/g, respectively (p < 0.001). The optimal cutoff values were 2.3 and 2.5 for hyperemic MBF and myocardial flow reserve, respectively. For MBF, these cutoff values showed a sensitivity, specificity, and accuracy for detecting significant CAD of 89%, 84%, and 86%, respectively, at a per-patient level and 87%, 85%, and 85% at a per-vessel level. The corresponding myocardial flow reserve values were 86%, 72%, and 78% (per patient) and 80%, 82%, and 81% (per vessel). Age and sex significantly affected diagnostic accuracy of quantitative PET. CONCLUSIONS Quantitative MBF measurements with the use of [O-15]H2O PET provided high diagnostic performance, but both sex and age should be taken into account.
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| 10. |
- Froklage, Femke E, et al.
(author)
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[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein.
- 2012
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In: EJNMMI Research. - 2191-219X. ; 2, s. 12-
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Journal article (peer-reviewed)abstract
- BACKGROUND: [11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate.METHODS: [11C]Flumazenil PET scans were performed in wild type (WT) (n = 9) and Mdr1a/1b, (the genes that encode for P-gp) double knockout (dKO) (n = 10) mice, and in naive rats (n = 10). In parallel to PET scanning, [11C]flumazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [11C]flumazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [11C]flumazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [11C]flumazenil concentrations were compared in all animals (pharmacological inhibition model).RESULTS: Mdr1a/1b dKO mice had approximately 70% higher [11C]flumazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [11C]flumazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [11C]flumazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small effect on plasma clearance of flumazenil.CONCLUSIONS: The present study showed that [11C]flumazenil is a P-gp substrate in rodents. Consequently, altered cerebral [11C]flumazenil uptake, as observed in epilepsy, may not reflect solely GABAA receptor density changes but also changes in P-gp activity.
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| 11. |
- Stuijfzand, Wijnand J, et al.
(author)
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Relative flow reserve derived from quantitative perfusion imaging may not outperform stress myocardial blood flow for identification of hemodynamically significant coronary artery disease
- 2015
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In: Circulation Cardiovascular Imaging. - 1941-9651 .- 1942-0080. ; 8:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Quantitative myocardial perfusion imaging is increasingly used for the diagnosis of coronary artery disease. Quantitative perfusion imaging allows to noninvasively calculate fractional flow reserve (FFR). This so-called relative flow reserve (RFR) is defined as the ratio of hyperemic myocardial blood flow (MBF) in a stenotic area to hyperemic MBF in a normal perfused area. The aim of this study was to assess the value of RFR in the detection of significant coronary artery disease.METHODS AND RESULTS: From a clinical population of patients with suspected coronary artery disease who underwent oxygen-15-labeled water cardiac positron emission tomography and invasive coronary angiography, 92 patients with single- or 2-vessel disease were included. Intermediate lesions (diameter stenosis, 30%-90%; n=75) were interrogated by FFR. Thirty-eight (41%) vessels were deemed hemodynamically significant (>90% stenosis or FFR≤0.80). Hyperemic MBF, coronary flow reserve, and RFR were lower for vessels with a hemodynamically significant lesion (2.01±0.78 versus 2.90±1.16 mL·min(-1)·g(-1); P<0.001, 2.27±1.03 versus 3.10±1.29; P<0.001, and 0.67±0.23 versus 0.93±0.15; P<0.001, respectively). The correlation between RFR and FFR was moderate (r=0.54; P<0.01). Receiver operator characteristic curve analysis showed an area under the curve of 0.82 for RFR, which was not significantly higher compared with that for hyperemic MBF and coronary flow reserve (0.76; P=0.32 and 0.72; P=0.08, respectively).CONCLUSIONS: Noninvasive estimation of FFR by quantitative perfusion positron emission tomography by calculating RFR is feasible, yet only a trend toward a slight improvement of diagnostic accuracy compared with hyperemic MBF assessment was determined.
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| 12. |
- Syvänen, Stina, et al.
(author)
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Altered GABAA Receptor Density and Unaltered Blood-Brain Barrier Transport in a Kainate Model of Epilepsy : An In Vivo Study Using 11C-Flumazenil and PET.
- 2012
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:12, s. 1974-1983
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Journal article (peer-reviewed)abstract
- The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the γ-aminobutyric acid A (GABA(A)) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of (11)C-flumazenil PET in epilepsy. METHODS: The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA(A) receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive (11)C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 μg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan. RESULTS: GABA(A) receptor density, B(max), was estimated as 44 ± 2 ng⋅mL(-1) in the hippocampus and as 33 ± 2 ng⋅mL(-1) in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. B(max) was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, K(D), was similar in both rat groups and all brain regions and was estimated as 5.9 ± 0.9 ng⋅mL(-1). There was no difference in flumazenil transport across the blood-brain barrier between control and kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence B(max) or K(D), compared with baseline(.) CONCLUSION: B(max) was decreased in kainate-treated rats, compared with controls, but no alteration in the blood-brain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but B(max) estimates were not influenced, suggesting that (11)C-flumazenil scanning is not confounded by alterations in P-gp function.
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| 13. |
- Syvänen, Stina, et al.
(author)
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[C-11]quinidine and [C-11]laniquidar PET imaging in a chronic rodent epilepsy model : Impact of epilepsy and drug-responsiveness
- 2013
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In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 40:6, s. 764-775
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Journal article (peer-reviewed)abstract
- Introduction: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [C-11]quinidine and [C-11]laniquidar.Methods: Metabolism and brain kinetics of both [C-11]quinidine and [C-11]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar.Results: [C-11]quinidine was metabolized rapidly, whereas [C-11]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [C-11]quinidine and [C-11]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [C-11]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [C-11]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment.Conclusions: We confirmed that both [C-11]quinidine and [C-11]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [C-11]quinidine between drug-resistant and drug-sensitive animals.
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| 14. |
- Syvänen, Stina, et al.
(author)
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(R)-[11C]verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus.
- 2011
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In: BMC medical imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 11, s. 1-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.METHODS: (R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).RESULTS: All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.CONCLUSIONS: P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.
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| 15. |
- Syvänen, Stina, et al.
(author)
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Simultaneous in vivo measurements of receptor density and affinity using [11C]flumazenil and positron emission tomography : comparison of full saturation and steady state methods.
- 2011
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In: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 57:3, s. 928-37
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Journal article (peer-reviewed)abstract
- The binding of PET radiotracer [(11)C]flumazenil to the GABA(A) receptors is described by the receptor density (B(max)) and binding affinity (K(D)). The estimation of B(max) and K(D) is usually based on Scatchard analysis including at least two PET scans at steady state of various specific activities. Recently, a novel full saturation method to estimate both B(max) and K(D) was proposed, in which a saturating dose of flumazenil is given to cover a wide range of different receptor occupancies within a single scan. The aim of the present study was a direct comparison of steady state and full saturation methods for determining B(max) and K(D) of [(11)C]flumazenil in the same group of male Sprague-Dawley rats. Fourteen rats underwent 3 consecutive [(11)C]flumazenil scans of 30 min duration each. A tracer dose was injected at the start of the first scan. Prior to the second scan the tracer was mixed with 5, 20, 100 or 500 μg unlabelled (cold) flumazenil to cover a wide range of receptor occupancies during the scan. The third scan was performed during a constant intravenous infusion of unlabelled flumazenil, resulting in ~50% GABA(A) receptor occupancy. The first and third scans were part of the steady state method, whilst the second scan was performed according to the full saturation method. For both methods, B(max) and K(D) were then derived by compartmental modelling. Both methods yielded similar B(max) and K(D) estimates. The full saturation method yielded B(max) values of 37 ± 5.8 ng · mL(-1) and K(D) values of 7.6 ± 2.0 ng · mL(-1), whilst the steady state method yielded B(max) values of 33 ± 5.4 ng · mL(-1) and K(D) values of 7.1 ± 0.8 ng · mL(-1). The main advantage of the full saturation method is that B(max) and K(D) can be obtained from a single PET scan.
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| 16. |
- Timmer, Stefan A J, et al.
(author)
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Reappraisal of a single-tissue compartment model for estimation of myocardial oxygen consumption by [11C]acetate PET : an alternative to conventional monoexponential curve fitting
- 2011
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In: Nuclear medicine communications. - 0143-3636 .- 1473-5628. ; 32:1, s. 59-62
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Journal article (peer-reviewed)abstract
- Background:Myocardial washout kinetics of carbon-11 labelled acetate ([11C]acetate) by positron emission tomography (PET) closely correlate with myocardial oxygen consumption (MVO2). Analysis of the tissue time activity curve by conventional monoexponential curve fitting, however, does not account for spillover effects and recirculating 11C activity. In theory, a compartment model considering variations of the arterial input function and metabolic 11C contamination, could improve consistency of MVO2 estimations. The objective of the study was to investigate this hypothesis.Methods: Nineteen healthy volunteers were studied under resting conditions with [11C]acetate PET. Time activity curves were analysed by automated monoexponential curve fitting and a single-tissue compartment model to obtain Kmono and k2, as noninvasive indices of MVO2. Subsequently, Kmono and k2 were related to the rate-pressure product, as an indirect marker of MVO2.Results:The rate-pressure product was significantly correlated to Kmono (r=0.46, P=0.047) and k2 (r=0.75, P<0.001).Conclusion:The results of this study suggest that a single-tissue compartment model yields more accurate noninvasive estimates of MVO2 by the use of [11C]acetate PET in humans, in comparison with monoexponential curve fitting.
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| 17. |
- Timmer, Stefan A J, et al.
(author)
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Relation of coronary microvascular dysfunction in hypertrophic cardiomyopathy to contractile dysfunction independent from myocardial injury
- 2011
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In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 107:10, s. 1522-1528
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Journal article (peer-reviewed)abstract
- We studied the spatial relations among hyperemic myocardial blood flow (hMBF), contractile function, and morphologic tissue alterations in 19 patients with hypertrophic cardiomyopathy (HC). All patients were studied with oxygen-15 water positron emission tomography during rest and adenosine administration to assess myocardial perfusion. Cardiovascular magnetic resonance was performed to derive delayed contrast-enhanced images and to calculate contractile function (Ecc) with tissue tagging. Eleven healthy subjects underwent similar positron emission tomographic and cardiovascular magnetic resonance scanning protocols and served as a control group. In the HC group, hMBF averaged 2.46 ± 0.91 ml/min/g and mean Ecc was −14.7 ± 3.4%, which were decreased compared to the control group (3.97 ± 1.48 ml/min/g and −17.7 ± 3.2%, respectively, p <0.001 for the 2 comparisons). Delayed contrast enhancement (DCE) was present only in patients with HC, averaging 6.2 ± 10.3% of left ventricular mass. In the HC group, Ecc and DCE in the septum (−13.7 ± 3.6% and 10.2 ± 13.6%) significantly differed from the lateral wall (−16.0 ± 2.8% and 2.4 ± 5.9%, p <0.001 for the 2 comparisons). In general, hMBF and Ecc were decreased in segments displaying DCE compared to nonenhanced segments (p <0.001 for the comparisons). In the HC group, univariate analysis revealed relations of hMBF to Ecc (r = −0.45, p <0.001) and DCE (r = −0.31, p <0.001). Multivariate analysis revealed that Ecc was independently related to hMBF (beta −0.37, p <0.001) and DCE (beta 0.28, p <0.001). In conclusion, in HC hMBF is impaired and related to contractile function independent from presence of DCE. When present, DCE reflected a progressed disease state as characterized by an increased perfusion deficit and contractile dysfunction.
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| 18. |
- van der Veldt, Astrid A M, et al.
(author)
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Absolute Quantification of [11C]docetaxel Kinetics in Lung Cancer Patients Using Positron Emission Tomography
- 2011
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 17:14, s. 4814-4824
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Journal article (peer-reviewed)abstract
- Purpose:Tumor resistance to docetaxel may be associated with reduced drug concentrations in tumor tissue. Positron emission tomography (PET) allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to therapy. The primary objective was to evaluate the feasibility of quantitative [11C]docetaxel PET scans in lung cancer patients. The secondary objective was to investigate whether [11C]docetaxel kinetics were associated with tumor perfusion, tumor size, and dexamethasone administration.Experimental Design:Thirty-four lung cancer patients underwent dynamic PET–computed tomography (CT) scans using [11C]docetaxel. Blood flow was measured using oxygen-15 labeled water. The first 24 patients were premedicated with dexamethasone. For quantification of [11C]docetaxel kinetics, the optimal tracer kinetic model was developed and a noninvasive procedure was validated.Results:Reproducible quantification of [11C]docetaxel kinetics in tumors was possible using a noninvasive approach (image derived input function). Thirty-two lesions (size ≥4 cm3) were identified, having a variable net influx rate of [11C]docetaxel (range, 0.0023–0.0229 mL·cm−3·min−1). [11C]docetaxel uptake was highly related to tumor perfusion (Spearman's ρ = 0.815;P < 0.001), but not to tumor size (Spearman's ρ = −0.140; P = 0.446). Patients pretreated with dexamethasone showed lower [11C]docetaxel uptake in tumors (P = 0.013). Finally, in a subgroup of patients who subsequently received docetaxel therapy, relative high [11C]docetaxel uptake was related with improved tumor response.Conclusions:Quantification of [11C]docetaxel kinetics in lung cancer was feasible in a clinical setting. Variable [11C]docetaxel kinetics in tumors may reflect differential sensitivity to docetaxel therapy. Our findings warrant further studies investigating the predictive value of [11C]docetaxel uptake and the effects of comedication on [11C]docetaxel kinetics in tumors.
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| 19. |
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| 20. |
- van der Veldt, Astrid A M, et al.
(author)
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Quantitative Parametric Perfusion Images Using 15O-Labeled Water and a Clinical PET/CT Scanner : test-retest variability in lung cancer
- 2010
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 51:11, s. 1684-1690
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Journal article (peer-reviewed)abstract
- Quantification of tumor perfusion using radioactive water (H215O) and PET is a promising method for monitoring treatment with antiangiogenic agents. However, use of dynamic H215O scans together with a fully 3-dimensional clinical PET/CT scanner needs to be validated. The purpose of the present study was to assess validity and reproducibility of dynamic H215O PET/CT scans for measuring tumor perfusion and validate the quantitative accuracy of parametric perfusion images.Methods:Eleven patients with non–small cell lung cancer were included in this study. Patients underwent 2 dynamic H215O (370 MBq) PET scans on the same day. During the first scan, arterial blood was withdrawn continuously. Input functions were derived from blood sampler data and the ascending aorta as seen in the images themselves (image-derived input function [IDIF]). Parametric perfusion images were computed using a basis function implementation of the standard single-tissue-compartment model. Volumes of interest (VOIs) were delineated on low-dose CT (LD-CT) and parametric perfusion images.Results:VOIs could be accurately delineated on both LD-CT and parametric perfusion images. These parametric perfusion images had excellent image quality and quantitative accuracy when compared with perfusion values determined by nonlinear regression. Good correlation between perfusion values derived from the blood sampler input function and IDIF was found (Pearson correlation coefficient, r = 0.964; P < 0.001). Test–retest variability of tumor perfusion was 16% and 20% when delineated on LD-CT and parametric perfusion images, respectively.Conclusion:The use of ascending aorta IDIFs is an accurate alternative to arterial blood sampling for quantification of tumor perfusion. Image quality obtained with a clinical PET/CT scanner enables generation of accurate parametric perfusion images. VOIs delineated on LD-CT have the highest reproducibility, and changes of more than 16% in tumor perfusion are likely to represent treatment effects.
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| 21. |
- van der Veldt, Astrid A. M., et al.
(author)
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Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy : Implications for Scheduling of Anti-Angiogenic Drugs
- 2012
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 21:1, s. 82-91
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Journal article (peer-reviewed)abstract
- Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([11C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [11C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.
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| 22. |
- van der Veldt, Astrid A. M., et al.
(author)
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Toward Prediction of Efficacy of Chemotherapy : A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography
- 2013
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:15, s. 4163-4173
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Journal article (peer-reviewed)abstract
- Purpose:Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([11C]docetaxel). The objective of this study was to investigate whether a [11C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel.Experimental Design:Docetaxel-naïve lung cancer patients underwent 2 [11C]docetaxel PET scans; one after bolus injection of [11C]docetaxel and another during combined infusion of [11C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2). Compartmental and spectral analyses were used to quantify [11C]docetaxel tumor kinetics. [11C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans.Results:Net rates of influx (Ki) of [11C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [11C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [11C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [11C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = −0.800; P = 0.010).Conclusions:Microdosing data of [11C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.
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| 23. |
- Verbeek, Joost, et al.
(author)
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[11C]phenytoin revisited : synthesis by [11C]CO carbonylation and first evaluation as a P-gp tracer in rats.
- 2012
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In: EJNMMI Research. - 2191-219X. ; 2:1, s. 36-
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Journal article (peer-reviewed)abstract
- ABSTRACT: BACKGROUND: At present, several positron emission tomography (PET) tracers are in use for imaging Pglycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [11C]phenytoin and to characterize its properties as a P-gp tracer. METHODS: [11C]CO was used to synthesize [11C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [11C]phenytoin were studied in rats. Effects of P-gp function on [11C]phenytoin uptake were assessed using predosing with tariquidar. RESULTS: [11C]phenytoin was synthesized via [11C]CO in an overall decay-corrected yield of 22 +/- 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [11C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [11C]phenytoin. CONCLUSIONS: Using [11C]CO, the radiosynthesis of [11C]phenytoin could be improved. [11C]phenytoin appeared to be a rather weak P-gp substrate.
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| 24. |
- Verbeek, Joost, et al.
(author)
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Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression
- 2018
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In: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 3:1
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Journal article (peer-reviewed)abstract
- Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.Results: [18F]2-(4-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]5) and [18F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]6) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [18F]5 and [18F]6 were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [18F]6 appeared to be metabolically unstable in vivo, while [18F]5 showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [18F]5 across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.Conclusion: In conclusion, [18F]5 and [18F]6 were successfully and reproducibly synthesized, albeit with low radiochemical yields. [18F]5 appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.
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| 25. |
- Verfaillie, Sander C.J., et al.
(author)
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Amyloid-β load is related to worries, but not to severity of cognitive complaints in individuals with subjective cognitive decline : The science project
- 2019
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In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11:JAN
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Journal article (peer-reviewed)abstract
- Objective: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer's Disease (AD). Early disease processes, such as amyloid-β aggregation measured with quantitative PET, may help to explain the phenotype of SCD. The aim of this study was to investigate whether quantitative amyloid-β load is associated with both self- and informant-reported cognitive complaints and memory deficit awareness in individuals with SCD. Methods: We included 106 SCD patients (mean ± SD age: 64 ± 8, 45%F) with 90 min dynamic [ 18 F]florbetapir PET scans. We used the following questionnaires to assess SCD severity: cognitive change index (CCI, self and informant reports; 2 × 20 items), subjective cognitive functioning (SCF, four items), and five questions “Do you have complaints?” (yes/no) for memory, attention, organization and language), and “Does this worry you? (yes/no).” The Rivermead Behavioral Memory Test (RBMT)-Stories (immediate and delayed recall) was used to assess objective episodic memory. To investigate the level of self-awareness, we calculated a memory deficit awareness index (Z-transformed (inverted self-reported CCI minus episodic memory); higher index, heightened self-awareness) and a self-proxy index (Z-transformed self- minus informant-reported CCI). Mean cortical [ 18 F]florbetapir binding potential (BPND) was derived from the PET data. Logistic and linear regression analyses, adjusted for age, sex, education, and depressive symptoms, were used to investigate associations between BPND and measures of SCD. Results: Higher mean cortical [ 18 F]florbetapir BPND was associated with SCD-related worries (odds ratio = 1.76 [95%CI = 1.07 ± 2.90]), but not with other SCD questionnaires (informant and self-report CCI or SCF, total scores or individual items, all p > 0.05). In addition, higher mean cortical [ 18 F]florbetapir BPND was associated with a higher memory deficit awareness index (Beta = 0.55), with an interaction between BPND and education (p = 0.002). There were no associations between [ 18 F]florbetapir BPND and self-proxy index (Beta = 0.11). Conclusion: Amyloid-β deposition was associated with SCD-related worries and heightened memory deficit awareness (i.e., hypernosognosia), but not with severity of cognitive complaints. Our findings indicate that worries about self-perceived decline may reflect an early symptom of amyloid-β related pathology rather than subjective cognitive functioning.
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