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Sökning: WFRF:(Lammertsma Adriaan A)

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1.
  • Bahce, Idris, et al. (författare)
  • Development of [11C]erlotinib Positron Emission Tomography for In Vivo Evaluation of EGF Receptor Mutational Status
  • 2013
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 183-193
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men
  • 2011
  • Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 10, s. 67-
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Parametric Methods for Dynamic (11)C-Phenytoin PET Studies.
  • 2017
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:3, s. 479-483
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Liver fat content in type 2 diabetes : relationship with hepatic perfusion and substrate metabolism.
  • 2010
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:11, s. 2747-2754
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Carriers of the hypertrophic cardiomyopathy MYBPC3 mutation are characterized by reduced myocardial efficiency in the absence of hypertrophy and microvascular dysfunction
  • 2011
  • Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 13:12, s. 1283-1289
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Effects of alcohol septal ablation on coronary microvascular function and myocardial energetics in hypertrophic obstructive cardiomyopathy
  • 2011
  • Ingår i: American Journal of Physiology. Heart and Circulatory Physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 301:1, s. H129-H137
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Right ventricular energetics in patients with hypertrophic cardiomyopathy and the effect of alcohol septal ablation
  • 2011
  • Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 17:10, s. 827-831
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • (R)-[(11)C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance : Evaluation in a rat epilepsy model
  • 2014
  • Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 85, s. 104-112
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • 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
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 64:14, s. 1464-1475
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • [11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein.
  • 2012
  • Ingår i: EJNMMI Research. - 2191-219X. ; 2, s. 12-
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Relative flow reserve derived from quantitative perfusion imaging may not outperform stress myocardial blood flow for identification of hemodynamically significant coronary artery disease
  • 2015
  • Ingår i: Circulation Cardiovascular Imaging. - 1941-9651 .- 1942-0080. ; 8:1
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • 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
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:12, s. 1974-1983
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • [C-11]quinidine and [C-11]laniquidar PET imaging in a chronic rodent epilepsy model : Impact of epilepsy and drug-responsiveness
  • 2013
  • Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 40:6, s. 764-775
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • (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
  • Ingår i: BMC medical imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 11, s. 1-
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • 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
  • Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 57:3, s. 928-37
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • 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
  • Ingår i: Nuclear medicine communications. - 0143-3636 .- 1473-5628. ; 32:1, s. 59-62
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Relation of coronary microvascular dysfunction in hypertrophic cardiomyopathy to contractile dysfunction independent from myocardial injury
  • 2011
  • Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 107:10, s. 1522-1528
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Absolute Quantification of [11C]docetaxel Kinetics in Lung Cancer Patients Using Positron Emission Tomography
  • 2011
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 17:14, s. 4814-4824
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Quantitative Parametric Perfusion Images Using 15O-Labeled Water and a Clinical PET/CT Scanner : test-retest variability in lung cancer
  • 2010
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 51:11, s. 1684-1690
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy : Implications for Scheduling of Anti-Angiogenic Drugs
  • 2012
  • Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 21:1, s. 82-91
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Toward Prediction of Efficacy of Chemotherapy : A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography
  • 2013
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:15, s. 4163-4173
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • [11C]phenytoin revisited : synthesis by [11C]CO carbonylation and first evaluation as a P-gp tracer in rats.
  • 2012
  • Ingår i: EJNMMI Research. - 2191-219X. ; 2:1, s. 36-
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • 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
  • Ingår i: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 3:1
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Amyloid-β load is related to worries, but not to severity of cognitive complaints in individuals with subjective cognitive decline : The science project
  • 2019
  • Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11:JAN
  • Tidskriftsartikel (refereegranskat)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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26.
  • Vermeltfoort, Ilse A., et al. (författare)
  • Feasibility of subendocardial and subepicardial myocardial perfusion measurements in healthy normals with (15)O-labeled water and positron emission tomography
  • 2011
  • Ingår i: Journal of Nuclear Cardiology. - : Springer Science and Business Media LLC. - 1071-3581 .- 1532-6551. ; 18:4, s. 650-656
  • Tidskriftsartikel (refereegranskat)abstract
    • Positron emission tomography (PET) enables robust and reproducible measurements of myocardial blood flow (MBF). However, the relatively limited resolution of PET till recently prohibited distinction between the subendocardial and the subepicardial layers in non-hypertrophied myocardium. Recent developments in hard- and software, however, have enabled to identify a transmural gradient difference in animal experiments. The aim of this study is to determine the feasibility of subendocardial and subepicardial MBF in normal human hearts assessed with (15)O-labeled water PET. Twenty-seven healthy subjects (mean age 41 +/- A 13 years; 11 men) were studied with (15)O-labeled water PET to quantify resting and hyperaemic (adenosine) MBF at a subendocardial and subepicardial level. In addition, cardiac magnetic resonance imaging was performed to determine left ventricular (LV) volumes and function. Mean rest MBF was 1.46 +/- A 0.49 in the subendocardium, and 1.14 +/- A 0.342 mL center dot A min(-1) center dot A g(-1) in the subepicardium (P < .001). MBF during vasodilation was augmented to a greater extent at the subepicardial level (subendocardium vs subepicardium: 3.88 +/- A 0.86 vs 4.14 +/- A 0.88 mL center dot A min(-1) center dot A g(-1), P = .013). The endocardial-to-epicardial MBF ratio decreased significantly during hyperaemia (1.35 +/- A 0.23 to 1.12 +/- A 0.20, P < .001). Hyperaemic transmural MBF was inversely correlated with left ventricular end-diastolic volume index (LVEDVI) (r (2) = 0.41, P = .0003), with greater impact however at the subendocardial level. (15)O-labeled water PET enables MBF measurements with distinction of the subendocardial and subepicardial layers in the normal human heart and correlates with LVEDVI. This PET technique may prove useful in evaluating patients with signs of ischaemia due to coronary artery disease or microvascular dysfunction.
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27.
  • Danad, Ibrahim, et al. (författare)
  • Carotid artery intima-media thickness, but not coronary artery calcium, predicts coronary vascular resistance in patients evaluated for coronary artery disease
  • 2012
  • Ingår i: European Heart Journal: Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 13:4, s. 317-323
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims There is growing evidence that coronary artery disease (CAD) affects not only the conduit epicardial coronary arteries, but also the microvascular coronary bed. Moreover, coronary microvascular dysfunction (CMVD) often precedes the stage of clinically overt epicardial CAD. Coronary artery calcium (CAC) and carotid intima-media thickness (C-IMT) measured with computed tomography (CT) and ultrasound, respectively, are among the available techniques to non-invasively assess atherosclerotic burden. An increased CAC score and C-IMT have also been associated with CMVD. It is therefore of interest to explore and compare the potential of CAC against C-IMT to predict minimal coronary vascular resistance (CVR). Methods and results We evaluated 120 patients (mean age 56 +/- 9 years, 58 men) without a documented history of CAD in whom and results obstructive CAD was excluded. All patients underwent C-IMT measurements, CAC scoring, and vasodilator stress O-15-water positron emission tomography (PET)/CT, during which the coronary flow reserve (CFR) and minimal CVR were analysed. Minimal CVR increased significantly with increasing tertiles of C-IMT (22 +/- 6, 27 +/- 11, and 28 +/- 9 mmHg mL(-1) min(-1) g(-1), P < 0.01), whereas the CFR was comparable across all C-IMT groups (P = 0.50). Minimal CVR increased significantly with an increase in CAC score (23 +/- 9, 27 +/- 8, 32 +/- 10, and 32 +/- 7 mmHg mL(-1) min(-1) g(-1). P < 0.01), whereas the CFR did not show a significant decrease with higher CAC scores (P = 0.18). Multivariable regression analysis revealed that C-IMT (P = 0.03), but not CAC, was independently associated with minimal CVR. Conclusion C-IMT, but not CAC score, independently predicts minimal CVR in patients with multiple cardiovascular risk factors and suspected of CAD.
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28.
  • Danad, Ibrahim, et al. (författare)
  • Coronary risk factors and myocardial blood flow in patients evaluated for coronary artery disease : a quantitative [15O]H2O PET/CT study
  • 2012
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:1, s. 102-112
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundThere has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [15O]H2O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD.MethodsA total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [15O]H2O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography.ResultsGlobal average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30  ml·min−1·g−1 (range 0.54–2.35  and 0.59–2.75 ml·min−1·g−1) in men and women, respectively (p < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min−1·g−1 in men and women, respectively; p = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min−1·g−1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min−1·g−1 (range 1.52–5.22 and 1.72–8.15 ml·min−1·g−1) in men and women, respectively (p < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF.ConclusionGender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.
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29.
  • Danad, Ibrahim, et al. (författare)
  • Effect of cardiac hybrid O-15-water PET/CT imaging on downstream referral for invasive coronary angiography and revascularization rate
  • 2014
  • Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 15:2, s. 170-179
  • Tidskriftsartikel (refereegranskat)abstract
    • This study evaluates the impact of hybrid imaging on referral for invasive coronary angiography (ICA) and revascularization rates. A total of 375 patients underwent hybrid O-15-water positron emission tomography (PET)/computed tomography (CT)-based coronary angiography (CTCA) imaging for the evaluation of coronary artery disease (CAD). Downstream treatment strategy within a 60-day period after hybrid PET/CTCA imaging for ICA referral and revascularization was assessed. CTCA examinations were classified as showing no (obstructive) CAD, equivocal (borderline test result), or obstructive CAD, while the PET perfusion images were classified into normal or abnormal. On the basis of CTCA imaging, 182 (49) patients displayed no (obstructive) CAD. Only 10 (5) patients who showed no (obstructive) CAD on CTCA were referred for ICA, which were all negative. An equivocal CT study was observed in 80 (21) patients, among whom 56 (70) showed normal myocardial perfusion imaging (MPI), resulting in referral rates for ICA of 18 for normal MPI and 71 for abnormal MPI, respectively. No revascularizations were performed in the presence of normal MPI, while 59 of those with abnormal MPI were revascularized. CTCA indentified obstructive CAD in 113 (30) patients accompanied in 59 (52) patients with abnormal MPI. Referral rate for ICA was 57 for normal MPI and 88 for those with abnormal MPI, resulting in revascularization rates of 26 and 72, respectively. Hybrid O-15-water PET/CTCA imaging impacts clinical decision-making with regard to referral for ICA and revascularization procedures. Particularly, in the presence of an equivocal or abnormal CTCA, MPI could guide in the decision to refer for ICA and revascularization.
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30.
  • Danad, Ibrahim, et al. (författare)
  • Impact of anatomical and functional severity of coronary atherosclerotic plaques on the transmural perfusion gradient : a [O-15]H2O PET study
  • 2014
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 35:31, s. 2094-U149
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Myocardial ischaemia occurs principally in the subendocardial layer, whereas conventional myocardial perfusion imaging provides no information on the transmural myocardial blood flow (MBF) distribution. Subendocardial perfusion measurements and quantification of the transmural perfusion gradient (TPG) could be more sensitive and specific for the detection of coronary artery disease (CAD). The current study aimed to determine the impact of lesion severity as assessed by the fractional flow reserve (FFR) on subendocardial perfusion and the TPG using [O-15]H2O positron emission tomography (PET) imaging in patients evaluated for CAD. Methods and results Sixty-six patients with anginal chest pain were prospectively enrolled and underwent [O-15] H2O myocardial perfusion PET imaging. Subsequently, invasive coronary angiography was performed and FFR obtained in all coronary arteries irrespective of the PET imaging results. Thirty (45%) patients were diagnosed with significant CAD(i.e. FFR <= 0.80), whereas on a per vessel analysis (n = 198), 53 (27%) displayed a positive FFR. Transmural hyperaemic MBF decreased significantly from 3.09 +/- 1.16 to 1.67 +/- 0.57 mL min(-1) g(-1) (P < 0.001) in non-ischaemic and ischaemic myocardium, respectively. The TPG decreased during hyperaemia when compared with baseline (1.20 +/- 0.14 vs. 0.94 +/- 0.17, P < 0.001), and was lower in arteries with a positive FFR (0.97 +/- 0.16 vs. 0.88 +/- 0.18, P < 0.01). ATPG threshold of 0.94 yielded an accuracy to detect CAD of 59%, which was inferior to transmural MBF with an optimal cutoff of 2.20 mL min(-1) g(-1) and an accuracy of 85% (P < 0.001). Diagnostic accuracy of subendocardial perfusion measurements was comparable with transmural MBF (83 vs. 85%, respectively, P = NS). Conclusion Cardiac [O-15]H2O PET imaging is able to distinguish subendocardial from subepicardial perfusion in the myocardium of normal dimensions. Hyperaemic TPG is significantly lower in ischaemic myocardium. This technique can potentially be employed to study subendocardial perfusion impairment in more detail. However, the diagnostic accuracy of subendocardial hyperaemic perfusion and TPG appears to be limited compared with quantitative transmural MBF, warranting further study.
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31.
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32.
  • de Haan, Stefan, et al. (författare)
  • Parametric imaging of myocardial viability using ¹⁵O-labelled water and PET/CT : comparison with late gadolinium-enhanced CMR
  • 2012
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:8, s. 1240-1245
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeThe perfusable tissue index (PTI) is a marker of myocardial viability. Recent technological advances have made it possible to generate parametric PTI images from a single [15O]H2O PET/CT scan. The purpose of this study was to validate these parametric PTI images.MethodsThe study population comprised 46 patients with documented or suspected coronary artery disease who were studied with [15O]H2O PET and late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR).ResultsOf the 736 myocardial segments included, 364 showed some degree of LGE. PTI and perfusable tissue fraction (PTF) diminished with increasing LGE. The areas under the curve of the PTI and PTF, used to predict (near) transmural LGE on CMR, were 0.86 and 0.87, respectively. Optimal sensitivity and specificity were 91 % and 73 % for PTI and 69 % and 87 % for PTF, respectively.ConclusionPTI and PTF assessed with a single [15O]H2O scan can be utilized as markers of myocardial viability in patients with coronary artery disease.
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33.
  • de Wilde, Arno, et al. (författare)
  • Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort : The ABIDE project
  • 2019
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. Methods: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between “AUC-consistent” and “AUC-inconsistent” patients. Results: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). Discussion: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.
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34.
  • Golla, Sandeep S V, et al. (författare)
  • Parametric Binding Images of the TSPO Ligand 18F-DPA-714.
  • 2016
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:10, s. 1543-1547
  • Tidskriftsartikel (refereegranskat)abstract
    • (18)F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of (18)F-DPA-714 binding.METHODS: Ninety-minute dynamic (18)F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input-based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images.RESULTS: Plasma-input Logan analysis (r(2) = 0.99; slope, 0.88) and spectral analysis (r(2) = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r(2) = 0.83; slope, 0.95) and reference Logan analysis (r(2) = 0.88; slope, 1.01) correlated well with nonlinear regression-based estimates.CONCLUSION: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of (18)F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.
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35.
  • Golla, Sandeep S. V., et al. (författare)
  • Partial volume correction of brain PET studies using iterative deconvolution in combination with HYPR denoising
  • 2017
  • Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Accurate quantification of PET studies depends on the spatial resolution of the PET data. The commonly limited PET resolution results in partial volume effects (PVE). Iterative deconvolution methods (IDM) have been proposed as a means to correct for PVE. IDM improves spatial resolution of PET studies without the need for structural information (e.g. MR scans). On the other hand, deconvolution also increases noise, which results in lower signal-to-noise ratios (SNR). The aim of this study was to implement IDM in combination with HighlY constrained back-PRojection (HYPR) denoising to mitigate poor SNR properties of conventional IDM.METHODS: An anthropomorphic Hoffman brain phantom was filled with an [18F]FDG solution of ~25 kBq mL-1 and scanned for 30 min on a Philips Ingenuity TF PET/CT scanner (Philips, Cleveland, USA) using a dynamic brain protocol with various frame durations ranging from 10 to 300 s. Van Cittert IDM was used for PVC of the scans. In addition, HYPR was used to improve SNR of the dynamic PET images, applying it both before and/or after IDM. The Hoffman phantom dataset was used to optimise IDM parameters (number of iterations, type of algorithm, with/without HYPR) and the order of HYPR implementation based on the best average agreement of measured and actual activity concentrations in the regions. Next, dynamic [11C]flumazenil (five healthy subjects) and [11C]PIB (four healthy subjects and four patients with Alzheimer's disease) scans were used to assess the impact of IDM with and without HYPR on plasma input-derived distribution volumes (VT) across various regions of the brain.RESULTS: In the case of [11C]flumazenil scans, Hypr-IDM-Hypr showed an increase of 5 to 20% in the regional VT whereas a 0 to 10% increase or decrease was seen in the case of [11C]PIB depending on the volume of interest or type of subject (healthy or patient). References for these comparisons were the VTs from the PVE-uncorrected scans.CONCLUSIONS: IDM improved quantitative accuracy of measured activity concentrations. Moreover, the use of IDM in combination with HYPR (Hypr-IDM-Hypr) was able to correct for PVE without increasing noise.
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36.
  • Golla, Sandeep S V, et al. (författare)
  • Quantification of [18F]DPA-714 binding in the human brain : initial studies in healthy controls and Alzheimer's disease patients
  • 2015
  • Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 35:5, s. 766-772
  • Tidskriftsartikel (refereegranskat)abstract
    • Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([(18)F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [(18)F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [(18)F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [(18)F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [(18)F]DPA-714 cannot be used for separating individual AD patients from healthy subjects, but further studies including TSPO binding status are needed to substantiate these findings.
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37.
  • Harms, Hendrik J., et al. (författare)
  • Noninvasive Quantification of Myocardial C-11-Meta-Hydroxyephedrine Kinetics
  • 2016
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:9, s. 1376-1381
  • Tidskriftsartikel (refereegranskat)abstract
    • C-11-meta-hydroxyephedrine (C-11-HED) kinetics in the myocardium can be quantified using a single-tissue-compartment model together with a metabolite-corrected arterial blood sampler input function (BSIF). The need for arterial blood sampling, however, limits clinical applicability. The purpose of this study was to investigate the feasibility of replacing arterial sampling with imaging-derived input function (IDIF) and venous blood samples. Methods: Twenty patients underwent 60-min dynamic C-11-HED PET/CT scans with online arterial blood sampling. Thirteen of these patients also underwent venous blood sampling. Data were reconstructed using both 3 dimensional row-action maximum-likelihood algorithm (3DR) and a time-of-flight (TF) list-mode reconstruction algorithm. For each reconstruction, IDIF results were compared with BSIF results. In addition, IDIF results obtained with venous blood samples and with a transformed venous-to-arterial metabolite correction were compared with results obtained with arterial metabolite corrections. Results: Correlations between IDIF- and BSIF-derived K-1 and V-T were high (r(2) > =0.89 for 3DR and TF). Slopes of the linear fits were significantly different from 1 for K-1, for both 3DR (slope = 0.94) and TF (slope = 1.06). For V-T, the slope of the linear fit was different from 1 for TF (slope = 0.93) but not for 3DR (slope = 0.98). Use of venous blood data introduced a large bias in V-T (r(2) = 0.96, slope = 0.84) and a small bias in K-1 (r(2) = 0.99, slope = 0.98). Use of a second-order polynomial venous-to-arterial transformation was robust and greatly reduced bias in V-T (r(2) = 0.97, slope = 0.99) with no effect on K-1. Conclusion: IDIF yielded precise results for both 3DR and TF. Venous blood samples can be used for absolute quantification of C-11-HED studies, provided a venous-to-arterial transformation is applied. A venous-to-arterial transformation enables noninvasive, absolute quantification of C-11-HED studies.
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38.
  • Harms, Hendrik J, et al. (författare)
  • Parametric Images of Myocardial Viability Using a Single 15O-H2O PET/CT Scan
  • 2011
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:5, s. 745-749
  • Tidskriftsartikel (refereegranskat)abstract
    • Perfusable tissue index (PTI) is a marker of myocardial viability and requires acquisition of transmission, 15O-CO, and 15O-H2O scans. The aim of this study was to generate parametric PTI images from a 15O-H2O PET/CT scan without an additional 15O-CO scan.Methods:Data from 20 patients undergoing both 15O-H2O and 15O-CO scans were used, assessing correlation between PTI based on 15O-CO (PTICO) and on fitted blood volume fractions (PTIVb). In addition, parametric PTIVb images of 10 patients undergoing 15O-H2O PET/CT scans were generated using basis-function methods and compared with PTIVb obtained using nonlinear regression. Simulations were performed to study the effects of noise on PTIVb.Results:Correlation between PTICO and PTIVb was high (r2 = 0.73). Parametric PTIVb correlated well with PTIVb obtained using nonlinear regression (r2 = 0.91). Simulations showed low sensitivity to noise (coefficient of variation < 10% at 20% noise).Conclusion:Parametric PTI images can be generated from a single 15O-H2O PET/CT scan.
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39.
  • Harms, Hendrik J, et al. (författare)
  • Quantification of [(11)C]-meta-hydroxyephedrine uptake in human myocardium
  • 2014
  • Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The aims of this study were to determine the optimal tracer kinetic model for [(11)C]-meta-hydroxyephedrine ([(11)C]HED) and to evaluate the performance of several simplified methods.METHODS: Thirty patients underwent dynamic 60-min [(11)C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (V T) data.RESULTS: The reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, V T derived using the single-tissue model correlated highly with that of the two-tissue model (r (2) = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in V T. RI and SUV can provide misleading results because of non-linear relationships with V T.CONCLUSIONS: Although the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with V T, and therefore, care has to be taken when using RI as a quantitative measure.
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40.
  • Harms, Hendrik J, et al. (författare)
  • Use of a Single 11C-Meta-Hydroxyephedrine Scan for Assessing Flow-Innervation Mismatches in Patients with Ischemic Cardiomyopathy
  • 2015
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 56:11, s. 1706-1711
  • Tidskriftsartikel (refereegranskat)abstract
    • UNLABELLED: Mismatch between areas of reduced myocardial blood flow (MBF) and reduced myocardial innervation (defect areas) may be used to estimate the risk for ventricular arrhythmias. The presence of a mismatch zone can be derived using a combined protocol consisting of both an MBF scan and an (11)C-meta-hydroxyephedrine ((11)C-HED) scan. The rate of influx from blood to myocardium (K1) of (11)C-HED is proportional to MBF and can potentially be used as an index for defining MBF defects. The aim of this study was to assess whether K1 derived from an (11)C-HED scan can be used as an index of MBF, potentially allowing for an assessment of MBF-innervation mismatch areas from a single (11)C-HED scan.METHODS: Seventeen patients with known ischemic cardiomyopathy underwent dynamic (15)O-water and (11)C-HED scans. Discrete arterial blood samples were taken during (11)C-HED scans for metabolite correction of the image-derived input function. (11)C-HED influx rate was obtained using a single-tissue-compartment model and compared with transmural MBF (MBFT), defined as MBF as measured with (15)O-water multiplied by perfusable tissue fraction. Defect sizes were obtained from parametric K1 and MBFT images, using 50% of a remote control segment as the cutoff value.RESULTS: There was a significant correlation between MBFT and K1 (y = 0.40x + 0.05 mL·g(-1)·min(-1), r = 0.80, P < 0.001), although K1 was significantly lower than MBFT (slope of the regression line significantly different from 1, P < 0.001). Correlation between MBFT and K1 defect sizes was high (y = 0.89x + 1.38%, r = 0.95, P < 0.001), with no significant difference in mean defect size based on K1 or MBFT (20.9% ± 11.3% and 20.1% ± 10.7% for MBFT and K1, respectively, P = 0.41).CONCLUSION: (11)C-HED influx rate K1 can be used as an alternative to a separate MBF scan for assessing mismatch areas between MBF and myocardial innervation.
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41.
  • Heeman, Fiona, et al. (författare)
  • [11C]PIB amyloid quantification : effect of reference region selection
  • 2020
  • Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The standard reference region (RR) for amyloid-beta (Aβ) PET studies is the cerebellar grey matter (GMCB), while alternative RRs have mostly been utilized without prior validation against the gold standard. This study compared five commonly used RRs to gold standard plasma input-based quantification using the GMCB. Methods: Thirteen subjects from a test–retest (TRT) study and 30 from a longitudinal study were retrospectively included (total: 17 Alzheimer’s disease, 13 mild cognitive impairment, 13 controls). Dynamic [11C]PiB PET (90 min) and T1-weighted MR scans were co-registered and time–activity curves were extracted for cortical target regions and the following RRs: GMCB, whole cerebellum (WCB), white matter brainstem/pons (WMBS), whole brainstem (WBS) and eroded subcortical white matter (WMES). A two-tissue reversible plasma input model (2T4k_Vb) with GMCB as RR, reference Logan and the simplified reference tissue model were used to derive distribution volume ratios (DVRs), and standardized uptake value (SUV) ratios were calculated for 40–60 min and 60–90 min intervals. Parameter variability was evaluated using TRT scans, and correlations and agreements with the gold standard (DVR from 2T4k_Vb with GMCB RR) were also assessed. Next, longitudinal changes in SUVs (both intervals) were assessed for each RR. Finally, the ability to discriminate between visually Aβ positive and Aβ negative scans was assessed. Results: All RRs yielded stable TRT performance (max 5.1% variability), with WCB consistently showing lower variability. All approaches were able to discriminate between Aβ positive and Aβ negative scans, with highest effect sizes obtained for GMCB (range − 0.9 to − 0.7), followed by WCB (range − 0.8 to − 0.6). Furthermore, all approaches provided good correlations with the gold standard (r ≥ 0.78), while the highest bias (as assessed by the regression slope) was observed using WMES (range slope 0.52–0.67), followed by WBS (range slope 0.58–0.92) and WMBS (range slope 0.62–0.91). Finally, RR SUVs were stable across a period of 2.6 years for all except WBS and WMBS RRs (60–90 min interval). Conclusions: GMCB and WCB are considered the best RRs for quantifying amyloid burden using [11C]PiB PET.
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42.
  • Knudsen, Gitte M, et al. (författare)
  • Guidelines for the content and format of PET brain data in publications and archives : A consensus paper
  • 2020
  • Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 40:8, s. 1576-1585
  • Tidskriftsartikel (refereegranskat)abstract
    • It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.
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43.
  • Lopes Alves, Isadora, et al. (författare)
  • Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging
  • 2021
  • Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer’s disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. Methods: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database (www.oasis-brains.org). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. Results: Although highly correlated to DVR (ρ =.96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). Conclusion: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.
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44.
  • Lubberink, Mark, et al. (författare)
  • Myocardial Oxygen Extraction Fraction Measured Using Bolus Inhalation of O-15-Oxygen Gas and Dynamic PET
  • 2011
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:1, s. 60-66
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to determine the accuracy of oxygen extraction fraction (OEF) measurements using a dynamic scan protocol after bolus inhalation of O-15(2). The method of analysis was optimized by investigating potential reuse of myocardial blood flow (MBF), perfusable tissue fraction, and blood and lung spillover factors derived from separate O-15-water and (CO)-O-15 scans. Methods: Simulations were performed to assess the accuracy and precision of OEF for a variety of models in which different parameters from O-15-water and (CO)-O-15 scans were reused. Reproducibility was assessed in 8 patients who underwent one 10-min dynamic scan after bolus injection of 1.1 GBq of O-15-water, two 10-min dynamic scans after bolus inhalation of 1.4 GBq of O-15(2), and a 6-min static scan after bolus inhalation of 0.8 GBq of (CO)-O-15 for region-of-interest definition. Results: Simulations showed that accuracy and precision were lowest when all parameters were determined from the O-15(2) scan. The optimal accuracy and precision of OEF were obtained when fixing MBF, perfusable tissue fraction, and blood spillover to values derived from a O-15-water scan and estimating spillover from the pulmonary gas volume using an attenuation map. Optimal accuracy and precision were confirmed in the patient study, showing an OEF test-retest variability of 13% for the whole myocardium. Correction of spillover from pulmonary gas volume requires correction of the lung time-activity curve for pulmonary blood volume, which could equally well be obtained from a O-15-water rather than (CO)-O-15 scan. Conclusion: Measurement of OEF is possible using bolus inhalation of O-15(2) and a dynamic scan protocol, with optimal accuracy and precision when other relevant parameters, such as MBF, are derived from an additional O-15-water scan.
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45.
  • Lubberink, Mark, et al. (författare)
  • Validity of Simplified 3′-Deoxy-3′-[18F]Fluorothymidine Uptake Measures for Monitoring Response to Chemotherapy in Locally Advanced Breast Cancer
  • 2012
  • Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:6, s. 777-782
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose:Positron emission tomography using 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) has been suggested as a means for monitoring response to chemotherapy. The aim of this study was to evaluate the validity of simplified uptake measures for assessing response to chemotherapy using [18F]FLT in locally advanced breast cancer (LABC).Procedures:Fifteen LABC patients underwent dynamic [18F]FLT scans both prior to and after the first cycle of chemotherapy with fluorouracil, epirubicin or doxorubicin, and cyclophosphamide. The net uptake rate constant of [18F]FLT, K i , determined by non-linear regression (NLR) of an irreversible two-tissue compartment model was used as the gold standard. In addition to Patlak graphical analysis, standardised uptake values (SUV) and tumour-to-whole blood ratio (TBR) were used for analysing [18F]FLT data. Correlations and relationships between simplified uptake measures and NLR before and after chemotherapy were assessed using regression analysis.Results: No significant differences in both pre- and post-chemotherapy relationships between any of the simplified uptake measures and NLR were found. However, changes in SUV between baseline and post-therapy scans showed a significant negative bias and slope less than one, while TBR did not.Conclusions:In LABC, TBR instead of SUV may be preferred for monitoring response to chemotherapy with [18F]FLT.
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46.
  • Perani, Daniela, et al. (författare)
  • A new perspective for advanced positron emission tomography–based molecular imaging in neurodegenerative proteinopathies
  • 2019
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260. ; 15:8, s. 1081-1103
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications.
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47.
  • Postnov, Andrey, et al. (författare)
  • Radiation Dose of the P-Glycoprotein Tracer 11C-Laniquidar.
  • 2013
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 54:12, s. 2101-2103
  • Tidskriftsartikel (refereegranskat)abstract
    • Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain may be caused by overexpression or overactivity of multidrug transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier. Laniquidar, an inhibitor of P-gp, has been labeled with (11)C for use in PET studies of P-gp expression in humans. Given potential interspecies differences in biodistribution, the purpose of this study was to ensure safe use of (11)C-laniquidar by determining the dosimetry of (11)C-laniquidar using whole-body PET studies.METHODS: Six healthy volunteers were subjected to a series of 10 whole-body PET scans within approximately 70 min. Five blood samples were taken during the series.RESULTS: High uptake of (11)C-laniquidar was seen in liver, spleen, kidneys, and lung, whereas brain uptake was low. The effective dose for (11)C-laniquidar was 4.76 ± 0.13 and 3.69 ± 0.01 μSv·MBq(-1) for women and men, respectively.CONCLUSION: Biodistribution and measured effective dose indicate that (11)C-laniquidar is a safe tracer for PET imaging, with a total dose of about 2 mSv for a brain PET/CT protocol.
  •  
48.
  • Timmers, Tessa, et al. (författare)
  • Amyloid PET and cognitive decline in cognitively normal individuals : the SCIENCe project
  • 2019
  • Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 79, s. 50-58
  • Tidskriftsartikel (refereegranskat)abstract
    • We examined the relationships between amyloid-β PET and concurrent and longitudinal cognitive performance in 107 cognitively normal individuals with subjective cognitive decline (age: 64 ± 8 years, 44% female, Mini-Mental State Examination score 29 ± 1). All underwent 90-minute dynamic [ 18 F]florbetapir PET scanning and longitudinal neuropsychological tests with a mean follow-up of 3.4 ± 3.0 years. Receptor parametric mapping was used to calculate [ 18 F]florbetapir binding potential (BP ND ), and we performed linear mixed models to assess the relationships between global [ 18 F]florbetapir BP ND and neuropsychological performance. Higher [ 18 F]florbetapir BP ND was related to lower concurrent Mini-Mental State Examination (β ± SE: −1.69 ± 0.63 p < 0.01) and to steeper rate of decline on tasks capturing memory (Rey Auditory Verbal Learning Task immediate [β ± SE −1.81 ± 0.81, p < 0.05] and delayed recall [β ± SE −1.19 ± 0.34, p < 0.01]), attention/executive functions (Stroop II [color] [β ± SE −0.02 ± 0.01, p < 0.05], Stroop III [word-color] [β ± SE −0.03 ± 0.02, p < 0.05]), and language (category fluency [β ± SE −0.04 ± 0.01, p < 0.01]). These findings suggest that higher amyloid-β load in cognitively normal individuals with subjective cognitive decline from a memory clinic is associated with lower concurrent global cognition and with faster rate of decline in a variety of cognitive domains.
  •  
49.
  • van Assema, Daniëlle ME, et al. (författare)
  • Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients : effect of polymorphisms in the ABCB1 gene
  • 2012
  • Ingår i: EJNMMI Research. - 2191-219X. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: P-glycoprotein is a blood-brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood-brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood-brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.METHODS: Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.RESULTS: In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.CONCLUSIONS: In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood-brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.
  •  
50.
  • van Assema, Danielle M. E., et al. (författare)
  • Blood-brain barrier P-glycoprotein function in Alzheimer's disease
  • 2012
  • Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135, s. 181-189
  • Tidskriftsartikel (refereegranskat)abstract
    • A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-beta from the brain may lead to these elevated amyloid-beta levels. One of the clearance pathways of amyloid-beta is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-beta. P-glycoprotein function can be assessed in vivo using (R)-[C-11]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[C-11]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 +/- 7 years, Mini-Mental State Examination 23 +/- 3), global (R)-[C-11]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 +/- 4 years, Mini-Mental State Examination 30 +/- 1). Global (R)-[C-11]verapamil binding potential values were 2.18 +/- 0.25 for patients with Alzheimer's disease and 1.77 +/- 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[C-11]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[C-11]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.
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