| 51. |
- van Assema, Danielle M. E., et al.
(författare)
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No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds
- 2012
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 32:8, s. 1468-1471
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Tidskriftsartikel (refereegranskat)abstract
- Decreased blood-brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[C-11] verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[C-11] verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[C-11] verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
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| 52. |
- van Assema, Danielle M. E., et al.
(författare)
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P-Glycoprotein Function at the Blood-Brain Barrier : Effects of Age and Gender
- 2012
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:6, s. 771-776
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Tidskriftsartikel (refereegranskat)abstract
- PurposeP-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood–brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females. Pgp function can be quantified in vivo using (R)-[11C]verapamil and positron emission tomography. The purpose of this study was to assess global and regional effects of both age and gender on BBB Pgp function.ProceduresThirty-five healthy men and women in three different age groups were included. Sixty minutes dynamic (R)-[11C]verapamil scans with metabolite-corrected arterial plasma input curves were acquired. Grey matter time–activity curves were fitted to a validated constrained two-tissue compartment plasma input model, providing the volume of distribution (V T) of (R)-[11C]verapamil as outcome measure.ResultsIncreased V T of (R)-[11C]verapamil with aging was found in several large brain regions in men. Young and elderly women showed comparable V T values. Young women had higher V T compared with young men.ConclusionsDecreased BBB Pgp is found with aging; however, effects of age on BBB Pgp function differ between men and women.
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| 53. |
- van Assema, Daniëlle Me, et al.
(författare)
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Reproducibility of quantitative (R)-[11C]verapamil studies
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundP-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data.MethodsDynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures.ResultsAnalysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data.ConclusionThe model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model.
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| 54. |
- van der Doef, Thalia F, et al.
(författare)
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In vivo (R)-[(11)C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis.
- 2016
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Ingår i: NPJ schizophrenia. - : Springer Science and Business Media LLC. - 2334-265X. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various in vivo and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer (R)-[(11)C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis in vivo at an early stage of the disease. (R)-[(11)C]PK11195 binding potential (BPND) was measured in 19 patients with recent onset psychosis and 17 age and gender-matched healthy controls. Total gray matter, as well as five gray matter regions of interest (frontal cortex, temporal cortex, parietal cortex, striatum, and thalamus) were defined a priori. PET data were analysed using a reference tissue approach and a supervised cluster analysis algorithm to identify the reference region. No significant difference in (R)-[(11)C]PK11195 BPND between patients and controls was found in total gray matter, nor one of the regions of interest. These findings suggest that microglia activation is not present in recent onset psychosis or that it is a subtle phenomenon that could not be detected using the design of the present study.
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| 55. |
- Verbeek, Joost, et al.
(författare)
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Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil.
- 2012
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 39:4, s. 530-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: (R)-[(11)C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood-brain barrier in man. A disadvantage of (R)-[(11)C]verapamil is the fact that its main metabolite, [(11)C]D617, also enters the brain. For quantitative analysis of (R)-[(11)C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are indeed similar and, if so, whether [(11)C]D617 itself could serve as an alternative PET tracer for P-gp.METHODS: [(11)C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [(11)C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg·kg(-1), intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15 mg·kg(-1), intravenously), as well as metabolite analysis (n=4).RESULTS: The precursor for the radiosynthesis of [(11)C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [(11)C]D617 was synthesized in 58%-77% decay-corrected yield with a radiochemical purity of ≥99%. The homogeneously distributed cerebral volume of distribution (V(T)) of [(11)C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.CONCLUSION: V(T) of [(11)C]D617 was comparable to that of (R)-[(11)C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[(11)C]verapamil and [(11)C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar.
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| 56. |
- Wolfensberger, Saskia P, et al.
(författare)
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Quantification of the neurokinin 1 receptor ligand [¹¹C]R116301
- 2011
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Ingår i: Nuclear medicine communications. - 0143-3636 .- 1473-5628. ; 32:10, s. 896-902
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:Neurokinin 1 (NK1) receptors have been implicated in depression, anxiety, and pain perception. Recently, it was shown that, in the human brain, a specific NK1 receptor-related signal was obtained with the novel radioligand, [¹¹C]R116301, using positron emission tomography. The purpose of this study was to evaluate various methods for quantifying specific [¹¹C]R116301 binding.METHODS:Two dynamic 90-min [¹¹C]R116301 scans, separated by 5 h, were performed in 11 healthy volunteers. In three patients, the second scan was performed after an oral blocking dose of 125 mg of aprepitant, whereas in the other eight, no intervention was performed (test-retest). Whole striatum was used as the tissue of interest, as it has the highest density of NK1 receptors. Cerebellum was used as the reference tissue.RESULTS:Reference tissue models were stable with the simplified reference tissue model (SRTM) performing best. Average (± standard deviation) SRTM-derived mean nondisplaceable binding potential (BP(ND)) of all (first) baseline scans was 0.64±0.31 (n=11), which reduced to -0.01±0.03 (n=3) after aprepitant administration. Test-retest results showed low variability (14.0±10.7%) and excellent reliability, as indicated by the intraclass correlation coefficient (0.93). The ratio of standardized uptake values of striatum and cerebellum minus 1, an approximation of BP(ND), showed very low variability (6.2±3.1%) with excellent reliability (intraclass correlation coefficient=0.98), and correlated well with SRTM-derived BP(ND) (R²=0.96).CONCLUSION:SRTM is the model of choice for quantifying [¹¹C]R116301 binding. Semiquantitative tissue ratios hold promise for routine clinical applications.
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| 57. |
- Wolters, Emma E., et al.
(författare)
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A novel partial volume correction method for accurate quantification of [18F] flortaucipir in the hippocampus
- 2018
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Off-target binding in the choroid plexus (CP) may cause spill-in of the tau PET tracer [18F] flortaucipir into the adjacent hippocampus region. The impact of this spill-in on hippocampal uptake was assessed using a novel partial volume correction method (PVC). Methods: PVC was performed on 20 [18F] flortaucipir dynamic PET scans (10 probable AD and 10 controls). Volumes of interest (VOIs) were defined for both hippocampus and CP. The correlation between hippocampal and CP distribution volume (VT), with and without PVC, was determined. Both anatomically defined and eroded VOIs were used. Results: For controls, the correlation between hippocampal and CP VT was significantly reduced after using PVC along with an eroded VOI (r2 = 0.59, slope = 0.80 versus r2 = 0.15, slope = 0.15; difference: p < 0.05). The same was true for AD patients (p < 0.05). Conclusion: PVC together with an optimized hippocampal VOI resulted in effective reduction of CP spill-in and improved accuracy of hippocampal VT.
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| 58. |
- Wong, Yeun Ying, et al.
(författare)
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Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization
- 2011
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 4:6, s. 700-706
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn idiopathic pulmonary arterial hypertension (IPAH), increased right ventricular (RV) power is required to maintain cardiac output. For this, RV O2 consumption (MVO2) must increase by augmentation of O2 supply and/or improvement of mechanical efficiency–ratio of power output to MVO2. In IPAH with overt RV failure, however, there is evidence that O2 supply (perfusion) reserve is reduced, leaving only increase in either O2 extraction or mechanical efficiency as compensatory mechanisms. We related RV mechanical efficiency to clinical and hemodynamic parameters of RV function in patients with IPAH and associated it with glucose metabolism.Methods and ResultsThe patients included were in New York Heart Association (NYHA) class II (n=8) and class III (n=8). They underwent right heart catheterization, MRI, and H215O-, 15O2-, C15O-, and 18FDG-PET. RV power and O2 supply were similar in both groups (NYHA class II versus class III: 0.54±0.14 versus 0.47±0.12 J/s and 0.109±0.022 versus 0.128±0.026 mL O2/min per gram, respectively). RV O2 extraction was near-significantly lower in NYHA class II compared with NYHA class III (63±17% versus 75±16%, respectively, P=0.10). As a result, MVO2 was significantly lower (0.066±0.012 versus 0.092±0.010 mL O2/min per gram, respectively, P=0.006). RV efficiency was reduced in NYHA class III (13.9±3.8%) compared with NYHA class II (27.8±7.6%, P=0.001). Septal bowing, measured by MRI, correlated with RV efficiency (r=−0.59, P=0.020). No relation was found between RV efficiency and glucose uptake rate. RV mechanical efficiency and ejection fraction were closely related (r=0.81, P<0.001).ConclusionsRV failure in IPAH was associated with reduced mechanical efficiency that was partially explained by RV mechanical dysfunction but not by a metabolic shift.
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| 59. |
- Wong, Yeun Ying, et al.
(författare)
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Supine-exercise-induced oxygen supply to the right myocardium is attenuated in patients with severe idiopathic pulmonary arterial hypertension
- 2011
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 97:24, s. 2069-2074
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundImpaired right ventricular (RV) myocardial blood flow (MBF) has been associated with RV dysfunction and fatal RV failure in idiopathic pulmonary hypertension during stress. MBF and O2 extraction from myocardial capillaries (O2 extraction fraction (OEF)) influence myocardial O2 supply.ObjectiveTo determine how the baseline RV OEF affects the amount of MBF increase induced by supine exercise, the authors hypothesise that higher baseline OEF (H-OEF) results in limited O2 extraction during exercise and that MBF must therefore be increased to obtain sufficient O2.MethodsIn 18 patients with idiopathic pulmonary hypertension, baseline OEF, resting MBF and exercise-induced MBF at 40% of maximal cardiopulmonary exercise testing load were measured using positron emission tomography and [15O]O2, [15O]H2O and [15O]CO.ResultsFor the whole population, exercise increased RV MBF from 0.68±0.16 to 1.13±0.38 ml/min/g (p<0.0001). The MBF exercise-to-rest ratio (reserve) was 1.7±0.7. The median baseline OEF was 0.73 at which the patient population was split into H-OEF and lower baseline OEF (L-OEF). Baseline MBF values (0.61±0.11 and 0.74±0.17 ml/min/g, respectively) were similar, and exercise induced a significant MBF increase in both groups (p=0.0001). However, exercise-induced increase in MBF was significantly less in the H-OEF group than in the L-OEF group (0.97±0.30 and 1.30±0.39 ml/min/g, respectively, p<0.05). Moreover, H-OEF patients had lower baseline stroke volume and cardiac output than the L-OEF group (52±19 ml and 4.0±1.1 l/min vs 78±18 ml and 5.5±0.9 l/min, respectively, both p<0.05).ConclusionsH-OEF patients were hemodynamically poorer and showed a lower exercise-induced MBF increase compared to L-OEF patients, suggesting exercise-induced O2 supply limitation.
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| 60. |
- Wong, Yeun Ying, et al.
(författare)
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Systolic pulmonary artery pressure and heart rate are main determinants of oxygen consumption in the right ventricular myocardium of patients with idiopathic pulmonary arterial hypertension
- 2011
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 13:12, s. 1290-1295
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Tidskriftsartikel (refereegranskat)abstract
- AimsIncreased afterload in idiopathic pulmonary arterial hypertension (IPAH) causes right ventricular (RV) hypertrophy and failure. Since RV remodelling occurs with alterations in RV oxygen metabolism, increasing our understanding in the factors determining RV O2 consumption in IPAH is necessary. In the left ventricle, it is known that heart rate and systolic blood pressure are the main determinants of myocardial O2 consumption (MVO2). However, the normal right heart has lower oxygen extraction and perfusion than the left myocardium, and RV energy metabolism is changed in hypertrophy. Therefore, it is not obvious that the relationsships of pressure and heart rate to MVO2 hold for the overloaded human right heart. We hypothesize that systolic pulmonary artery pressure (PAP) and heart rate (HR) are the major determinants of RV MVO2 in IPAH.Methods and resultsIn 18 IPAH patients (New York Heart Association class II and III), RV MVO2 was determined using positron emission tomography and 15O tracers. PAP and HR were measured during right heart catheterization. RV MVO2 was found to be related to systolic PAP (R2 = 0.54, P < 0.001), and inversely to stroke volume (R2 = 0.32, P = 0.015) and HR (R2 = 0.32, P = 0.014). Relationships of MVO2 to the rate pressure product (RPP), i.e. systolic pressure × HR, and wall stress were R2 = 0.55, P < 0.001, and R2 = 0.30, P = 0.020, respectively. Multiple regression of MVO2 on HR and systolic PAP gave R2 = 0.59, P = 0.001.ConclusionSystolic PAP and HR are the major determinants of RV MVO2 in IPAH. A further increase of HR and PAP with IPAH progression suggests a compromised RV myocardial oxygen availability.
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