Atm Willemsen

Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography

1 Homozygously mdr1a gene disrupted mice (mdr1a(−/−) mice) and wild type mice (mdr1a(+/+) mice) were used to develop a method for P‐glycoprotein (P‐gp) function imaging non‐invasively and to study the effect of a P‐gp reversal agent on its function in vivo. 2 [11C]verapamil (0.1 mg/kg) was administered and the changes in tissue concentrations were determined ex vivo by organ extirpation and in vivo with PET. To block P‐gp function, cyclosporin A was administered. 3 Biodistribution studies revealed 9.5‐fold (P<0.001) and 3.4‐fold (P<0.001) higher [11C]verapamil in the brain and testes of mdr1a(−/−) mice than in mdr1a(+/+) mice. Cyclosporin A (25 mg/kg) increased [11C]verapamil levels in the brain and testes of mdr1a(+/+) mice in both cases 3.3‐fold (P<0.01 (brain); P<0.001 (testes)). Fifty mg/kg cyclosporin A increased [11C]verapamil in the brain 10.6‐fold (P<0.01) and in the testes 4.1‐fold (P<0.001). No increases were found in the mdr1a(−/−) mice. This indicates complete inhibition of P‐gp mediated [11C]verapamil efflux. 4 Positron camera data showed lower [11C]verapamil levels in the brain of mdr1a(+/+) mice compared to those in mdr1a(−/−) mice. [11C]verapamil accumulation in the brain of mdr1a(+/+) mice was increased by cyclosporin A to levels comparable with those in mdr1a(−/−) mice, indicating that reversal of P‐gp mediated efflux can be monitored by PET. 5 We conclude that cyclosporin A can fully block the P‐gp function in the blood brain barrier and the testes and that PET enables the in vivo measurement of P‐gp function and reversal of its function non‐invasively.

One brain, two selves

Having a sense of self is an explicit and high-level functional specialization of the human brain. The anatomical localization of self-awareness and the brain mechanisms involved in consciousness were investigated by functional neuroimaging different emotional mental states of core consciousness in patients with Multiple Personality Disorder (i.e., Dissociative Identity Disorder (DID)). We demonstrate specific changes in localized brain activity consistent with their ability to generate at least two distinct mental states of self-awareness, each with its own access to autobiographical trauma-related memory. Our findings reveal the existence of different regional cerebral blood flow patterns for different senses of self. We present evidence for the medial prefrontal cortex (MPFC) and the posterior associative cortices to have an integral role in conscious experience.

Automated ejection fraction determination from gated myocardial FDG-PET data

BackgroundThe aim of this study was to determine the potential of the automated calculation of the left ventricular ejection fraction from gated myocardial positron emission tomography (PET) scans.MethodsWe retrospectively analyzed the data of 20 patients who underwent both gated fluorine 18 deoxyglucose (FDG)-PET and equilibrium radionuclide angiography (ERNA). Gated PET data were analyzed by 2 independent programs (ie, quantitative gated single photon emission computed tomography [QGS]) originally developed for gated single photon emission computed tomography studies and functional polarmap (FPM) originally developed for the analysis of (functional) dynamic PET studies. ERNA data were used as the gold standard.ResultsBoth QGS and FPM left ventricular ejection fraction results correlated highly with ERNA (y=0.90 × x-5.9, r =0.86, P <.0001; y =0.80 × x+3.3, r = 0.84, P < .0001, respectively). The correlation between FPM and QGS left ventricular ejection fraction results was even higher (y=0.89 × x+8.6, r=0.97, P<.0001). Bland-Altman plots showed systematic differences in the left ventricular ejection fraction of −9.6%±7.5% (QGS vs ERNA), −3.8%±7.8% (FPM vs ERNA), and −5.8%±3.5% (QGS vs FPM). Further comparison of the left ventricular volumes revealed systematic difference between QGS and FPM. Our results indicate that the correlation between the different left ventricular ejection fractions shows little sensitivity to errors in the left ventricular volumes; however, the exact relationship is influenced by these errors.ConclusionIt is concluded that the automated determination of the left ventricular ejection fraction from gated PET data has significant potential; its results are highly and significantly correlated with ERNA. However, the methods presented here require additional calibration before final accuracy and clinical applicability can be determined.

Interscan displacement-induced variance in PET activation data is excluded by a scan-specific attenuation correction.

In PET activation studies, linear changes in regional cerebral blood flow may be caused by subject interscan displacements rather than by changes in cognitive state. The aim of this study was to investigate the impact of these artifacts and to assess whether they can be removed by applying a scan-specific calculated attenuation correction (CAC) instead of the default measured attenuation correction (MAC). Two independent data sets were analyzed, one with large (data I) and one with small (data II) interscan displacements. After attenuation correction (CAC or MAC), data were analyzed using SPM99. Interscan displacement parameters (IDP), obtained during scan realignment, were included as additional regressors in the General Linear Model and their impact was assessed by variance statistics revealing the affected brain volume. For data I, this volume reduced dramatically from 579 to 12 cm(3) (approximately 50-fold) at P(uncorr) </= 0.001 and from 100 to 0 cm(3) at P(corr) </= 0.05 when CAC was applied instead of MAC. Surprisingly, for data II, applying CAC instead of MAC still resulted in a substantial (approximately 10-fold) reduction of the affected volume from 23 to 2 cm(3) at P(uncorr) </= 0.001. We conclude that interscan displacement-induced variance can be prevented by applying a (realigned attenuation correction scan (e.g., CAC). With MAC data, introducing IDP covariates is not an alternative since they model only this variance. Even in data with minor interscan displacements, applying a (realigned attenuation correction method (e.g., CAC) is superior to a nonaligned MAC with IDP covariates.

Iterative versus Filtered Backprojection Reconstruction for Statistical Parametric Mapping of PET Activation Measurements: A Comparative Case Study

The significance of task-induced cerebral blood flow responses, assessed using statistical parametric mapping, depends, among other things, on the signal-to-noise ratio (SNR) of these responses. Generally, positron emission tomography sinograms of H(2)(15)O activation studies are reconstructed using filtered backprojection (FBP). Alternatively, the acquired data can be reconstructed using an iterative reconstruction procedure. It has been demonstrated that the application of iterative reconstruction methods improves image SNR as compared with FBP. The aim of this study was to compare FBP with iterative reconstruction, to assess the statistical power of H(2)(15)O-PET activation studies using statistical parametric mapping. For this case study, PET data originating from a bimanual motor task were reconstructed using both FBP and maximum likelihood expectation maximization (ML-EM), an iterative algorithm. Both resulting data sets were statistically analyzed using statistical parametric mapping. It was found, with this dataset, that the statistical analysis of the iteratively reconstructed data confirm the a priori expected physiological response. In addition, increased Z scores were obtained in the iteratively reconstructed data. In particular, for the expected task-related response, activation of the posterior border of the left angular gyrus, the Z score increased from 3.00 to 3.96. Furthermore, the number of statistically significant clusters doubled while their volume increased by more than 50%. In conclusion, iterative reconstruction has the potential to increase the statistical power in H(2)(15)O-PET activation studies as compared with FBP reconstruction.

Iterative versus filtered backprojection reconstruction for statistical parametric mapping of PET activation measurements : A comparative study.

The significance of task-induced cerebral blood flow responses, assessed using statistical parametric mapping, depends, among other things, on the signal-to-noise ratio (SNR) of these responses. Generally, positron emission tomography sinograms of H(2)(15)O activation studies are reconstructed using filtered backprojection (FBP). Alternatively, the acquired data can be reconstructed using an iterative reconstruction procedure. It has been demonstrated that the application of iterative reconstruction methods improves image SNR as compared with FBP. The aim of this study was to compare FBP with iterative reconstruction, to assess the statistical power of H(2)(15)O-PET activation studies using statistical parametric mapping. For this case study, PET data originating from a bimanual motor task were reconstructed using both FBP and maximum likelihood expectation maximization (ML-EM), an iterative algorithm. Both resulting data sets were statistically analyzed using statistical parametric mapping. It was found, with this dataset, that the statistical analysis of the iteratively reconstructed data confirm the a priori expected physiological response. In addition, increased Z scores were obtained in the iteratively reconstructed data. In particular, for the expected task-related response, activation of the posterior border of the left angular gyrus, the Z score increased from 3.00 to 3.96. Furthermore, the number of statistically significant clusters doubled while their volume increased by more than 50%. In conclusion, iterative reconstruction has the potential to increase the statistical power in H(2)(15)O-PET activation studies as compared with FBP reconstruction.

Positron Emission Tomography in Oncology

Nowadays a variety of two- and three-dimensional medical imaging modalities is available. The different modalities can be divided into two groups: one giving anatomical and one giving functional or metabolic information. Images made by the first group display tissue density (ultrasound), tissue absorption of X-rays (Computerized Tomography, CT) or physical parameters with respect to the proton density or proton relaxation times (Magnetic Resonance Imaging, MRI). Images from the second group represent functional information such as perfusion, metabolism or receptor density. Single Photon Emission Computerized Tomography (SPECT) and especially Positron Emission Tomography (PET) are generating this functional information by using a whole spectrum of radioactive compounds (radiopharmaceuticals). By measuring the 3D-spatial and temporal distributions of the radiopharmaceutical PET is able to quantify biochemistry in vivo. PET combines a high spatial resolution with a very high sensitivity and is able to quantify the measured radioactivity in absolute terms, i.e. in Becquerel per pixel. Examples of quantitative in vivo measurements are the glucose consumption, blood flow and protein synthesis rate (PSR). Glycolysis and protein synthesis is of broad, interest since energy metabolism and proteins are involved in cellular homeostasis, enzyme function, growth and development, plasticity and the response to drugs. In pathological states (e.g. brain tumors, inborn errors of metabolism, neurodegeneration) the metabolism may be altered.