Harmonisation of PET/CT contrast recovery performance for brain studies.

PURPOSE: In order to achieve comparability of image quality, harmonisation of PET system performance is imperative. In this study, prototype harmonisation criteria for PET brain studies were developed. METHODS: Twelve clinical PET/CT systems (4 GE, 4 Philips, 4 Siemens, including SiPM-based "digital" systems) were used to acquire 30-min PET scans of a Hoffman 3D Brain phantom filled with ~ 33 kBq·mL-1 [18F]FDG. Scan data were reconstructed using various reconstruction settings. The images were rigidly coregistered to a template (voxel size 1.17 × 1.17 × 2.00 mm3) onto which several volumes of interest (VOIs) were defined. Recovery coefficients (RC) and grey matter to white matter ratios (GMWMr) were derived for eroded (denoted in the text by subscript e) and non-eroded grey (GM) and white (WM) matter VOIs as well as a mid-phantom cold spot (VOIcold) and VOIs from the Hammers atlas. In addition, left-right hemisphere differences and voxel-by-voxel differences compared to a reference image were assessed. RESULTS: Systematic differences were observed for reconstructions with and without point-spread-function modelling (PSFON and PSFOFF, respectively). Normalising to image-derived activity, upper and lower limits ensuring image comparability were as follows: for PSFON, RCGMe = [0.97-1.01] and GMWMre = [3.51-3.91] for eroded VOI and RCGM = [0.78-0.83] and GMWMr = [1.77-2.06] for non-eroded VOI, and for PSFOFF, RCGMe = [0.92-0.99] and GMWMre = [3.14-3.68] for eroded VOI and RCGM = [0.75-0.81] and GMWMr = [1.72-1.95] for non-eroded VOI. CONCLUSIONS: To achieve inter-scanner comparability, we propose selecting reconstruction settings based on RCGMe and GMWMre as specified in "Results". These proposed standards should be tested prospectively to validate and/or refine the harmonisation criteria.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-ß deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study.

The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study.

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [11C]GR205171.

The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n = 17) and healthy controls (n = 17) using positron emission tomography and the radiotracer [11C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders.

CT-perfusion versus [(15)O]H2O PET in lung tumors: effects of CT-perfusion methodology.

PURPOSE: Nowadays, PET and dynamic contrast enhanced CT or MRI are used to assess tumor blood perfusion. Although [(15)O]H2O PET is the gold standard, it is hardly available for routine clinical practice, due to the short half-life of (15)O. However, the lack of uniformity in scanning and analytic methods limits the use of CT perfusion (CTP) in clinical trials and practice. This study compares [(15)O]H2O PET with CT based perfusion in lung tumors and assesses the effects of various CTP postprocessing and analytical methods on the CTP results using [(15)O]H2O PET as the reference technique. METHODS: Various CTP analysis and image postprocessing methods were assessed. Furthermore, parametric images were obtained using the Slope method. Volumes of interests were defined using several different segmentation methods including Hounsfield unit based contouring thresholds, both with and without framewise application of dynamic contouring thresholds to exclude lung tissue or intravascular contrast. A head-to-head comparison of tumor perfusion obtained by CTP and [(15)O]H2O PET was performed using linear regressions, Bland-Altman plots, and an intraclass correlation coefficient (ICC). In addition, the different postprocessing methods were compared reciprocally. RESULTS: In six lung cancer patients, perfusion assessed using CTP studies combined with the Slope method correlated best with [(15)O]H2O PET (ICC = 0.88; R(2) = 0.89; Y = 0.80). The Mullani-Gould method showed best correlation with the Slope method (ICC ≥ 0.71; R(2) ≥ 0.80; Y = 0.71-1.35). These correlations were obtained using dynamic contouring thresholds and show the influence of CTP postprocessing methods. CONCLUSIONS: Tumor perfusion assessed by CTP in combination with dynamic contouring thresholds using the Slope method correlates well with [(15)O]H2O PET. This suggests that CTP can be used as a method to evaluate tumor perfusion in lung cancer.

Carbon-11 labeled tracers for in vivo imaging P-glycoprotein function: kinetics, advantages and disadvantages.

P-glycoprotein (P-gp) is a drug efflux transporter with broad substrate specificity localized in the blood-brain barrier and in several peripheral organs. In order to understand the role of P-gp in physiological and patho-physiological conditions, several carbon-11 labelled P-gp tracers have been developed and validated. This review provides an overview of the spectrum of radiopharmaceuticals that is available for this purpose. A short overview of the physiology of the blood-brain barrier in health and disease is also provided. Tracer kinetic modelling for quantitative analysis of P-gp function and expression is highlighted, and the advantages and disadvantages of the various tracers are discussed.

Cardiac PET-CT: advanced hybrid imaging for the detection of coronary artery disease.

Hybrid imaging of positron emission tomography (PET) together with computed tomography (CT) is rapidly emerging. In cardiology, this new advanced hybrid imaging modality allows quantification of cardiac perfusion in combination with assessment of coronary anatomy within a single scanning session of less than 45 minutes. The near-simultaneous anatomical evaluation of coronary arteries using CT and corresponding functional status using PET provides a wealth of complementary information in patients who are being evaluated for (suspected) coronary artery disease, and could help guide clinical patient management in a novel manner. Clinical experience gained with this recently introduced advanced hybrid imaging tool, however, is still limited and its implementation into daily clinical practice remains largely unchartered territory. This review discusses principles of perfusion PET, its diagnostic accuracy, and potential clinical applications of cardiac PET-CT in patients with ischaemic heart disease. (Neth Heart J 2010;18:90-8.).

Potential of [11C]acetate for measuring myocardial blood flow: Studies in normal subjects and patients with hypertrophic cardiomyopathy.

BACKGROUND: Measuring the rate of clearance of carbon-11 labelled acetate from myocardium using positron emission tomography (PET) is an accepted technique for noninvasively assessing myocardial oxygen consumption. Initial myocardial uptake of [(11)C]acetate, however, is related to myocardial blood flow (MBF) and several tracer kinetic models for quantifying MBF using [(11)C]acetate have been proposed. The objective of this study was to assess these models. METHODS: Eighteen healthy subjects and 18 patients with hypertrophic cardiomyopathy (HCM) were studied under baseline conditions with [(11)C]acetate and [(15)O]water. Four previously reported methods, including single- and multi-tissue compartment models, were used to calculate MBF from the measured [(11)C]acetate rate of influx K (1) and the (previously) reported relationship between K (1) and MBF. These MBF values were then compared with those derived from corresponding [(15)O]water studies. RESULTS: For all models, correlations between [(11)C]acetate and [(15)O]water-derived MBF ranged from .67 to .86 (all P < .005) in the control group and from .73 to .85 (all P < .001) in the HCM group. Two out of four models systematically underestimated perfusion with [(11)C]acetate, whilst the third model resulted in an overestimation. The fourth model, based on a simple single tissue compartment model with spillover, partial volume and recirculating metabolite corrections, resulted in a regression equation with a slope of near unity and an Y-intercept of almost zero (controls, K(1) = .74[MBF] + .09, r = .86, SEE = .13, P < .001 and HCM, K(1) = .89[MBF] + .03, r = .85, SEE = .12, P < .001). CONCLUSION: [(11)C]acetate enables quantification of MBF in fairly good agreement with actual MBF in both healthy individuals and patients with HCM. A single tissue compartment model with standardized correction for recirculating metabolites and with corrections for partial volume and spillover provided the best results.

A method to measure PET scatter fractions for daily quality control.

PURPOSE: Regular monitoring of PET scanner performance is mandatory to assure quality of acquired data. While extensive performance measurements include many scanner characteristics such as resolution, count rate, uniformity, sensitivity, and scatter fraction (SF), most daily QC protocols are limited to uniformity and sensitivity measurements. These measurements may be too insensitive to detect more subtle drifts in detector gains that could lead to reduced detection of primary and increased detection of scattered events. Current methods to measure SF, such as those prescribed by the NEMA protocols (SF-NEMA), however, require specially designed phantoms and are too cumbersome to be performed on a daily basis. METHODS: In this study, a simple and versatile method to determine SF is described. This method (SF-DAILY) does not require additional measurements, making it suitable for daily QC. The method was validated for four different scanners by comparing results with those obtained with the NEMA 1994 protocol. RESULTS: For all scanner types and acquisition modes, excellent agreement was found between SF-NEMA and SF-DAILY. CONCLUSIONS: The proposed method is a very practical and valuable addition to current daily QC protocols. In addition, the method can be used to accurately measure SF in phantoms with other dimensions than the NEMA phantom.

Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease.

The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure and PD neurodegeneration. In the present study BBB P-gp function was investigated in vivo in 10 early stage PD patients and 8 healthy control subjects using (R)-[(11)C]-verapamil and PET. Cerebral volume of distribution (V(d)) of verapamil was used as measure of P-gp function. Both region of interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM) were performed to assess regional brain P-gp function. In addition, MDR1 genetic polymorphism was assessed. In the present study, a larger variation in V(d) of (R)-[(11)C]-verapamil was seen in the PD group as compared to the control group. However, decreased BBB P-gp function in early stage PD patients could not be confirmed.

The role of (124)I-PET in diagnosis and treatment of thyroid carcinoma.

Iodine-124 is a positron-emitting iodine isotope, enabling measurement of iodine uptake using positron emission tomography (PET). There is a number of situations where the use of (124)I-PET/computed tomography (CT) can improve the current clinical practice in the diagnosis and treatment of thyroid cancer. Firstly, (124)I-PET/CT can aid in the staging of patients, because of better detection of metastatic disease and measurement of metabolic tumour volume, and thus separate low-risk from high risk patients. Secondly, the much higher sensitivity and spatial resolution of PET compared to gamma scintigraphy can also improve detection of recurrent disease. Furthermore, (124)I-PET can be used for patient-specific radioiodine therapy radiation dosimetry. Simultaneous administration of the therapeutic dose of (131)I and a tracer dose of (124)I allows for accurate measurement of iodine uptake during therapy. The decay scheme of (124)I, with few positrons and many gamma rays emitted per decay, often simultaneously, poses a challenge to quantitative PET imaging. Improved correction methods and the use of last-generation PET/CT scanners with faster electronics and better energy resolution can overcome this.

Quantification aspects of patient studies with 52Fe in positron emission tomography.

Quantification accuracy in positron emission tomography (PET) using non-pure positron emitters, such as 52Fe, may be influenced by gamma radiation emitted in the decay of these isotopes. High-energy positrons, emitted in the decay of the 52Fe-daughter 52mMn, also affect the quantification accuracy. A specific problem of the 52Fe/52mMn decay chain in vivo is that the kinetics of iron and manganese are different, and that PET cannot discriminate between the two nuclides. The effect of the decay properties of 52Fe/52mMn on the performance of PET was investigated using phantoms. Minor degradation in PET performance was found for 52Fe/52mMn compared to the pure low-energy positron emitter 18F. A method is presented to obtain a correction factor for the 52mMn radioactivity in blood. A model for correction of 52mMn-radioactivity in organs, based on existing data on manganese kinetics, is given. The presented corrections are discussed and illustrated in a patient study.

Positron emission tomography and radioimmunotargeting--general aspects.

To optimize radioimmunotherapy, in vivo information on individual patients, such as radionuclide uptake, kinetics, metabolic patterns and optimal administration methods, is important. An overriding problem is to determine accurately the absorbed dose in the target organ as well as critical organs. Positron Emission Tomography (PET) is a superior technique to quantify regional kinetics in vivo with a spatial resolution better than 1 cm3 and a temporal resolution better than 10 s. However, target molecules often have distribution times of several hours to days. Conventional PET nuclides are not applicable and alternative positron-emitting nuclides with matching half-lives and with suitable labelling properties are thus necessary. Over many years we have systematically developed convenient production methods and labelling techniques of suitable positron nuclides, such as 110In(T(1/2) = 1.15 h), 86Y(T(1/2) = 14 h), 76Br(T(1/2) = 16 h) and 124I(T(1/2) = 4 days). 'Dose planning' can be done, for example, with 86Y- or 124I-labelled ligands before therapy, and 90Y- and 131I-labelled analogues and double-labelling, e.g. with a 86Y/90Y-labelled ligand, can be used to determine the true radioactivity integral from a pure beta-emitting nuclide. The usefulness of these techniques was demonstrated in animal and patient studies by halogen-labelled MAbs and EGF-dextran conjugates and peptides chelated with metal ions.

Positron emission tomography and radioimmunotargeting--aspects of quantification and dosimetry.

Positron emission tomography (PET) is a medical imaging tool with high resolution and good quantitative properties, which makes it suitable for in vivo quantification of radioimmunotargeting agents. Most radionuclides used in radioimmunotherapy have positron-emitting analogues, which can be used for PET imaging, and this opens the possibility of performing dosimetry with PET. These isotopes, however, often emit gamma radiation and high-energy positrons in their decay, influencing the imaging properties of PET. Spatial resolution, reconstructed background and line source recovery for a number of non-pure positron emitters were investigated and compared with the imaging properties of 18F. PET imaging properties did not degrade severely for these non-pure positron emitters, but caution has to be applied when doing quantitative measurements. To assess the possibility of conducting PET studies during therapy, by combining, for example, a small amount of 124I with 131I, the influence of the presence of large amounts of gamma radiation on PET count rate characteristics was studied. The results of these studies were related to the necessary amounts of radioactivity needed for treatment of post-operative remains of glioma. The results indicate that the count rate capabilities of 2D PET permit PET studies for dose evaluation during radioimmunotherapy.

Kinetics of 76Br-labeled anti-CEA antibodies in pigs; aspects of dosimetry and PET imaging properties.

A monoclonal antibody labeled with the positron-emitting radionuclide 76Br (T(1/2) 16.2 h) has previously been shown useful for positron emission tomography (PET) imaging of experimental tumors. Our aim in the present study was to investigate the effects of the complex decay scheme of this radionuclide on normal organ dosimetry and PET image quality. Three mini-pigs were injected intravenously with 46-75 MBq of the 76Br-labeled anti-CEA antibody 38S1, and the whole-body kinetics followed by PET imaging for 19 h. From PET data, absorbed doses in human organs were estimated using the MIRDOSE 3.0 software. The highest 76Br concentrations were found in lungs, after a correction for the air volume in this organ. The lungs received the highest absorbed dose (mGy/MBq, mean+/-maximum error), 0.84+/-0.16, followed by liver, 0.74+/-0.28, and small intestine, 0.55+/-0.05, while the effective dose equivalent was 0.41+/-0.03 mSv/MBq. The PET imaging properties of 76Br in a two-dimensional 2D PET camera, including central area resolution and scattering effects, were investigated in phantoms and compared to those of 18F. In a 0.97 g/cm3 material, approximating soft tissue density, the FMHW ("full width at half-maximum") value of the point spread function was 7.7+/-0.2 mm for 76Br and 6.0+/-0.1 mm for 18F. In conclusion, radioimmuno PET using 76Br-labeled antibodies resulted in a fairly even distribution of the radiation dose, where the highest absorbed organ doses were only about two to three times higher than the mean absorbed body dose. The high energy beta+ spectrum in the 76Br decay had only minor effects on the resolution, but may decrease the quantification accuracy, especially in organs with a lower density such as a lung.

Kinetic analysis of 52Fe-labelled iron(III) hydroxide-sucrose complex following bolus administration using positron emission tomography.

Kinetic analysis of a single intravenous injection of 100 mg iron(III) hydroxide-sucrose complex (Venofer) mixed with 52Fe(III) hydroxide-sucrose as a tracer was followed for 3-6 h in four generally anaesthetized, artificially ventilated minipigs using positron emission tomography (PET). The amount of injected radioactivity ranged from 30 to 200 MBq. Blood radioactivity, measured by PET in the left ventricle of the heart, displayed a fast clearance phase followed by a slow one. In the liver and bone marrow a fast radioactivity uptake occurred during the first 30 min, followed by a slower steady increase. In the liver a slight decrease in radioactivity uptake was noted by the end of the study. A kinetic analysis using a three-compartment (namely blood pool, reversible and irreversible tissue pools) model showed a fairly high distribution volume in the liver as compared with the bone marrow. In conclusion, the pharmacokinetics of the injected complex was clearly visualized with the PET technique. The organs of particular interest, namely the heart (for blood kinetics), liver and bone marrow could all be viewed by a single setting of a PET tomograph with an axial field of view of 10 cm. The half-life (T1/2) of 52Fe (8.3 h) enables a detailed kinetic study up to 24 h. A novel method was introduced to verify the actual 52Fe contribution to the PET images by removing the interfering radioactive daughter 52mMn positron emissions. The kinetic data fitted the three-compartment model, from which rate constants could be obtained for iron transfer from the blood to a pool of iron in bone marrow or liver to which it was bound during the study period. In addition, there was a reversible tissue pool of iron, which in the liver slowly equilibrated with the blood, to give a net efflux from the liver some hours after i.v. administration. The liver uptake showed a relatively long distribution phase, whereas the injected iron was immediately incorporated into the bone marrow. Various transport mechanisms seem to be involved in the handling of the injected iron complex.

Pharmacokinetics and red cell utilization of iron(III) hydroxide-sucrose complex in anaemic patients: a study using positron emission tomography.

The pharmacokinetics of a single intravenous injection of 100 mg iron hydroxide-sucrose complex labelled with a tracer in the form of 52Fe/59Fe was followed in six anaemic patients for a period ranging from 6 to 8 3 h using positron emission tomography (PET). Red cell utilization of the labelled iron was followed for 4 weeks. PET data showed radioactive uptake by the liver, spleen and bone marrow. The uptake by the macrophage-rich spleen demonstrated the reticuloendothelial uptake of this iron preparation, with subsequent effective release of that iron for marrow utilization. Red cell utilization, followed for 4 weeks, ranged from 59% to 97%. The bone marrow influx rate constant was independent of blood iron concentration, indicating non-saturation of the transport system in bone marrow. This implied that higher doses of the iron complex can probably be used in the same setting. A higher influx rate into the marrow compared with the liver seemed to be consistent with higher red cell utilization. This would indicate that early distribution of the injected iron complex may predict the long-term utilization.