High Resolution Research Tomograph Research Articles

Image-derived input function in PET brain studies

Image-derived input function (IDIF) from carotid arteries is an elegant alternative to full arterial blood sampling for brain PET studies. However, a recent study using blood-free IDIFs found that this method is particularly vulnerable to patient motion. The present study used both simulated and clinical [11C](R)-rolipram data to assess the robustness of a blood-based IDIF method (a method that is ultimately normalized with blood samples) with regard to motion artifacts. The impact of motion on the accuracy of IDIF was first assessed with an analytical simulation of a high-resolution research tomograph using a numerical phantom of the human brain, equipped with internal carotids. Different degrees of translational (from 1 to 20 mm) and rotational (from 1 to 15°) motions were tested. The impact of motion was then tested on the high-resolution research tomograph dynamic scans of three healthy volunteers, reconstructed with and without an online motion correction system. IDIFs and Logan-distribution volume (VT) values derived from simulated and clinical scans with motion were compared with those obtained from the scans with motion correction. In the phantom scans, the difference in the area under the curve (AUC) for the carotid time-activity curves was up to 19% for rotations and up to 66% for translations compared with the motionless simulation. However, for the final IDIFs, which were fitted to blood samples, the AUC difference was 11% for rotations and 8% for translations. Logan-VT errors were always less than 10%, except for the maximum translation of 20 mm, in which the error was 18%. Errors in the clinical scans without motion correction appeared to be minor, with differences in AUC and Logan-VT always less than 10% compared with scans with motion correction. When a blood-based IDIF method is used for neurological PET studies, the motion of the patient affects IDIF estimation and kinetic modeling only minimally.

Scanning rats on the high resolution research tomograph (HRRT): A comparison study with a dedicated micro‐PET

The Siemens ECAT high resolution research tomograph (HRRT) is a dedicated human brain PET camera with a 6% absolute sensitivity and a (2.3 mm)(3) spatial resolution, improving to (1.8 mm)(3) when point spread function (PSF) modeling algorithms are used. These values are very close to those of dedicated small animal PET cameras such as the Siemens microPET FOCUS 120 (F120). The larger axial and transaxial field of view of the HRRT compared to the F120 allows, in principle, for simultaneous imaging of several rodents thus potentially reducing scanning costs and time. This study investigates the feasibility of using the HRRT for quantitative small animal brain studies. We compare, in terms of magnitude, reproducibility, and asymmetry, the nondisplaceable tissue input binding potentials (BP(ND)) in the striata obtained from [(11)C]methylphenidate scans of the same rats imaged on both the F120 and the HRRT. The animal studies are complemented by a phantom study aimed at investigating noise properties relevant to the size of typical regions of interest used in rat brain image analysis. (i) The BP(ND) values obtained from HRRT data are lower than those obtained on the F120 by 38% when PSF modeling is not used, while they are 7% higher with PSF modeling. (ii) The within animal reproducibility on the HRRT is 18% without PSF modeling, worse than the 6% reproducibility on the F120, and is even further degraded to a value of 27% with the use of PSF modeling. (iii) The asymmetry between the left and right striatum in healthy rats worsens from 4.7% in the F120 images to 7.8% in the HRRT images reconstructed without PSF modeling, and is even worse with a value of 14.8% when PSF modeling is used. (iv) Overshooting artifacts and clumpiness in the noise structure of the HRRT images reconstructed with PSF modeling are clearly visible. The spatial resolution achieved on the HRRT without the use of resolution recovery techniques is not sufficient to allow for reliable quantitative small animal brain imaging. While PSF modeling in the reconstruction of the HRRT images in principle improves the resolution close to the level of the F120, it also introduces small scale nonuniformity artifacts and overshooting artifacts which preclude reliable quantitative small animal brain imaging on the HRRT.

3.5D dynamic PET image reconstruction incorporating kinetics-based clusters

Standard 3D dynamic positron emission tomographic (PET) imaging consists of independent image reconstructions of individual frames followed by application of appropriate kinetic model to the time activity curves at the voxel or region-of-interest (ROI). The emerging field of 4D PET reconstruction, by contrast, seeks to move beyond this scheme and incorporate information from multiple frames within the image reconstruction task. Here we propose a novel reconstruction framework aiming to enhance quantitative accuracy of parametric images via introduction of priors based on voxel kinetics, as generated via clustering of preliminary reconstructed dynamic images to define clustered neighborhoods of voxels with similar kinetics. This is then followed by straightforward maximum a posteriori (MAP) 3D PET reconstruction as applied to individual frames; and as such the method is labeled ‘3.5D’ image reconstruction. The use of cluster-based priors has the advantage of further enhancing quantitative performance in dynamic PET imaging, because: (a) there are typically more voxels in clusters than in conventional local neighborhoods, and (b) neighboring voxels with distinct kinetics are less likely to be clustered together. Using realistic simulated 11C-raclopride dynamic PET data, the quantitative performance of the proposed method was investigated. Parametric distribution-volume (DV) and DV ratio (DVR) images were estimated from dynamic image reconstructions using (a) maximum-likelihood expectation maximization (MLEM), and MAP reconstructions using (b) the quadratic prior (QP-MAP), (c) the Green prior (GP-MAP) and (d, e) two proposed cluster-based priors (CP-U-MAP and CP-W-MAP), followed by graphical modeling, and were qualitatively and quantitatively compared for 11 ROIs. Overall, the proposed dynamic PET reconstruction methodology resulted in substantial visual as well as quantitative accuracy improvements (in terms of noise versus bias performance) for parametric DV and DVR images. The method was also tested on a 90 min 11C-raclopride patient study performed on the high-resolution research tomography. The proposed method was shown to outperform the conventional method in visual as well as quantitative accuracy improvements (in terms of noise versus regional DVR value performance).

Positron emission tomography shows elevated cannabinoid CB1 receptor binding in men with alcohol dependence.

Several lines of evidence link cannabinoid (CB) type 1 (CB (1) ) receptor-mediated endogenous CB (eCB) signaling to the etiology of alcohol dependence (AD). However, to date, only peripheral measures of eCB function have been collected in living humans with AD and no human in vivo data on the potentially critical role of the brain CB (1) receptor in AD have been published. This is an important gap in the literature, because recent therapeutic developments suggest that these receptors could be targeted for the treatment for AD. Medication-free participants were scanned during early abstinence 4weeks after their last drink. Using positron emission tomography (PET) with a high-resolution research tomograph and the CB (1) receptor selective radiotracer [(11) C]OMAR, we determined [(11) C]OMAR volume of distribution ( V (T) ) values, a measure of CB (1) receptor density, in a priori selected brain regions in men with AD (n=8, age 37.4±7.9years; 5 smokers) and healthy control (HC) men (n=8, age 32.5±6.9years; all nonsmokers). PET images reconstructed using the MOLAR algorithm with hardware motion correction were rigidly aligned to the subject-specific magnetic resonance (MR) image, which in turn was warped to an MR template. Time-activity curves (TACs) were extracted from the dynamic PET data using a priori selected regions of interest delineated in the MR template space. In AD relative to HC, [(11) C]OMAR V (T) values were elevated by approximately 20% (p=0.023) in a circuit, including the amygdala, hippocampus, putamen, insula, anterior and posterior cingulate cortices, and orbitofrontal cortex. Age, body mass index, or smoking status did not influence the outcome. These findings agree with preclinical evidence and provide the first, albeit still preliminary in vivo evidence suggesting a role for brain CB (1) receptors in AD. The current study design does not answer the important question of whether elevated CB (1) receptors are a preexisting vulnerability factor for AD or whether elevations develop as a consequence of AD.

Optimization of methods for quantification of rCBF using high-resolution [15O]H2O PET images

This study aimed to derive accurate estimates of regional cerebral blood flow (rCBF) from noisy dynamic [15O]H2O PET images acquired on the high-resolution research tomograph, while retaining as much as possible the high spatial resolution of this brain scanner (2–3 mm) in parametric maps of rCBF. The PET autoradiographic method and generalized linear least-squares (GLLS), with fixed or extended to include spatially variable estimates of the dispersion of the measured input function, were compared to nonlinear least-squares (NLLS) for rCBF estimation. Six healthy volunteers underwent two [15O]H2O PET scans with continuous arterial blood sampling. rCBF estimates were obtained from three image reconstruction methods (one analytic and two iterative, of which one includes a resolution model) to which a range of post-reconstruction filters (3D Gaussian: 2, 4 and 6 mm FWHM) were applied. The optimal injected activity was estimated to be around 11 MBq kg−1 (800 MBq) by extrapolation of patient-specific noise equivalent count rates. Whole-brain rCBF values were found to be relatively insensitive to the method of reconstruction and rCBF quantification. The grey and white matter rCBF for analytic reconstruction and NLLS were 0.44 ± 0.03 and 0.15 ± 0.03 mL min−1 cm−3, respectively, in agreement with literature values. Similar values were obtained from the other methods. For generation of parametric images using GLLS or the autoradiographic method, a filter of ⩾4 mm was required in order to suppress noise in the PET images which otherwise produced large biases in the rCBF estimates.

Direct 4D parametric imaging for linearized models of reversibly binding PET tracers using generalized AB-EM reconstruction

Due to high noise levels in the voxel kinetics, development of reliable parametric imaging algorithms remains one of most active areas in dynamic brain PET imaging, which in the vast majority of cases involves receptor/transporter studies with reversibly binding tracers. As such, the focus of this work has been to develop a novel direct 4D parametric image reconstruction scheme for such tracers. Based on a relative equilibrium (RE) graphical analysis formulation (Zhou et al 2009b Neuroimage 44 661–70), we developed a closed-form 4D EM algorithm to directly reconstruct distribution volume (DV) parametric images within a plasma input model, as well as DV ratio (DVR) images within a reference tissue model scheme (wherein an initial reconstruction was used to estimate the reference tissue time–activity curves). A particular challenge with the direct 4D EM formulation is that the intercept parameters in graphical (linearized) analysis of reversible tracers (e.g. Logan or RE analysis) are commonly negative (unlike for irreversible tracers, e.g. using Patlak analysis). Subsequently, we focused our attention on the AB-EM algorithm, derived by Byrne (1998, Inverse Problems 14 1455–67) to allow inclusion of prior information about the lower (A) and upper (B) bounds for image values. We then generalized this algorithm to the 4D EM framework, thus allowing negative intercept parameters. Furthermore, our 4D AB-EM algorithm incorporated and emphasized the use of spatially varying lower bounds to achieve enhanced performance. As validation, the means of parameters estimated from 55 human 11C-raclopride dynamic PET studies were used for extensive simulations using a mathematical brain phantom. Images were reconstructed using conventional indirect as well as proposed direct parametric imaging methods. Noise versus bias quantitative measurements were performed in various regions of the brain. Direct 4D EM reconstruction resulted in notable qualitative and quantitative accuracy improvements (over 35% noise reduction, with matched bias, in both plasma and reference-tissue input models). Similar improvements were also observed in the coefficient of variation of the estimated DV and DVR values even for relatively low uptake cortical regions, suggesting the enhanced ability for robust parameter estimation. The method was also tested on a 90 min 11C-raclopride patient study performed on the high-resolution research tomograph wherein the proposed method was shown across a variety of regions to outperform the conventional method in the sense that for a given DVR value, improved noise levels were observed.

Gap compensation during PET image reconstruction by constrained, total variation minimization

Positron emission tomography (PET) is a noninvasive molecular imaging tool with various clinical and preclinical applications. The polygonal structure of small-diameter PET scanners that are designed for specific purposes can lead to gaps between the detector modules and result in loss of PET data during measurement. In the current study, the authors applied the compressed sensing (CS)-based total variation (TV) minimization method to PET image reconstructions to reduce the artifacts caused by gaps in small-diameter PET systems. The first step in each iteration estimates whether an image is consistent with the measured PET data using the existing common reconstruction algorithms (ART, OSEM, and RAMLA). The second step recovers sparsity in the gradient domain of the image by minimizing the TV of an estimated image. The authors evaluated the gap-compensable reconstruction algorithms with uniform disk and Shepp-Logan phantoms by simulating sinograms which contained Poisson random noise and a data loss due to detector gaps. In addition, these methods were applied to real high resolution research tomography (HRRT)-like sinograms of human brain and uniform phantom. A comparison with other methods for gap compensation prior to or during image reconstruction was also made. Quantitative evaluations were performed by computing the uniformity, root mean squared error, and difference between the reconstructed images of nongapped and gapped sinograms. The simulation results showed that the gap-compensable methods incorporating TV minimization could control gap artifacts, as well as Poisson random noise. In particular, OSEM-TV and RAMLA-TV showed distinct potential via the properties of convergence and robustness to different noise levels and gap angle. A TV minimization strategy incorporated into commonly used PET reconstruction algorithms was useful for reducing the occurrence of artifacts due to gaps between detector modules in small-diameter PET scanners.

Quantification of serotonin transporter availability with [11C]MADAM — A comparison between the ECAT HRRT and HR systems

The High Resolution Research Tomograph (HRRT) is the PET system providing the highest resolution for imaging of the human brain. In this study, the improved quantitative performance of the HRRT was evaluated in comparison with a previously developed lower resolution PET system, the ECAT HR. The radioligand [(11)C]MADAM was chosen for the purpose since it provides a signal for serotonin transporter (5-HTT) binding in cortical and sub-cortical brain regions of different sizes and expressing different 5-HTT densities. A secondary objective was to assess the effect of partial volume effect (PVE) correction on the cross-comparability between the two systems. Six male control subjects (ages 20-35 yr) were examined twice using the HRRT and the HR system, respectively. Regions of interest (ROIs) included cortical regions (frontal cortex, temporal cortex, insula, anterior cingulate cortex, and hippocampus), sub-cortical regions (caudate, putamen, thalamus, dorsal brainstem and ventral midbrain) and cerebellum. The ROIs were manually delineated on T1-weighted MRI-images and subsequently applied to both HRRT and HR images. Regional binding potential (BP(ND)) values were calculated with the simplified reference tissue model (SRTM) using cerebellum as the reference region. The percent difference in BP(ND) between the systems was calculated for each ROI. In addition, both HRRT and HR data were corrected for PVE using established MRI-based methods described by Meltzer and Müller-Gärtner. The effect of PVE correction (PVEc) on the agreement between the systems was assessed via percent difference calculation and linear regression analysis. Quantification with SRTM showed that regional BP(ND) values for [(11)C]MADAM were on average 23% higher for the HRRT than those obtained by the HR system. More specifically, BP(ND) measured with HRRT was 31.1±48.1% higher in neocortical/limbic regions and 14.6±20.9% higher in sub-cortical regions. The effect of PVEc varied between regions. After correction according to Müller-Gärtner, the agreement between systems was best in the neocortical/limbic regions (3.7±22.5%). With the exception of the caudate, in which the agreement was improved by approximately 17% using the Meltzer method, the effect of PVEc in sub-cortical regions was less pronounced. Linear regression analysis showed improved correlation between the two systems after PVEc, particularly in the neocortical/limbic regions. As expected, BP(ND) values measured with the HRRT were higher than those measured with the HR due to higher resolution and recovery. The difference in BP(ND) between the two systems was approximately 30% in the neocortical/limbic regions. PVEc improved the agreement between the systems in particular for the neocortical/limbic regions. In these regions, the best agreement was found after applying Müller-Gärtner's PVEc. The demonstrated agreement provides an opportunity for combining data between the two systems in clinical studies aimed at evaluating receptor/transporter availability in cortical brain regions.

Lack of association between prior depressive episodes and cerebral [11C]PiB binding

Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-β (Aβ) levels using [11C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51–75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50–76, 12 women) were included. All subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [11C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [11C]PiB binding (p = 0.5) and no associations to number of depressive episodes, cognitive performance, or antidepressant treatment. Patients with late onset of depression had increased severity of white matter lesions (p = 0.04). In this study depressive episodes were not associated with increased levels of [11C]PiB. Thus, our results do not support the notion that depressive episodes previously in life are a risk factor for developing AD.

Serotonin Transporter Occupancy and the Functional Neuroanatomic Effects of Citalopram in Geriatric Depression

The functional neuroanatomic changes associated with selective serotonin reuptake inhibitor (SSRI) treatment have been the focus of positron emission tomography (PET) studies of cerebral glucose metabolism in geriatric depression. To evaluate the underlying neurochemical mechanisms, both cerebral glucose metabolism and serotonin transporter (SERT) availability were measured before and during treatment with the SSRI, citalopram. It was hypothesized that SERT occupancy would be observed in cortical and limbic brain regions that have shown metabolic effects, as well as striatal and thalamic regions that have been implicated in prior studies in midlife patients. Psychiatric outpatient clinic. Seven depressed patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for current major depressive episode were enrolled. Patients underwent a 12-week open-label trial of the SSRI, citalopram. Patients underwent high-resolution research tomography PET scans to measure changes in cerebral glucose metabolism and SERT occupancy by citalopram treatment (after 8-10 weeks of treatment). Three different tracer kinetic models were applied to the [¹¹C]-DASB region-of-interest data and yielded similar results of an average of greater than 70% SERT occupancy in the striatum and thalamus during citalopram treatment. Voxel-wise analyses showed significant SERT occupancy in these regions, as well as cortical (e.g., anterior cingulate, superior and middle frontal, precuneus, and limbic (parahippocampal gyrus) areas that also showed reductions in glucose metabolism. The findings suggest that cortical and limbic SERT occupancy may be an underlying mechanism for the regional cerebral metabolic effects of citalopram in geriatric depression.

Synthesis and evaluation of [18F]exendin (9–39) as a potential biomarker to measure pancreatic β-cell mass

Glucagon-like peptide 1 (GLP-1) is released in response to food intake and plays an important role in maintaining blood glucose homeostasis. Exendin (9-39), a potent glucagon-like peptide 1 receptor antagonist, has been labeled with In-111 for SPECT imaging. We report here the first radiosynthesis of [(18)F]exendin (9-39) ([(18)F]Ex(9-39)) and an evaluation of its potential as a biomarker for in vivo positron emission tomography (PET) imaging of pancreatic β-cell mass (BCM) in rats. F-18 label was introduced by conjugation of [(18)F]4-fluorobenzaldehyde with an Ex(9-39) derivative containing a 6-hydrazinonicotinyl group on the ε-amine of Lys27. Positron emission tomography imaging was carried out in Sprague-Dawley rats (five control and five streptozotocin-induced diabetic) and BioBreeding diabetes-prone rats (three at 7 weeks and three at 12 weeks) using the high-resolution research tomograph (HRRT) after 0.187 ± 0.084 mCi [(18)F]Ex(9-39) administration. Time-activity curves were obtained from pancreas, liver and kidney. Pancreases were assayed for insulin content after the imaging study. Site-specifically labeled [(18)F]Ex(9-39) was purified on a G15 open column with radiochemical and chemical purities >98%. Positron emission tomography imaging showed pancreatic standardized uptake value (SUV) peaked at 10 min and plateaued by 50 min to the end of scan (240 min). No correlations of pancreatic SUV with postmortem measures of insulin content were seen. [(18)F]Ex(9-39) was successfully prepared and used for PET imaging for the first time to measure pancreatic BCM. The results suggest that derivatization of the Lys27 residue might reduce binding affinity, as evidenced by the absence of specific binding. Exendin analogues radiolabeled at other sites may elucidate the active site required for binding.

A custom-built PET phantom design for quantitative imaging of printed distributions

This note presents a practical approach to a custom-made design of PET phantoms enabling the use of digital radioactive distributions with high quantitative accuracy and spatial resolution. The phantom design allows planar sources of any radioactivity distribution to be imaged in transaxial and axial (sagittal or coronal) planes. Although the design presented here is specially adapted to the high-resolution research tomograph (HRRT), the presented methods can be adapted to almost any PET scanner. Although the presented phantom design has many advantages, a number of practical issues had to be overcome such as positioning of the printed source, calibration, uniformity and reproducibility of printing. A well counter (WC) was used in the calibration procedure to find the nonlinear relationship between digital voxel intensities and the actual measured radioactive concentrations. Repeated printing together with WC measurements and computed radiography (CR) using phosphor imaging plates (IP) were used to evaluate the reproducibility and uniformity of such printing. Results show satisfactory printing uniformity and reproducibility; however, calibration is dependent on the printing mode and the physical state of the cartridge. As a demonstration of the utility of using printed phantoms, the image resolution and quantitative accuracy of reconstructed HRRT images are assessed. There is very good quantitative agreement in the calibration procedure between HRRT, CR and WC measurements. However, the high resolution of CR and its quantitative accuracy supported by WC measurements made it possible to show the degraded resolution of HRRT brain images caused by the partial-volume effect and the limits of iterative image reconstruction.

Serotonin 1B receptor imaging in pathological gambling

Objectives. Although serotonergic mechanisms have been implicated in pathological gambling (PG), no ligand-based imaging studies have assessed serotonin receptors in individuals with PG. Given its role in substance addictions and its abundance in brain regions implicated in PG, we evaluated serotonin 1B receptors (5-HT1BRs) in PG. Methods. Ten medication-free subjects with PG (mean ± SD age = 36.3 ± 9.4 years, nine men) and ten control comparison (CC) subjects (mean ± SD age = 35.8 ± 9.9 years, nine men) underwent [11C]P943 positron emission scanning on a high resolution research tomograph. Results. 5-HT1BR BPND values were similar in PG and CC subjects (P > 0.1). Among PG subjects, scores on the South Oaks Gambling Screen (SOGS) correlated positively with 5-HT1BR BPND values in the ventral striatum (r = 0.66; P = 0.04), putamen (r = 0.67; P = 0.03) and anterior cingulate cortex (r = 0.73; P = 0.02). Conclusions. These findings provide the first evidence that PG severity in humans is linked to increased levels of 5-HT1BRs in regions previously implicated in functional neuroimaging studies of PG. These findings indicate a potential role for serotonergic function in the ventral striatum and anterior cingulate cortex contributing to problem gambling severity and warrant further studies to investigate whether numbers of available 5-HT1BRs might represent a vulnerability factor for PG or develop in relationship to problem gambling.

Glucose metabolism of the midline nuclei raphe in the brainstem observed by PET–MRI fusion imaging

The brainstem contains various important monoaminergic neuronal centers, including the raphe nuclei which contain serotonergic neurons. The raphe nuclei, however, are not easily identifiable and located by conventional neuroimaging. Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed in seven healthy subjects using a new PET-MRI, which consists of a high-resolution research tomograph (HRRT) PET and 7.0 T-MRI. Glucose metabolism of raphe nuclei was semiquantitatively measured and identified along the midline brainstem region in vivo. Midline nuclei clustered in four groups appeared to be the raphe nuclei and could be clearly visualized; specifically, we identified the groups as the dorsal raphe, raphe reticularis centralis superior, raphe pontis, and raphe magnus group. FDG imaging of the midline raphe nuclei in vivo could potentially be an important tool for investigating brain diseases as well as conducting functional brain studies in the context of sleep disorders, depression, and neurodegenerative disease.

Motion Tracking for Medical Imaging: A Nonvisible Structured Light Tracking Approach

We present a system for head motion tracking in 3D brain imaging. The system is based on facial surface reconstruction and tracking using a structured light (SL) scanning principle. The system is designed to fit into narrow 3D medical scanner geometries limiting the field of view. It is tested in a clinical setting on the high resolution research tomograph (HRRT), Siemens PET scanner with a head phantom and volunteers. The SL system is compared to a commercial optical tracking system, the Polaris Vicra system, from NDI based on translatory and rotary ground truth motions of the head phantom. The accuracy of the systems was similar, with root mean square (rms) errors of 0.09 degrees for ±20 degrees axial rotations, and rms errors of 0.24 mm for ± 25 mm translations. Tests were made using (1) a light emitting diode (LED) based miniaturized video projector, the Pico projector from Texas Instruments, and (2) a customized version of this projector replacing a visible light LED with a 850 nm near infrared LED. The latter system does not provide additional discomfort by visible light projection into the patient's eyes. The main advantage over existing head motion tracking devices, including the Polaris Vicra system, is that it is not necessary to place markers on the patient. This provides a simpler workflow and eliminates uncertainties related to marker attachment and stability. We show proof of concept of a marker less tracking system especially designed for clinical use with promising results.

Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high‐resolution PET study

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects.

Cross-validation of Input Functions Obtained by H2 15O PET Imaging of Rat Heart and a Blood Flow-through Detector

Positron emission tomography (PET) with ¹⁵O-labeled water (H₂ ¹⁵O) facilitates the visualization and quantification of blood flow in clinical investigations and also in small animals. The quantification of blood flow requires an input function, which is generally obtained by measuring radioactivity in arterial blood withdrawn during PET scanning. However, this approach is not always feasible, because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop and cross-validate two methods, namely, a blood- and an image-based method for obtaining the input function for blood flow studies from rat H₂ ¹⁵O PET. The study material consisted of two separate groups of rats. Group 1 rats were imaged twice by a high-resolution research tomograph PET camera at resting condition for a test-retest study (n = 4), and group 2 rats were imaged with and without adenosine infusion for a rest-stress study (n = 4). In group 1, radioactivity concentration in arterial blood was measured with a new flow-through detector during imaging and a blood-based input function was obtained. The image-based input function was estimated using time-activity curves from the left ventricle and myocardial regions. To validate the two input function methods, myocardial blood flow (MBF) and cerebral blood flow (CBF) were computed, and the methods were tested for reproducibility (test-retest study) and changes (rest-stress study). The blood- and image-based input functions were similar, and the corresponding CBF values differed only by -6.9 ± 8.1%. In the test-retest study, both MBF and CBF showed good reproducibility, and in the rest-stress study, adenosine significantly increased both MBF (P = 0.035) and CBF (P = 0.029), compared with the resting condition. It is possible both to measure the input function from rat arteria femoralis during H₂ ¹⁵O PET imaging and to estimate the input function from rat H₂ ¹⁵O PET images, thereby facilitating the assessment of blood flow in organs visible in PET images.

Fully 3D iterative scatter-corrected OSEM for HRRT PET using a GPU

Accurate scatter correction is especially important for high-resolution 3D positron emission tomographies (PETs) such as high-resolution research tomograph (HRRT) due to large scatter fraction in the data. To address this problem, a fully 3D iterative scatter-corrected ordered subset expectation maximization (OSEM) in which a 3D single scatter simulation (SSS) is alternatively performed with a 3D OSEM reconstruction was recently proposed. However, due to the computational complexity of both SSS and OSEM algorithms for a high-resolution 3D PET, it has not been widely used in practice. The main objective of this paper is, therefore, to accelerate the fully 3D iterative scatter-corrected OSEM using a graphics processing unit (GPU) and verify its performance for an HRRT. We show that to exploit the massive thread structures of the GPU, several algorithmic modifications are necessary. For SSS implementation, a sinogram-driven approach is found to be more appropriate compared to a detector-driven approach, as fast linear interpolation can be performed in the sinogram domain through the use of texture memory. Furthermore, a pixel-driven backprojector and a ray-driven projector can be significantly accelerated by assigning threads to voxels and sinograms, respectively. Using Nvidia's GPU and compute unified device architecture (CUDA), the execution time of a SSS is less than 6 s, a single iteration of OSEM with 16 subsets takes 16 s, and a single iteration of the fully 3D scatter-corrected OSEM composed of a SSS and six iterations of OSEM takes under 105 s for the HRRT geometry, which corresponds to acceleration factors of 125× and 141× for OSEM and SSS, respectively. The fully 3D iterative scatter-corrected OSEM algorithm is validated in simulations using Geant4 application for tomographic emission and in actual experiments using an HRRT.

Imaging of the Striatal and Extrastriatal Dopamine Transporter with 18F-LBT-999: Quantification, Biodistribution, and Radiation Dosimetry in Nonhuman Primates

The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand (18)F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((18)F-LBT-999) in nonhuman primates. The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V(T)), nondisplaceable distribution volume (V(ND)), binding potential relative to the free concentration of radioligand in plasma (BP(F)), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP(ND)) = V(T) - V(ND)/V(ND) using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software. (18)F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissue-compartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V(T), BP(F), and BP(ND). When the different models were compared with the 2-tissue-compartment model, the underestimation of V(T) or BP(ND) was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of (18)F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of (18)F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq. (18)F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used (18)F-labeled radioligands, for example, (18)F-FDG (0.024-0.027 mSv/MBq).

Glucose metabolism in small subcortical structures in Parkinson’s disease

Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei. Using the HRRT, we performed [(18)F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism. The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD. The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2-deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe.