System evaluation of automated production and inhalation of 15O-labeled gaseous radiopharmaceuticals for the rapid 15O-oxygen PET examinations.

BACKGROUND: 15O-oxygen inhalation PET is unique in its ability to provide fundamental information regarding cerebral hemodynamics and energy metabolism in man. However, the use of 15O-oxygen has been limited in a clinical environment largely attributed to logistical complexity, in relation to a long study period, and the need to produce and inhale three sets of radiopharmaceuticals. Despite the recent works that enabled shortening of the PET examination period, radiopharmaceutical production has still been a limiting factor. This study was aimed to evaluate a recently developed radiosynthesis/inhalation system that automatically supplies a series of 15O-labeled gaseous radiopharmaceuticals of C15O, 15O2, and C15O2 at short intervals. METHODS: The system consists of a radiosynthesizer which produces C15O, 15O2, and C15O2; an inhalation controller; and an inhalation/scavenging unit. All three parts are controlled by a common sequencer, enabling automated production and inhalation at intervals less than 4.5 min. The gas inhalation/scavenging unit controls to sequentially supply of qualified radiopharmaceuticals at given radioactivity for given periods at given intervals. The unit also scavenges effectively the non-inhaled radioactive gases. Performance and reproducibility are evaluated. RESULTS: Using an 15O-dedicated cyclotron with deuteron of 3.5 MeV at 40 µA, C15O, 15O2, and C15O2 were sequentially produced at a constant rate of 1400, 2400, and 2000 MBq/min, respectively. Each of radiopharmaceuticals were stably inhaled at < 4.5 min intervals with negligible contamination from the previous supply. The two-hole two-layered face mask with scavenging device minimized the gaseous radioactivity surrounding subject's face, while maintaining the normocapnia during examination periods. Quantitative assessment of net administration doses could be assessed using a pair of radio-detectors at inlet and scavenging tubes, as 541 ± 149, 320 ± 103, 523 ± 137 MBq corresponding to 2-min supply of 2574 ± 255 MBq for C15O, and 1-min supply of 2220 ± 766 and 1763 ± 174 for 15O2 and C15O2, respectively. CONCLUSIONS: The present system allowed for automated production and inhalation of series of 15O-labeled radiopharmaceuticals as required in the rapid 15O-Oxygen PET protocol. The production and inhalation were reproducible and improved logistical complexity, and thus the use of 15O-oxygen might have become practically applicable in clinical environments.

Cerebral blood flow and metabolism associated with cerebral microbleeds in small vessel disease.

OBJECTIVE: Cerebral microbleeds (CMBs), probably reflecting microangiopathy, have not yet sufficiently been examined in association with cerebral blood flow (CBF) and metabolism. We investigated the relationships between CMBs, and CBF and metabolism in symptomatic small vessel disease. METHODS: We enrolled 22 patients with symptomatic small vessel disease without severe stenosis (>50 %) in major cerebral arteries. Volumes of white matter lesions (WMLs) and number of CMBs were assessed on images of fluid-attenuated inversion recovery and gradient-echo T2*-weighted magnetic resonance imaging, respectively. Patients were divided into two groups according to the median number of CMBs (group I <5, n = 10; group II ≥5, n = 12). Parametric images of CBF, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction and cerebral blood volume were estimated using positron emission tomography and (15)O-labeled gases. The functional values in the cortex-subcortex, basal ganglia, and centrum semiovale were compared between the two groups. RESULTS: Volumes of WMLs of group II were larger than those of group I (median: 38.4; range: 25.1-91.5 mL vs. median: 11.3; range: 4.2-73.4 mL, p = 0.01). In the centrum semiovale, the mean CBF of group II was significantly lower than that of group I (12.6 ± 2.6 vs. 15.6 ± 3.3 mL/100 g/min, p = 0.04). In the other regions, there were no significant differences in either CBF or CMRO2 between the two groups. CONCLUSIONS: Our study indicated that increases in the number of CMBs with larger volumes of WMLs were associated with cerebral ischemia in the deep white matter in patients with symptomatic small vessel disease.

PET quantification of cerebral oxygen metabolism in small animals.

Understanding cerebral oxygen metabolism is of great importance in both clinical diagnosis and animal experiments because oxygen is a fundamental source of brain energy and supports brain functional activities. Since small animals such as rats are widely used to study various diseases including cerebral ischemia, cerebrovascular diseases, and neurodegenerative diseases, the development of a noninvasive in vivo measurement method of cerebral oxygen metabolic parameters such as oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) as well as cerebral blood flow (CBF) and cerebral blood volume (CBV) has been a priority. Although positron emission tomography (PET) with (15)O labeled gas tracers has been recognized as a powerful way to evaluate cerebral oxygen metabolism in humans, this method could not be applied to rats due to technical problems and there were no reports of PET measurement of cerebral oxygen metabolism in rats until an (15)O-O2 injection method was developed a decade ago. Herein, we introduce an intravenous administration method using two types of injectable (15)O-O2 and an (15)O-O2 gas inhalation method through an airway placed in the trachea, which enables oxygen metabolism measurements in rats.

Validity of using a 3-dimensional PET scanner during inhalation of 15O-labeled oxygen for quantitative assessment of regional metabolic rate of oxygen in man.

Use of 15O labeled oxygen (15O2) and positron emission tomography (PET) allows quantitative assessment of the regional metabolic rate of oxygen (CMRO2) in vivo, which is essential to understanding the pathological status of patients with cerebral vascular and neurological disorders. The method has, however, been challenging, when a 3D PET scanner is employed, largely attributed to the presence of gaseous radioactivity in the trachea and the inhalation system, which results in a large amount of scatter and random events in the PET assessment. The present study was intended to evaluate the adequacy of using a recently available commercial 3D PET scanner in the assessment of regional cerebral radioactivity distribution during an inhalation of 15O2. Systematic experiments were carried out on a brain phantom. Experiments were also performed on a healthy volunteer following a recently developed protocol for simultaneous assessment of CMRO2 and cerebral blood flow, which involves sequential administration of 15O2 and C15O2. A particular intention was to evaluate the adequacy of the scatter-correction procedures. The phantom experiment demonstrated that errors were within 3% at the practically maximum radioactivity in the face mask, with the greatest radioactivity in the lung. The volunteer experiment demonstrated that the counting rate was at peak during the 15O gas inhalation period, within a verified range. Tomographic images represented good quality over the entire FOV, including the lower part of the cerebral structures and the carotid artery regions. The scatter-correction procedures appeared to be important, particularly in the process to compensate for the scatter originating outside the FOV. Reconstructed images dramatically changed if the correction was carried out using inappropriate procedures. This study demonstrated that accurate reconstruction could be obtained when the scatter compensation was appropriately carried out. This study also suggested the feasibility of using a state-of-the-art 3D PET scanner in the quantitative PET imaging during inhalation of 15O labeled oxygen.

Quantification of myocardial blood flow using (201)Tl SPECT and population-based input function.

OBJECTIVES: Thallium-201 ((201)Tl) single photon emission computed tomography (SPECT) is an important tool in the diagnosis of ischemic heart disease. Absolute quantification of myocardial blood flow (MBF) has the potential to provide more useful information on myocardial perfusion than semi-quantitative assessments. This study aimed to validate the quantification of MBF using (201)Tl cardiac SPECT based on a population-averaged input function (STD-IF) and one-point blood sample technique. METHODS: (201)Tl emission and computed tomography (CT)-based attenuation scans were performed on 11 healthy volunteers at rest using a SPECT/CT scanner. Individual input functions (IND-IFs) during the emission scans were based on arterial blood samples. The STD-IF technique was validated as follows: (1) optimal time to calibrate a STD-IF was determined to minimize differences between the calibrated STD-IF and the IND-IFs. (2) Tissue time-activity curves (TTACs) were generated based on a single-tissue compartment model for MBFtrue = 0.5, 1.0, 1.5, and 2.0 mL/min/g, a constant distribution volume of 45 mL/mL, and IND-IFs. The pseudo STD-IF for each subject was generated using the leave-one-out technique. Using the optimal calibration time and the pseudo STD-IFs, MBF values were estimated on the TTACs with an autoradiography method. Optimal mid-scan time (MST) with a fixed duration of 20 min was determined to minimize intersubject variation in estimated MBF errors, and (3) Global and regional MBF values estimated with pseudo STD-IFs were compared to those with IND-IFs using the optimal calibration time and MST. RESULTS: The optimal calibration time and MST were both 20 min after (201)Tl injection. Global MBF determined using both IND-IFs and pseudo STD-IF showed significant correlations with rate-pressure products, R (2) = 0.645; p < 0.01 and R (2) = 0.303; p < 0.05, respectively. The mean percent error in regional MBF using pseudo STD-IFs was 0.69 ± 7.80 % (-12.80 to 14.25 %). No significant difference was observed between regional MBF values using IND-IFs and pseudo STD-IFs. CONCLUSION: This study demonstrated that the proposed technique based on a STD-IF and one-point blood sample provided hemodynamically reasonable global MBF values and the regional MBF values comparable to those with IND-IFs.

Adequacy of a compartment model for CMRO2 quantitation using ¹5O-labeled oxygen and PET: a clearance measurement of ¹5O-radioactivity following intracarotid bolus injection of ¹5O-labeled oxyhemoglobin on Macaca fascicularis.

We aimed at evaluating the adequacy of the commonly employed compartmental model for quantitation of cerebral metabolic rate of oxygen (CMRO2) using (15)O-labeled oxygen ((15)O2) and positron emission tomography (PET). Sequential PET imaging was carried out on monkeys following slow bolus injection of blood samples containing (15)O2-oxyhemoglobin ((15)O2-Hb), (15)O-labeled water (H2(15)O), and C(15)O-labeled hemoglobin (C(15)O-Hb) into the internal carotid artery (ICA). Clearance slopes were assessed in the middle cerebral artery territory of the injected hemisphere. The time-activity curves were bi-exponential for both (15)O2-Hb and H2(15)O. Single exponential fitting to the early (5 to 40 seconds) and late (80 to 240 seconds) periods after the peak was performed and the (15)O2-Hb and H2(15)O results were compared. It was found that a significant difference between the clearance rates of the (15)O2-Hb and H2(15)O injections is unlikely, which supports the mathematical model that is widely used to describe the kinetics of (15)O2-Hb and H2(15)O in cerebral tissues and is the basis of recent approaches to simultaneously assess CMRO2 and cerebral blood flow in a single PET session. However, it should be noted that more data are necessary to unequivocally confirm the result.

Three-dimensional brain phantom containing bone and grey matter structures with a realistic head contour.

INTRODUCTION: A physical 3-dimensional phantom that simulates PET/SPECT images of static regional cerebral blood flow in grey matter with a realistic head contour has been developed. This study examined the feasibility of using this phantom for evaluating PET/SPECT images. METHODS: The phantom was constructed using a transparent, hydrophobic photo-curable polymer with a laser-modelling technique. The phantom was designed to contain the grey matter, the skull, and the trachea spaces filled with a radioactive solution, a bone-equivalent solution of K(2)HPO(4), and air, respectively. The grey matter and bone compartments were designed to establish the connectivity. A series of experiments was performed to confirm the accuracy and reproducibility of the phantom using X-ray CT, SPECT, and PET. RESULTS: The total weight was 1997 ± 2 g excluding the inner liquid, and volumes were 563 ± 1 and 306 ± 2 mL, corresponding to the grey matter and bone compartments, respectively. The apparent attenuation coefficient averaged over the whole brain was 0.168 ± 0.006 cm(-1) for Tc-99 m, which was consistent with the previously reported value for humans (0.168 ± 0.010 cm(-1)). Air bubbles were well removed from both grey-matter and bone compartments, as confirmed by X-ray CT. The phantom was well adapted to experiments using PET and SPECT devices. CONCLUSION: The 3-dimensional brain phantom constructed in this study may be of use for evaluating the adequacy of SPECT/PET reconstruction software programs.

Quantitative assessment of regional cerebral blood flow by dynamic susceptibility contrast-enhanced MRI, without the need for arterial blood signals.

In dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI), an arterial input function (AIF) is usually obtained from a time-concentration curve (TCC) of the cerebral artery. This study was aimed at developing an alternative technique for reconstructing AIF from TCCs of multiple brain regions. AIF was formulated by a multi-exponential function using four parameters, and the parameters were determined so that the AIF curves convolved with a model of tissue response reproduced the measured TCCs for 20 regions. Systematic simulations were performed to evaluate the effects of possible error sources. DSC-MRI and positron emission tomography (PET) studies were performed on 14 patients with major cerebral artery occlusion. Cerebral blood flow (CBF) images were calculated from DSC-MRI data, using our novel method alongside conventional AIF estimations, and compared with those from (15)O-PET. Simulations showed that the calculated CBF values were sensitive to variations in the assumptions regarding cerebral blood volume. Nevertheless, AIFs were reasonably reconstructed for all patients. The difference in CBF values between DSC-MRI and PET was -2.2 ± 7.4 ml/100 g/min (r = 0.55, p < 0.01) for our method, versus -0.2 ± 8.2 ml/100 g/min (r = 0.47, p = 0.01) for the conventional method. The difference in the ratio of affected to unaffected hemispheres between DSC-MRI and PET was 0.07 ± 0.09 (r = 0.82, p < 0.01) for our method, versus 0.07 ± 0.09 (r = 0.83, p < 0.01) for the conventional method. The contrasts in CBF images from our method were the same as those from the conventional method. These findings suggest the feasibility of assessing CBF without arterial blood signals.

Breath-hold CT attenuation correction for quantitative cardiac SPECT.

BACKGROUND: Attenuation correction of a single photon emission computed tomography (SPECT) image is possible using computed tomography (CT)-based attenuation maps with hybrid SPECT/CT. CT attenuation maps acquired during breath holding can be misaligned with SPECT, generating artifacts in the reconstructed images. The purpose of this study was to investigate the effects of respiratory phase during breath-hold CT acquisition on attenuation correction of cardiac SPECT imaging. METHODS: A series of 201Tl-emission and 99mTc-based transmission computed tomography (TCT) scans was carried out along with CT-attenuation scans on 11 young normal volunteers using a hybrid SPECT/CT scanner. The CT scans were performed at three respiratory phases: end-inspiration (INS), end-expiration (EXP), and the midpoint (MID) between these phases. Using alignment parameters between attenuation maps and SPECT images without attenuation or scatter corrections, quantitative SPECT images were reconstructed, including corrections for attenuation and scatter. Regional radioactivity concentrations normalized by the subjects' weights were compared between CT- and TCT-based attenuation correction techniques. RESULTS: SPECT images with CT attenuation maps at the EXP phase showed significant differences in regional weight-normalized radioactivity concentrations relative to the images using the other attenuation maps (p < 0.05), as well as systematic positive bias errors, compared to TCT-based images for all myocardial segments, 5.7% ± 2.7% (1.9% to 10.0%). No significant differences in regional weight-normalized radioactivity concentrations were observed between images with CT attenuation maps at MID and INS phases or between these and the TCT-based images, but regional tendencies were found: for anterior to anterolateral segment, positive bias of 5.0% ± 2.2% (1.3% to 8.1%) and 5.6% ± 1.9% (2.6% to 8.5%) and for inferior to inferoseptal segment, negative bias of -5.3% ± 2.6% (-9.1% to -1.7%) and -4.6% ± 2.5% (-8.8% to -1.5%) for the MID and INS phases, respectively. CONCLUSIONS: Use of breath-hold CT attenuation maps at INS and MID phases for attenuation and scatter corrections demonstrated accurate quantitative images that would prove beneficial in cardiac SPECT/CT studies.