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Unlabelled: PET with (15)O gas has been used for the quantitative measurement of cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF), and cerebral blood volume (CBV) in humans. However, several technical difficulties limit its use in experiments on small animals. Herein, we describe the application of the (15)O gas steady-state inhalation method for normal anesthetized rats., Methods: Eight normal male Sprague-Dawley rats (mean body weight ± SD, 268 ± 14 g) under anesthesia were investigated by (15)O-labeled gas PET. After tracheotomy, an airway tube was placed in the trachea, and the animals were connected to a ventilator (tidal volume, 3 cm(3); frequency, 60/min). The CBF and OEF were measured according to the original steady-state inhalation technique under artificial ventilation with (15)O-CO(2) and (15)O-O(2) gases delivered through the radioactive gas stabilizer. CBV was measured by (15)O-CO gas inhalation and corrected for the intravascular hemoglobin-bound (15)O-O(2). Arterial blood sampling was performed during each study to measure the radioactivity of the whole blood and plasma. MR image was performed with the same acrylic animal holder immediately after the PET. Regions of interest were placed on the whole brain of the PET images with reference to the semiautomatically coregistered PET/MR fused images., Results: The data acquisition time for the whole PET experiment in each rat was 73.3 ± 5.8 (range, 68-85) min. In both the (15)O-CO(2) and the (15)O-O(2) studies, the radioactivity count of the brain reached a steady state by approximately 10 min after the start of continuous inhalation of the gas. The quantitative PET data of the whole brain were as follows: CBF, 32.3 ± 4.5 mL/100 mL/min; CMRO(2), 3.23 ± 0.42 mL/100 mL/min; OEF, 64.6% ± 9.1%; and CBV, 5.05 ± 0.45 mL/100 mL., Conclusion: Although further technical improvements may be needed, this study demonstrated the feasibility of quantitative PET measurement of CBF, OEF, and CMRO(2) using the original steady-state inhalation method of (15)O-CO(2) and (15)O-O(2) gases and measurement of CBV using the (15)O-CO gas inhalation method in the brain of normal anesthetized rats.

Introduction: Measurement of regional cerebral blood flow (rCBF) in rodents can provide knowledge of pathophysiology of the cerebral circulation, but generally requires blood sampling for analysis during positron emission tomography (PET). We therefore tested the feasibility of using an arteriovenous (AV) shunt in rats for less invasive blood analysis., Methods: Six anesthetized rats received [15O]H2O and [15O]CO PET scans with their femoral artery and vein connected by an AV shunt, the activity within which was measured with a germanium ortho-oxysilicate scintillation detector. The [15O]H2O was intravenously injected either at a faster or slower injection rate, while animals were placed either with their head or heart centered in the gantry. The time-activity curve (TAC) from the AV shunt was compared with that from the cardiac ventricle in PET image. The rCBF values were calculated by a nonlinear least-square method using the dispersion-corrected AV-shunt TAC as an input., Results: The AV-shunt TAC had higher signal-to-noise ratio, but also had delay and dispersion compared with the image-derived TAC. The delay time between the AV-shunt TAC and image-based TAC ranged from 11 to 21 s, while the dispersion was estimated to be ∼5 s as a time constant of the dispersion model of exponential function, and both were properly corrected. In a steady-state condition of [15O]CO PET, the blood activity concentration by AV-shunt TAC was also comparable in height with the image-based TAC corrected for partial volume. Whole-brain CBF values measured by [15O]H2O were 0.37±0.04 (mean±S.D.) ml/g/min, partition coefficient was 0.73±0.04 ml/g, and the CBF varied in a linear relationship with partial pressure of carbon dioxide during each scan., Conclusions: The AV-shunt technique allows less invasive, quantitative and reproducible measurement of rCBF in [15O]H2O PET studies in rats than direct blood sampling and radioassay., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: This study is intended to evaluate the feasibility of using a high-resolution pinhole SPECT system and iodine-123-N-isopropyl-4-iodoamphetamine ((123)I-IMP) for three-dimensional (3D) absolute quantitation of regional cerebral blood flow (rCBF) in mice., Methods: The pinhole SPECT system consists of a rotating stage and a pinhole collimator attached to a clinical gamma camera. The collimator's focal length is 251 mm. Phantom studies were performed to evaluate sensitivity and full-width half-maximum (FWHM) spatial resolution. The aperture-to-object distance was 15 mm. Six mice were studied. Cerebral infarctions were induced by ligating and disconnecting the distal portion of the left middle cerebral artery. Ex vivo SPECT studies were performed using harvested brains and skulls. The CBF volumetric image was computed using the standardized input function., Results: Excellent spatial resolution of 0.9-mm FWHM and uniform sensitivity throughout the 3D volume were demonstrated in the phantom experiments. The CBF images showed a defect in the infarcted areas and a reduction of CBF values in the infarcted region as compared with the control region., Conclusions: This study demonstrated the feasibility of the 3D quantitation of rCBF in mice using a high-resolution pinhole SPECT system and (123)I-IMP., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF), and cerebral blood volume (CBV) are quantitatively measured with PET with (15)O gases. Kudomi et al. developed a dual tracer autoradiographic (DARG) protocol that enables the duration of a PET study to be shortened by sequentially administrating (15)O(2) and C(15)O(2) gases. In this protocol, before the sequential PET scan with (15)O(2) and C(15)O(2) gases ((15)O(2)-C(15)O(2) PET scan), a PET scan with C(15)O should be preceded to obtain CBV image. C(15)O has a high affinity for red blood cells and a very slow washout rate, and residual radioactivity from C(15)O might exist during a (15)O(2)-C(15)O(2) PET scan. As the current DARG method assumes no residual C(15)O radioactivity before scanning, we performed computer simulations to evaluate the influence of the residual C(15)O radioactivity on the accuracy of measured CBF and OEF values with DARG method and also proposed a subtraction technique to minimize the error due to the residual C(15)O radioactivity., Methods: In the simulation, normal and ischemic conditions were considered. The (15)O(2) and C(15)O(2) PET count curves with the residual C(15)O PET counts were generated by the arterial input function with the residual C(15)O radioactivity. The amounts of residual C(15)O radioactivity were varied by changing the interval between the C(15)O PET scan and (15)O(2)-C(15)O(2) PET scan, and the absolute inhaled radioactivity of the C(15)O gas. Using the simulated input functions and the PET counts, the CBF and OEF were computed by the DARG method. Furthermore, we evaluated a subtraction method that subtracts the influence of the C(15)O gas in the input function and PET counts., Results: Our simulations revealed that the CBF and OEF values were underestimated by the residual C(15)O radioactivity. The magnitude of this underestimation depended on the amount of C(15)O radioactivity and the physiological conditions. This underestimation was corrected by the subtraction method., Conclusions: This study showed the influence of C(15)O radioactivity in DARG protocol, and the magnitude of the influence was affected by several factors, such as the radioactivity of C(15)O, and the physiological condition.

Cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF) and cerebral blood flow (CBF) images can be quantified using positron emission tomography (PET) by administrating (15)O-labelled water (H(15)(2)O) and oxygen ((15)O(2)). Conventionally, those images are measured with separate scans for three tracers C(15)O for CBV, H(15)(2)O for CBF and (15)O(2) for CMRO(2), and there are additional waiting times between the scans in order to minimize the influence of the radioactivity from the previous tracers, which results in a relatively long study period. We have proposed a dual tracer autoradiographic (DARG) approach (Kudomi et al 2005), which enabled us to measure CBF, OEF and CMRO(2) rapidly by sequentially administrating H(15)(2)O and (15)O(2) within a short time. Because quantitative CBF and CMRO(2) values are sensitive to arterial input function, it is necessary to obtain accurate input function and a drawback of this approach is to require separation of the measured arterial blood time-activity curve (TAC) into pure water and oxygen input functions under the existence of residual radioactivity from the first injected tracer. For this separation, frequent manual sampling was required. The present paper describes two calculation methods: namely a linear and a model-based method, to separate the measured arterial TAC into its water and oxygen components. In order to validate these methods, we first generated a blood TAC for the DARG approach by combining the water and oxygen input functions obtained in a series of PET studies on normal human subjects. The combined data were then separated into water and oxygen components by the present methods. CBF and CMRO(2) were calculated using those separated input functions and tissue TAC. The quantitative accuracy in the CBF and CMRO(2) values by the DARG approach did not exceed the acceptable range, i.e., errors in those values were within 5%, when the area under the curve in the input function of the second tracer was larger than half of the first one. Bias and deviation in those values were also compatible to that of the conventional method, when noise was imposed on the arterial TAC. We concluded that the present calculation based methods could be of use for quantitatively calculating CBF and CMRO(2) with the DARG approach.

The threshold of cerebral blood flow (CBF) into infarction in rats has been indicated to be similar to that in patients. However, CBF does not reflect metabolic function, and so estimations of oxygen metabolism have been required. Here, we estimated changes in oxygen metabolism after occluding the right middle cerebral artery (MCA) in rats using an injectable (15)O-O(2) we developed. A decrease in CBF (left: 0.67+/-0.22 mL/min/g, right: 0.44+/-0.17 mL/min/g, P<0.05) and compensatory increase in the oxygen extraction fraction (OEF) (left: 0.42+/-0.13, right: 0.50+/-0.19, P<0.05) were observed at 1-h after occlusion. In contrast, a marked decrease in CBF and the cerebral metabolic rate for oxygen and a collapse of the compensatory OEF mechanism were found at 24 h after occlusion. Injectable (15)O-O(2) could be used to reliably estimate oxygen metabolism in an infarction rat model with positron emission tomography.

A new method has been developed for diffusible tracers, to quantify CBF at rest and after pharmacological stress from a single session of dynamic scans with dual bolus administration of a radiotracer. The calculation process consisted of three steps, including the procedures of incorporating background radioactivity contaminated from the previous scan. Feasibility of this approach was tested on clinical SPECT studies on 16 subjects. Two sequential SPECT scans, 30 min apart, were carried out on each subject, after each of two split-dose administrations of 111 MBq IMP. Of these, 11 subjects received acetazolamide at 10 min before the second IMP injection. Additional PET scans were also carried out on 6 subjects on a separate day, at rest and after acetazolamide administration. The other 5 subjects were scanned only at rest during the whole study period. Quantitative CBF obtained by this method was in a good agreement with those determined with PET (y(ml/100 g/min)=1.07x(ml/100 g/min)-1.14, r=0.94). Vasareactivity was approximately 40% over the whole cerebral area on healthy controls, which was consistent with a literature value. Reproducibility of CBF determined in the rest-rest study was 1.5+/-5.7%. Noise enhancement of CBF images, particularly the second CBF, was reduced, providing reasonable image quality. Repeat assessment of quantitative CBF from a single session of scans with split-dose IMP is accurate, and may be applied to clinical research for assessing vascular reactivity in patients with chronic cerebral vascular disease.

Purpose: An image-based scatter correction (IBSC) method was developed to convert scatter-uncorrected into scatter-corrected SPECT images. The purpose of this study was to validate this method by means of phantom simulations and human studies with 99mTc-labeled tracers, based on comparison with the conventional triple energy window (TEW) method., Methods: The IBSC method corrects scatter on the reconstructed image I(mub)AC with Chang's attenuation correction factor. The scatter component image is estimated by convolving I(mub)AC with a scatter function followed by multiplication with an image-based scatter fraction function. The IBSC method was evaluated with Monte Carlo simulations and 99mTc-ethyl cysteinate dimer SPECT human brain perfusion studies obtained from five volunteers. The image counts and contrast of the scatter-corrected images obtained by the IBSC and TEW methods were compared., Results: Using data obtained from the simulations, the image counts and contrast of the scatter-corrected images obtained by the IBSC and TEW methods were found to be nearly identical for both gray and white matter. In human brain images, no significant differences in image contrast were observed between the IBSC and TEW methods., Conclusion: The IBSC method is a simple scatter correction technique feasible for use in clinical routine.

Cerebral blood flow (CBF) and rate of oxygen metabolism (CMRO(2)) may be quantified using positron emission tomography (PET) with (15)O-tracers, but the conventional three-step technique requires a relatively long study period, attributed to the need for separate acquisition for each of (15)O(2), H(2)(15)O, and C(15)O tracers, which makes the multiple measurements at different physiologic conditions difficult. In this study, we present a novel, faster technique that provides a pixel-by-pixel calculation of CBF and CMRO(2) from a single PET acquisition with a sequential administration of (15)O(2) and H(2)(15)O. Experiments were performed on six anesthetized monkeys to validate this technique. The global CBF, oxygen extraction fraction (OEF), and CMRO(2) obtained by the present technique at rest were not significantly different from those obtained with three-step method. The global OEF (gOEF) also agreed with that determined by simultaneous arterio-sinus blood sampling (gOEF(A-V)) for a physiologically wide range when changing the arterial PaCO(2) (gOEF=1.03gOEF(A-V)+0.01, P<0.001). The regional values, as well as the image quality were identical between the present technique and three-step method for CBF, OEF, and CMRO(2). In addition, a simulation study showed that error sensitivity of the present technique to delay or dispersion of the input function, and the error in the partition coefficient was equivalent to that observed for three-step method. Error sensitivity to cerebral blood volume (CBV) was also identical to that in the three-step and reasonably small, suggesting that a single CBV assessment is sufficient for repeated measures of CBF/CMRO(2). These results show that this fast technique has an ability for accurate assessment of CBF/CMRO(2) and also allows multiple assessment at different physiologic conditions.

The difference in tracer arrival times between the external radiation detector and the brain following administration of radioactivity (delay time) must be estimated correctly in order to quantitatively measure regional cerebral blood flow (rCBF) with positron emission tomography and [15O]H2O by autoradiographic method. Instead of intervenous injection of [15O]H2O, bolus inhalation of [15O]CO2 gas is sometimes used to simplify the measurement of rCBF. In the case of [15O]CO2, radioactive gas in mask and nasal cavity contributes large artifact on the sinogram data and it is difficult to estimate delay time from the sinogram data. In this paper, we proposed a new method to estimate the delay time using the sinogram data and the attenuation map (attenuation weighted sinogram method). In the present method, the attenuation map was used to eliminate the effect of the gas outside the brain region from the sinogram data. For the validation of the present method, PET data with [15O]CO2 (n = 10) were analyzed. Three methods, namely the image method, the sinogram method and the attenuation weighted sinogram method were used to estimate the delay time. The estimated delay times and calculated rCBF images by three methods were compared. Due to the radioactivity outside of the brain, the sinogram method significantly overestimated the delay time and thus underestimated the rCBF value compared with the image base method. On the other hand, there were good agreements between the delay times estimated by the attenuation weighted sinogram method and the image method. The present method can eliminate the effect of the radioactivity outside of the brain on the sinogram data and estimate the delay time accurately and fast enough for clinical use.

The coupling of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) during physiologic and pathophysiologic conditions remains the subject of debate. In the present study, we have developed a theoretical model for oxygen delivery and metabolism, which describes the diffusion of oxygen at the capillary-tissue interface and the nonlinear nature of hemoglobin (Hb) affinity to oxygen, allowing a variation in simple-capillary oxygen diffusibility, termed "effective oxygen diffusibility (EOD)." The model was used to simulate the relationship between CBF and CMRO2, as well as oxygen extraction fraction (OEF), when various pathophysiologic conditions were assumed involving functional activation, ischemia, hypoxia, anemia, or hypo- and hyper-capnic CBF variations. The simulations revealed that, to maintain CMRO2 constant, a variation in CBF and Hb required active change in EOD. In contrast, unless the EOD change took place, the brain allowed small but significant nonlinear change in CMRO2 directly dependent upon oxygen delivery. Application of the present model to quantitative neuroimaging of CBF and CMRO2 enables us to evaluate the biologic response at capillary level other than Hb- and flow-dependent properties of oxygen transport and may give us another insight regarding the physiologic control of oxygen delivery in the human brain.

The purpose of this study was to develop a reliable and practical strategy that generates quantitative CBF and OEF maps accurately from PET data sets obtained with 15O-tracers. Sequential sinogram data sets were acquired after the administration of 15O-tracers, and combined single-frame images were obtained. The delay time between sampled input function and the brain was estimated from the H2(15)O study with the whole brain and the arterial time-activity curves (TACs). The whole-brain TACs were obtained from the reconstructed images (image-base method) and the sinogram data (sinogram-base method). Six methods were also evaluated for the dead-time and decay correction procedures in the process of generating a single-frame image from the dynamic sinogram. The estimated delay values were similar with both the sinogram-based and image-based methods. A lumped correction factor to a previously added single-frame sinogram caused an underestimation of CBF, OEF and CMRO2 by 16% at maximum, as compared with the correction procedure for a short sinogram. This suggested the need for a dynamic acquisition of a sinogram with a short interval. The proposed strategy provided an accurate quantification of CBF and OEF by PET with 15O-tracers.

This study proposes a new method for the pixel-by-pixel quantification of regional CBF (rCBF) with positron emission tomography and H(15)(2)O by using a reference tissue region. No arterial blood is required. Simulation studies revealed that the calculation of rCBF was fairly stable provided that the frame time was relatively short compared with total scan time. In practice, calculated CBF images correlated significantly with those obtained with the dynamic/integral method. Because the method accurately detects changes in CBF, it is particularly suitable for brain activation studies.

This study proposes a new solution for the quantification of rCBF pixel-by-pixel using PET and 15O-H2O. The method represents an application of weighted integration that used PET image only, requiring no input function of arterial blood. It generates the rCBF image quickly and automatically. Simulation studies revealed that the calculation of rCBF was fairly stable as long as a relatively shorter scan frame time and longer scan time were selected. Calculated images of actual PET study by this method correlated significantly with those identified by the dynamic/integral method. Because this procedure could detect whole brain CBF change between different studies as accurately as by the dynamic/integral method, this procedure may be the most suitable for brain activation studies.

Unlabelled: A noninvasive method, the double-integration method, was developed to estimate regional cerebral blood flow (rCBF) by using 15O-water and PET. It relies on the acquisition of images with a correction of nonlinearity of brain tissue counts and can produce rCBF images on a pixel-by-pixel basis., Methods: Oxygen-15-water PET studies were performed on five normal human volunteers, and continuous sampling from the radial artery was conducted to generate functional CBF images according to the invasive catheterization method. The method centers on a computer-based program elaborated to calculate an arterial input function with an assumption of the whole brain blood rate of 50 ml/dl/min and consequently does not require arterial catheterization or arterial input function sampled from other studies., Results: The results indicate a good correlation between this method and the invasive method (r > 0.966, p < 0.001)., Conclusion: This noninvasive method was demonstrated to provide an accurate estimation of rCBF and may simplify the activation studies.