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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 equivalent mixture of cis-3-hexenol and trans-2-hexenal (hexenol/hexenal), 'green odor', is known to have a healing effect on the psychological damage caused by stress. Behavioral studies in humans and monkeys have revealed that hexenol/hexenal prevents the prolongation of reaction time caused by fatigue. In the present study, we investigated which brain regions are activated by the odor of hexenol/hexenal using positron emission tomography with alert monkeys. Regional cerebral blood flow (rCBF) in the prepyriform area (the primary olfactory cortex) was commonly increased by the passive application of odor: acetic acid, isoamylacetate or hexenol/hexenal. We observed rCBF increases in the orbitofrontal cortex (the secondary olfactory cortex) by these olfactory stimuli in two of three monkeys, and found no predominance of laterality of the activated hemisphere. Furthermore, rCBF increase in the cerebellum was observed in two of three monkeys, and the odor of acetic acid increased rCBF in the substantia innominata in all monkeys. In addition to these olfactory related regions, the anterior cingulate gyrus was activated by the odor of hexenol/hexenal. These findings suggest that the increase of rCBF in the anterior cingulate gyrus by the odor of hexenol/hexenal may contribute the healing effects of this mixture observed in the monkey.

Cerebral metabolic rate for oxygen (CMRO(2)) and cerebral oxygen extraction fraction (OEF) are some of the most fundamental parameters to characterize the pathophysiologic status of cerebral tissue. Although O-15-labeled gases inhalation method is performed in clinical studies, application of the inhalation method on small animals requires too many intensive procedures. On this basis, the development of a new method to measure CMRO(2) and OEF in small animals is of interest. This study was aimed at developing a method to assess CMRO(2) and OEF using intravenously injectable oxygen (injectable 15O-O(2)) for small animals such as rats. Injectable 15O-O(2), 72 MBq/mL of radioactivity, was obtained after 15O-O(2) gas circulation into the artificial lung. OEF after injection of injectable 15O-O(2) was calculated using the same equation as that applied to the bolus inhalation of 15O-O(2) gas method. Values of 44 +/- 4.5 mL. min-1. 100 g-1 of CBF and 0.54 +/- 0.11 of OEF were obtained (n = 13). This OEF value was well accordance with OEF evaluated by arterial-venous difference of oxygen concentration (0.57 +/- 0.13). This method is useful to study the CMRO(2) and OEF in small animals using an animal positron emission tomography system. It may accelerate the basic research of several cerebral perfusion diseases.

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.

In quantitative functional neuroimaging with positron emission tomography (PET) and magnetic resonance imaging (MRI), cerebral blood volume (CBV) and its three components, arterial, capillary, and venous blood volumes are important factors. The arterial fraction for systemic circulation of the whole body has been reported to be 20-30%, but there is no report of this fraction in the brain. In the present study, we estimated the arterial fraction of CBV with PET in the living human brain. C(15)O and dynamic H2(15)O PET studies were performed in each of seven healthy subjects to determine the CBV and arterial blood volume (Va), respectively. A two-compartment model (influx: K1, efflux: k2) that takes Va into account was applied to describe the regional time-activity curve of dynamic H2(15)O PET. K1, k2 and Va were calculated by a non-linear least squares fitting procedure. The Va and CBV values were 0.011 +/- 0.004 ml/ml and 0.031 +/- 0.003 ml/ml (mean +/- SD), respectively, for cerebral cortices. The arterial fraction of CBV was 37%. Considering the limited first-pass extraction fraction of H2(15)O, the true arterial fraction of CBV is estimated to be about 30%. The estimated arterial fraction of CBV was quite similar to that of the systemic circulation, whereas it was greater than that (16%) widely used for the measurement of cerebral metabolic rate of oxygen (CMRO2) using PET. The venous plus capillary fraction of CBV was 63-70% which is a important factor for the measurement of CMRO2 with MRI.

Background: Positron emission tomography (PET) metabolic studies have investigated the pathways involved in fatty acid, glucose, and oxidative metabolism in cardiomyopathy and the impairments that occur in the damaged myocardium, but none have provided absolute quantitative variables. Recently, quantitative measurements of the metabolic rate of oxygen (MMRO2) and oxygen extraction fraction (OEF) using O2-15-labeled oxygen gas have been validated in animals and healthy volunteers. The purposes of the current study were to measure MMRO2 and OEF in cardiomyopathy with left ventricular (LV) dysfunction., Methods: The authors selected 25 study participants: 16 patients (10 with ischemic and 6 with dilated) cardiomyopathy with LV dysfunction, and 9 healthy volunteers. As evaluated by echocardiography, LV ejection fraction (LVEF) was decreased in patients (35%+/-9% vs. 65%+/-5%, P<0.01). The PET protocol consisted of transmission, C O2-15 static, H2 O-15 dynamic, and O2-15 gas inhalation steady state scans. An entire myocardial region of interest was drawn to encompass the entire LV myocardium on three midventricular slices in each participant., Results: Data showed in patients with dilated cardiomyopathy significant reductions of MMRO2 (0.051+/-0.02 ml x min(-1) x g(-1) vs. 0.108+/-0.02 ml x min(-1) x g(-1), p = 0.01) and OEF (0.55+/-0.15 vs. 0.71+/-0.08, P = 0.01) when compared with healthy volunteers. Furthermore, OEF decreased significantly in lateral and inferior walls. Significant correlations were observed among OEF and the rate-pressure product (RPP) (P = 0.02), LVEF (P<0.001), MMRO2 and RPP (P = 0.04), and LVEF (P = 0.05). In patients with ischemic cardiomyopathy, MMRO2 was significantly reduced (0.039+/-0.02 ml x min(-1) x g(-1) vs. 0.108+/-0.02 ml x min(-1) x g(-1); p = 0.005) but not OEF (0.63+/-0.2 vs. 0.71+/-0.08; P = NS), when compared with healthy volunteers. Significant correlations were observed among OEF and RPP (P = 0.03), LVEF (P = 0.002), MMRO2 and RPP (P<0.01), and LVEF (P = 0.03)., Conclusions: These data show that O2-15 gas inhalation and PET allow myocardial MMRO2 and OEF to be measured in patients with cardiomyopathy.

Unlabelled: A method has been proposed to quantitate the myocardial water-perfusable tissue fraction (PTF) in the area of hypoperfused asynergic segments using (15)O-water (H2(15)O) and PET. This study investigated the histochemical correlates of PTF (and perfusable tissue index, PTI) in a canine model of old myocardial infarction., Methods: Myocardial infarction was produced in 12 mongrel dogs, and PET was performed 1 mo later, providing quantitative parametric images of PTF, regional myocardial blood flow (MBF), and extravascular density from H2(15)O, (15)O-carbon monoxide, and transmission datasets. At the end of scanning, the myocardium was sectioned, and the PET images were compared directly with the corresponding myocardial sections., Results: The distribution of tissue necrosis identified by histochemical staining corresponded well with the defect in PTF but not in MBF. PTF agreed with the equilibrium images of myocardial H2(15)O distribution, obtained after injection of a large bolus of H2(15)O. The defect surface area identified on PTF agreed well quantitatively with the morphometric estimates of the surface area of myocardial infarction. PTI agreed with the absolute proportion of histochemically defined normal myocardium (0.87 +/- 0.09 and 0.83 +/- 0.08, respectively; P < 0.01). Both PTF and PTI decreased significantly in segments of myocardial infarction and showed a significant difference between the transmural and nontransmural myocardial infarction., Conclusion: The absolute mass and proportion of histochemically defined noninfarcted tissue may be quantitated with PTF and PTI in the area of myocardial infarction segments.

One of the most limiting factors for the accurate quantification of physiologic parameters with positron emission tomography (PET) is the partial volume effect (PVE). To assess the magnitude of this contribution to the measurement of regional cerebral blood flow (rCBF), the authors have formulated four kinetic models each including a parameter defining the perfusable tissue fraction (PTF). The four kinetic models used were 2 one-tissue compartment models with (Model A) and without (Model B) a vascular term and 2 two-tissue compartment models with fixed (Model C) or variable (Model D) white matter flow. Furthermore, rCBF based on the autoradiographic method was measured. The goals of the study were to determine the following in normal humans: (1) the optimal model, (2) the optimal length of fit, (3) the model parameters and their reproducibility, and (4) the effects of data acquisition (2D or 3D). Furthermore, the authors wanted to measure the activation response in the occipital gray matter compartment, and in doing so test the stability of the PTF, during perturbations of rCBF induced by visual stimulation. Eight dynamic PET scans were acquired per subject (n = 8), each for a duration of 6 minutes after IV bolus injection of H2(15)O. Four of these scans were performed using 2D and four using 3D acquisition. Visual stimulation was presented in four scans, and four scans were during rest. Model C was found optimal based on Akaike's Information Criteria (AIC) and had the smallest coefficient of variance after a 6-minute length of fit. Using this model the average PVE corrected rCBF during rest in gray matter was 1.07 mL x min(-1) x g(-1) (0.11 SD), with an average coefficient of variance of 6%. Acquisition mode did not affect the estimated parameters, with the exception of a significant increase in the white matter rCBF using the autoradiographic method (2D: 0.17 mL x min(-1) x g(-1) (0.02 SD); 3D: 0.21 mL x min(-1) x g(-1) (0.02 SD)). At a 6-minute fit the average gray matter CBF using Models C and D were increased by 100% to 150% compared with Models A and B and the autoradiographic method. There were no significant changes in the perfusable tissue fraction by the activation induced rCBF increases. The largest activation response was found using Model C (median = 39.1%). The current study clearly demonstrates the importance of PVE correction in the quantitation of rCBF in normal humans. The potential use of this method is to cost-effectively deliver PVE corrected measures of rCBF and tissue volumes without reference to imaging modalities other than PET.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H2(15)O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL x min(-1) x g(-1) for models with a term for gray matter tissue and 0.5 mL x min(-1) x g(-1) for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H2(15)O autoradiography (approximately 0.40 mL x min(-1) x g(-1)). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaike's Information Criteria. Error sensitivity analysis suggested the model that fits three parameters of the gray matter CBF, the gray matter fraction, and the white matter fraction with fixed white matter CBF as the most reliable and suitable for estimating the gray matter CBF. Reproducibility with this model was 11% for estimating the gray matter CBF. The volume of gray matter tissue can also be estimated using this model and was significantly correlated with the results from the stereologic analysis. However, values were significantly smaller compared with those measured by stereologic analysis by 40%, which can not be explained by the methodologic errors. In conclusion, the partial volume correction was essential in quantitation of regional CBF. The method presented in this article provided the PVE-corrected regional CBF in the cortical gray matter tissue. This study also suggests that further studies are required before using MRI derived anatomic information for PVE correction in PET.

Hypercapnia and hypocapnia produce cerebral vasodilation and vasoconstriction, respectively. However, regional differences in the vascular response to changes in Paco2 in the human brain are not pronounced. In the current study, these regional differences were evaluated. In each of the 11 healthy subjects, cerebral blood flow (CBF) was measured using 15O-water and positron emission tomography at rest and during hypercapnia and hypocapnia. All CBF images were globally normalized for CBF and transformed into the standard brain anatomy. t values between rest and hypercapnia or hypocapnia conditions were calculated on a pixel-by-pixel basis. In the pons, cerebellum, thalamus, and putamen, significant relative hyperperfusion during hypercapnia was observed, indicating a large capacity for vasodilatation. In the pons and putamen, a significant relative hypoperfusion during hypocapnia, that is, a large capacity for vasoconstriction, was also observed, indicating marked vascular responsiveness. In the temporal, temporo-occipital, and occipital cortices, significant relative hypoperfusion during hypercapnia and significant relative hypoperfusion during hypocapnia were observed, indicating that cerebral vascular tone at rest might incline toward vasodilatation. Such regional heterogeneity of the cerebral vascular response should be considered in the assessment of cerebral perfusion reserve by hypercapnia and in the correction of CBF measurements for variations in subjects' resting Paco2.

Background: Preserved myocardial oxygen consumption estimated by carbon 11-acetate and positron emission tomography (PET) in myocardial regions with chronic but reversibly depressed contractile function in patients with ischemic heart disease have been suggested to be caused by repeated short episodes of acute myocardial ischemia. To evaluate this hypothesis myocardial 11C-acetate PET imaging was performed before and after acute repetitive myocardial ischemia., Methods and Results: In open chest dogs (n = 8), the left anterior descending coronary artery was occluded 4 times for 5 minutes alternating with 5 minutes of reperfusion. Before and after repetitive coronary occlusions, oxygen 15 water/oxygen 15 carbon monoxide (blood flow), and 11C-acetate (oxygen consumption) PET imaging were performed. Left ventricular regional systolic wall thickening was measured with sonomicrometry. Forty-five minutes after the ischemic episodes, systolic ventricular wall thickening was decreased by 90%, whereas myocardial blood flow was reduced by 21% compared with baseline values (P < .05). Ninety minutes after the ischemic episodes, estimated oxygen consumption was unaltered compared with the baseline level despite a sustained 70% decrease in the regional contractile function (P < .05)., Conclusions: Oxygen consumption estimated by 11C-acetate PET imaging is preserved after repeated episodes of acute myocardial ischemia despite a severe impairment of contractile function.

Recently, a method has been proposed for the quantitative measurement of regional myocardial blood flow (MBF) using oxygen-15-labelled water and positron emission tomography (PET). A multicentre project was organized with the intention of evaluating the accuracy of this method, particularly as a multicentre clinical investigative tool. Each of seven institutions performed PET studies on more than five normal volunteers following a specified protocol. The PET study included a transmission scan, a 15O-carbon monoxide static scan and a 15O-water dynamic scan, thereby yielding MBF values which should have been independent of the spatial resolution of the PET scanner employed. Fifty-three subjects (aged 20-63 years, mean+/-SD 36+/-12 years) were studied at rest, and 31 of these subjects were also studied after dipyridamole in five institutions. Inter-institution consistency and intra-subject variation in MBF values were then evaluated. MBF averaged for all subjects was 0.93+/-0.34 ml min(-1) g(-1) at rest and 3.40+/-1.73 ml min(-1) g(-1) after the administration of dipyridamole, and the flow reserve (defined as the ratio of the two MBF values) was 3.82+/-2.12; these values are consistent with previous reports. Resting MBF values were significantly correlated with the heart rate-blood pressure product (RPP) (y=0.31+6.56E-5x, P<0.010), and RPP was in resting MBF observed in all institutions was well explained by the age-dependent RPP. No significant difference was observed in resting MBF among the institutions. Except in one institution, no significant difference was seen in dipyridamole MBF or myocardial flow reserve. No significant difference was found among the myocardial segments. Regional variation was reasonably small in five institutions, but was not acceptable in two institutions, which was attributed to the scanner performance. These observations suggest that the 15O-water PET technique is useful for a multicentre clinical study if the PET scanner can provide time-activity data with good count statistics.

Background and Purpose: Dipyridamole increases the concentration of circulating adenosine, which is a potent vasodilator, by inhibition of uptake of adenosine into the erythrocytes, and hence produces coronary vasodilation. However, the effects of dipyridamole on cerebral circulation is not pronounced. This study investigates the effects of intravenous dipyridamole on cerebral blood flow (CBF) in humans with use of positron emission tomography (PET)., Methods: In each of 13 healthy subjects, CBF was measured using (15)O-labeled water and PET at rest and during hypercapnia, hypocapnia, and dipyridamole stress; corresponding CBF values were then compared., Results: CBF values during dipyridamole stress were significantly lower than those measured at rest. The dipyridamole stress PaCO(2) was also significantly lower than the resting PaCO(2). The change in CBF during dipyridamole stress relative to PaCO(2) closely followed the relationship between CBF and PaCO(2) during hypocapnia., Conclusions: These results indicate that the observed decrease in CBF during dipyridamole stress was caused by a decrease in PaCO(2) rather than by any direct action of dipyridamole on CBF. The decrease in PaCO(2) during dipyridamole stress was most likely due to hyperventilation, which was a side effect of adenosine. These results support the hypothesis that circulating adenosine is largely prevented from binding to adenosine receptors of cerebral vessels by the blood-brain barrier.

Unlabelled: The aim of this study was to compare reproducibility and accuracy of two reconstruction methods in quantification of myocardial blood flow and oxygen metabolism with 15O-labeled tracers and PET. A new iterative Bayesian reconstruction method based on median root prior (MRP) was compared with filtered backprojection (FBP) reconstruction method, which is traditionally used for image reconstruction in PET studies., Methods: Regional myocardial blood flow (rMBF), oxygen extraction fraction (rOEF) and myocardial metabolic rate of oxygen consumption (rMMRO2) were quantified from images reconstructed in 27 subjects using both MRP and FBP methods. For each subject, regions of interest (ROIs) were drawn on the lateral, anterior and septal regions on four planes. To test reproducibility, the ROI drawing procedure was repeated. By using two sets of ROIs, variability was evaluated from images reconstructed with the MRP and the FBP methods., Results: Correlation coefficients of mean values of rMBF, rOEF and rMMRO2 were significantly higher in the images reconstructed with the MRP reconstruction method compared with the images reconstructed with the FBP method (rMBF: MRP r = 0.896 versus FBP r = 0.737, P < 0.001; rOEF: 0.915 versus 0.855, P < 0.001; rMMRO2: 0.954 versus 0.885, P < 0.001). Coefficient of variation for each parameter was significantly lower in MRP images than in FBP images (rMBF: MRP 23.5% +/- 11.3% versus FBP 30.1% +/- 14.7%, P < 0.001; rOEF: 21.0% +/- 11.1% versus 32.1% +/- 19.8%, P < 0.001; rMMRO2: 23.1% +/- 13.2% versus 30.3% +/- 19.1%, P < 0.001)., Conclusion: The MRP reconstruction method provides higher reproducibility and lower variability in the quantitative myocardial parameters when compared with the FBP method. This study shows that the new MRP reconstruction method improves accuracy and stability of clinical quantification of myocardial blood flow and oxygen metabolism with 15O and PET.

(+)N-[11C]methyl-3-piperidyl benzilate, a relatively low affinity muscarinic cholinergic receptor antagonist was synthesized by N-[11C]methylation of (+)3-piperidyl benzilate using [11C]methyl iodide. The product was isolated by HPLC, and obtained with radiochemical yield of 60-70% from [11C]methyl iodide, and a specific activity of 500-1000 Ci mmol-1 (18.5-37 GBq mumol-1) at EOS and radiochemical purity of > 98%. In vitro autoradiographic studies showed selective binding for this radiotracer in the different regions of the rat brain: high in corpus striatum, hippocampus and cerebral cortex, and low in cerebellum, consistent with muscarinic cholinergic receptor distributions. This radiotracer thus had potential as radioligand for positron emission tomography.

Unlabelled: Measurement of the arterial input function is essential for quantitative assessment of physiological function in vivo using PET. However, frequent arterial blood sampling is invasive and labor intensive. Recently, a PET system has been developed that consists of two independent PET tomographs for simultaneously scanning the brain and heart, which should avoid the need for arterial blood sampling. The aim of this study was to validate noninvasive quantitation with this system for 15O-labeled compounds., Methods: Twelve healthy volunteers underwent a series of PET studies after C15O inhalation and intravenous H2(15)O administration using a Headtome-V-Dual tomograph (Shimadzu Corp., Kyoto, Japan). The C15O study provided gated blood-pool images of the heart simultaneously with quantitative static blood-volume images of both the brain and heart. Weighted-integrated H2(15)O sinograms were acquired for estimating rate constant (K1) and distribution-volume (Vd) images in the brain, in addition to single-frame sinograms for estimating autoradiographic cerebral blood flow images. Noninvasive arterial input functions were determined from the heart scanner (left ventricular chamber) according to a previously developed model and compared directly to invasive input functions measured with an on-line beta probe in six subjects., Results: The noninvasive input functions derived from this PET system were in good agreement with those obtained by continuous arterial blood sampling in all six subjects. There was good agreement between quantitative values obtained noninvasively and those using the invasive input function: average autoradiographic regional cerebral blood flow was 0.412 +/- 0.058 and 0.426 +/- 0.062 ml/min/g, K1 of H2(15)O was 0.416 +/- 0.073 and 0.420 +/- 0.067 ml/min/ml and Vd of H2(15)O was 0.800 +/- 0.080 and 0.830 +/- 0.070 ml/ml for the noninvasive and invasive input functions, respectively. In addition to the brain functional parameters, the system also simultaneously provided cardiac function such as regional myocardial blood flow (0.84 +/- 0.19 ml/min/g), left ventricular volume (132 +/- 22 mm at end diastole and 45 +/- 14 ml at end systole) and ejection fraction (66% +/- 5%)., Conclusion: This PET system allows noninvasive quantitation in both the brain and heart simultaneously without arterial cannulation, and may prove useful in clinical research.

Exaggerated vasoconstriction and blunted vasodilation of peripheral resistance arteries to various vasoactive agents characterize patients with IDDM. We characterized the hemodynamic effects of insulin in skeletal muscle in patients with IDDM. Muscle blood flow and blood volume were measured basally and during a high-dose insulin infusion (5 mU x kg(-1) x min[-1]) in seven normotensive patients with IDDM (age, 30 +/- 6 years; BMI, 24.5 +/- 2.0 kg/m2; blood pressure, 124 +/- 12/78 +/- 11 mmHg) and nine matched normal subjects, using [15O]H2O, [15O]CO, and positron emission tomography (PET). Whole-body insulin sensitivity was determined using the euglycemic insulin clamp technique. Insulin-stimulated whole-body glucose uptake was significantly lower in the patients with IDDM (45 +/- 15 micromol x kg(-1) x min[-1]) than in the normal subjects (62 +/- 14 micromol x kg(-1) x min[-1]) (P < 0.05). Insulin increased muscle blood flow by 111 +/- 69% above basal from 3.0 +/- 2.0 to 5.8 +/- 3.0 ml x 100 g(-1) muscle x min(-1) (P < 0.005) in the normal subjects, but only by 42 +/- 30% from 2.0 +/- 0.9 to 2.9 +/- 1.4 ml x 100 g(-1) muscle x min(-1) (P < 0.005) in patients with IDDM (P < 0.05 for change in flow in IDDM vs. normal subjects). The calculated muscle vascular resistances were comparable basally, but higher during hyperinsulinemia in the patients with IDDM (37 +/- 17 mmHg x 100 g x min x ml[-1]) than in the normal subjects (16 +/- 7 mmHg x 100 g x min x ml[-l]) (P < 0.05). Muscle blood volume increased significantly by insulin in both groups without any difference between the groups. We conclude that the ability of supraphysiological concentrations of insulin to stimulate muscle blood flow is blunted in patients with IDDM, because of the inability of insulin to stimulate linear flow velocity rather than blood volume in skeletal muscle. This defect adds yet another defect to the list of abnormalities in vascular function in IDDM, which might predispose these patients to develop hypertension.

To detect changes in vascular physiology associated with early atherosclerosis, we studied whether alterations in coronary flow reserve, as assessed by positron emission tomography imaging with intravenous dipyridamole, would be related to risk factor variables in healthy young men. The number of conventional risk variables correlated significantly with coronary flow reserve (r = -0.58, p = 0.0007), suggesting that alterations in functional vascular reactivity are related to the cardiovascular risk status already in healthy young men.

Unlabelled: The aim of the present study was to evaluate quantitation of muscle blood flow using [15O]H2O and PET., Methods: The autoradiographic (ARG) and the steady-state methods using PET were used to measure femoral muscle blood flow. A simulation study was performed to examine the errors due to contamination of radioactivity in the blood content in muscle tissue, statistical noise and delay and the dispersion of the input curve in the ARG method. Five separate paired muscle blood flow examinations were carried out for comparison of the ARG and the steady-state techniques, including measurement of muscle blood volume in each subject. To obtain the normal range for resting muscle blood flow, additional measurements with the ARG method were performed in 16 normal subjects., Results: When the integration time in ARG was increased to 200-300 sec, the errors due to arterial blood volume, statistical noise, delay and dispersion of the input curve were significantly reduced. Muscle blood flow values in the ARG (200 sec) and the steady-state studies were in good agreement, and each provided an estimated accuracy of 5%. Resting muscle blood flow averaged 3.12 +/- 1.55 ml/min.100 g muscle (range 1.43-6.72 ml/min.100 g muscle, n = 18)., Conclusion: The ARG and the steady-state methods provided consistent blood flow values for skeletal muscle when a long tissue integration time (> or = 200 sec) was applied in the ARG study. Based on the lower effective radiation dose and the shorter total scan duration, the ARG method is favored over the steady-state method in the measurement of muscle blood flow.

An algorithm is presented for the reconstruction of PET images using prior anatomical information derived from MR images of the same subject. The cross-entropy or Kullback-Leiber distance is a measure of dissimilarity between two images. We propose to reconstruct PET images by minimizing a weighted sum of two cross-entropy terms. The first is the cross-entropy between the measured emission data and the forward projection of the current estimate of the PET image. Minimizing this term alone is equivalent to the ML-EM reconstruction. The second term is the cross-entropy between the current estimate of the PET image and a prior image model which incorporates anatomical information derived from registered MR images. A weighting parameter determines the relative emphasis given to the emission data and the prior model in the reconstruction. Details of this algorithm are presented as well as test reconstructions for real and simulated data. The performance of the algorithm was evaluated with respect to errors in prior anatomical information. The algorithm provided significant improvement in the quality of reconstructed images as compared with the ML-EM reconstruction technique. The reconstructed images had higher resolution as compared with the images obtained from MAP-like reconstructions which do not utilize anatomical information. The algorithm displayed robustness with respect to errors in prior anatomical information.

Background: A method has been developed to measure the regional myocardial metabolic rate of oxygen consumption (rMMRO2) and oxygen extraction fraction (rOEF) quantitatively and noninvasively in humans by use of 15O2 inhalation and positron emission tomography. This article describes the theory, an error analysis of the technique, and procedures of the method used in a human feasibility study., Methods and Results: Inhaled 15O2 is transported to peripheral tissues, where it is converted to 15O-labeled water of metabolism, which exchanges with the relatively large extravascular tissue space. Quantification of this buildup of radioactivity allows the calculation of rMMRO2 and rOEF. However, a correction for the spillover of the pulmonary gas radioactivity signal into myocardial regions is required and has been made by use of a gas volume distribution estimated from the transmission scan. This was validated by comparative measurements using the inert gas [11C]CH4 in four greyhounds. Spillover of the cardiac chamber radioactivity has been corrected for with an inhaled [13O]CO (blood volume) scan. The underestimation of myocardial radioactivity due to wall motion and thickness has been corrected for by use of values of tissue fraction obtained from the flow measurement [15OKCO2 scan). Values of rOEF were similar (within 4%) whether obtained from gas volume measurements determined from the transmission or [11C]CH4 scan data. 15O2 scan information from six healthy volunteers showed a clear distribution of myocardial radioactivity after the vascular and pulmonary gas 15O background was subtracted. Subsequent compartmental analysis resulted in values for rOEF and rMMRO2 of 0.60 +/- 0.11 and 0.10 +/- 0.03 mL.min-1.g-1 in the human myocardium at rest., Conclusions: The results of this study are in good agreement with established values. This is the first known approach to allow the direct quantitative determination of rOEF and oxygen metabolism to be made noninvasively on a regional basis.

Background: The purpose of this study was to validate a novel method for noninvasive quantification of regional myocardial oxygen consumption (MMRO2, mL.min-1 x 100 g-1) and oxygen extraction fraction (OEF) by use of positron emission tomography (PET) and inhalation of 15O-labeled molecular oxygen gas (15O2)., Methods and Results: Twenty-four measurements were performed in eight closed-chest anesthetized greyhounds at baseline and during infusions of adenosine (100 to 200 micrograms.kg-1.min-1), isoproterenol (1 to 10 microgram/min), and propranolol (5 mg botus +0.2 to 1 mg/min) with morphine (5 mg slow infusion +0.2 to 0.5 mg/ min) to obtain a wide range of oxidative metabolism. The PET imaging protocol consisted of 15O2 emission (OEF and MMRO2), transmission, [15O]CO emission (blood pool), and [15O]CO2 emission (myocardial blood flow: MBF(pets) mL.min-1.g-1) scans. OEF was calculated from the PET data (OEFpet) by three different analytical techniques: steady-state, 5-minute, and 8-minute autoradiographic analyses. Reference measurements of MBF (MBFref) and OEF (OEFref) were obtained during 15O2 inhalation with radiolabeled microspheres and paired arterial and coronary sinus blood sampling, respectively. MMRO2 was calculated from the PET (MMRO2pet) and the reference (MMRO2ref) data as follows: MMRO2 = OEF x MBF x (O2 content of arterial blood). OEF measured by the steady-state PET method was well correlated with the reference data over the range 0.16 to 0.73 (OEFpet = 1.03 OEFref -0.01, r = .97), as was MMRO2 over the range 2.4 to 27.5 mL.min-1 x 100 g-1 (MMRO2pet = 0.98 MMRO2ref +0.91, r = .94). OEFpet calculated by use of the 5-minute and 8-minute autoradiographic analyses were equally well correlated with the reference measurements (r = .95 and r = .97, respectively). There were no significant differences between values of MMRO2pet calculated by use of the steady-state, 5-minute, and 8-minute autoradiographic analyses (P = NS by ANOVA). Regional values of MBFpet, OEFpet, and MMRO2pet were homogeneously distributed and similar to the whole-heart values both at baseline and during the various pharmacological interventions., Conclusions: Accurate quantification of OEF and MMRO2 is feasible with 15O2 inhalation and PET imaging using both the steady-state and autoradiographic analytical approaches. These studies suggest the applicability of this method for quantitative assessments of regional cardiac oxidative metabolism in clinical studies.

To elucidate the mechanism of large neutral amino acid (LNAA) transport in cerebral gliomas and to evaluate the clinical usefulness of positron emission tomography (PET) with fluorine-18 fluorophenylalanine (18F-Phe), we examined 18 patients with cerebral glioma using dynamic PET and 18F-Phe. By employing two-compartment model analysis, the influx rate K1, the efflux rate k2 and the distribution volume (Vd) of 18F-Phe were estimated in tumour tissue and contralateral normal grey matter. 18F-Phe showed increased accumulation in tumour tissue regardless of the grade of malignancy in all patients. The rate of uptake of 18F-Phe in high-grade glioma was significantly higher than in low-grade glioma (P <0.05). However, it was difficult to evaluate the tumour grade only from the 18F-Phe accumulation in individual cases. Values of K1 and Vd were significantly increased in the tumour tissue. The K1 value of the tumour tissue tended to decrease with increasing LNAA concentration in plasma. Therefore, influx of 18F-Phe into tumour tissue is mainly related to the carrier-mediated active transport. It is concluded that PET with 18F-Phe is of clinical value for tumour detection rather than assessment of tumour malignancy.

Accidental coincidence rate and scatter coincidence rate of 3-dimensional (3D) acquisition of positron emission tomograph (PET) are higher than 2-dimensional (2D) acquisition and count loss becomes higher because slice shield collimator is not used in 3D acquisition. If one could decrease the gamma ray from outside of the axial field of view (FOV), it may be possible to improve image quality of 3D acquisition. Thus, using a Shimadzu SET-2300W (Headtome V) PET camera, we developed and tested a front shield for brain study to shut off gamma ray from the outside of the axial FOV. Using the front shield, gamma ray from outside of the FOV and the accidental coincidence rate could be decreased. The count loss in high count rate was also decreased. With these effect, the image quality of the clinical studies in 3D acquisition could be increased.

We obtained the concentration range of better S/N in 3D than 2D acquisition by measuring count rate for phantoms of different size and length. We used noise equivalent count rate (NECR) for evaluation of S/N of images. For 20 cm diameter 15 cm length cylindrical phantom, NECR of 2D was higher than that of 3D more than 1.2 microCi/ml. For 30 cm diameter 15 cm length cylindrical phantom, NECR of 2D was higher than that of 3D more than 0.7 microCi/ml. For 14 cm diameter 25 cm length cylindrical phantom, NECR of 3D was lower than that of 25 cm length phantom. With these results, though 3D is useful when administered dose is small, image quality of 2D becomes better than 3D more than a certain concentration. For the larger diameter or longer object, the advantage of 3D is diminished at lower concentration.

High insulin concentrations increase blood flow in the leg, but it is unknown whether this effect is associated with a change in muscle blood volume. In the present study, we used positron emission tomography combined with inhalation of [15O]carbon monoxide to quantitate the effect of insulin on skeletal muscle blood volume in humans. The reproducibility of the method was determined from two consecutive measurements performed in the basal state in five normal subjects. The coefficient of variation of the repeated measurements was 3.0 +/- 1.8%. In 14 normal subjects [age 35 +/- 3 yr, body mass index 24.9 +/- 1.3 (SE) kg/m2], skeletal muscle blood volume was determined in the femoral region in the basal state and during euglycemic hyperinsulinemia (serum insulin 3,200 +/- 190 pmol/l). The mean muscle blood volume was 3.3 +/- 0.1 ml/0.1 kg muscle in the basal state. Insulin increased muscle blood volume by 9 +/- 2% to 3.6 +/- 0.2 ml/0.1 kg muscle (P < 0.01). The rate of whole body glucose uptake was 53 +/- 6 mumol.kg-1.min-1 and correlated with muscle blood volume during insulin stimulation (r = 0.65, P < 0.02). We conclude that high insulin concentrations exert a true vasodilatory effect in human skeletal muscle.

Unlabelled: Neutral amino acids (NAAs) are transported from the blood to the brain using the same carrier system in a competitive fashion. The purpose of this study is to establish a method for evaluating neutral amino acid transport at the blood-brain barrier (BBB) in humans and to examine the aging effect of amino acid transport., Methods: A dynamic PET study with L-(2-18F)-fluorophenylalanine (18F-Phe) was performed in 14 normal volunteers (age 21-71 yr; mean +/- s.d., age range 48.0 +/- 17.1 yr). By using a two-compartment model analysis and a weighted integration technique, the influx rate constant K1, the efflux rate constant k2 and distribution volume Vd of 18F-Phe were estimated in various brain structures., Results: The value of K1 was inversely correlated with plasma NAA concentration (r = -0.69, p < 0.01). The cerebellum showed the highest value of K1, while the white matter showed the lowest. There was no significant change in K1 during aging. The value of k2 was significantly increased with age., Conclusion: No decline of K1 during aging indicated that NAA transport from the blood to the brain is a limiting process of age in amino acid incorporation. Fluorine-18-Phe PET imaging is a feasible method to study NAA transport at the BBB in vivo in humans and can be applied to pathological conditions of the brain.

Objective: A fully automatic multimodality image registration algorithm is presented. The method is primarily designed for 3D registration of MR and PET images of the brain. However, it has also been successfully applied to CT-PET, MR-CT, and MR-SPECT registrations., Materials and Methods: The head contour is detected on the MR image using a gradient threshold method. The head region in the MR image is then segmented into a set of connected components using the K-means clustering algorithm. When the two image sets are registered, the segmentation of the MR image indirectly generates a segmentation of the PET image. The best registration is taken to be the one that optimizes the segmentation induced on the PET image. In this article, the K-means minimum variance criterion is used as a cost function, and the optimization is performed using the method of coordinate descent., Results: The algorithm was tested on 80 H2 15O PET and MR image pairs from 10 subjects. Qualitatively correct results were obtained in all cases. With use of external markers visible in both image modalities, the average registration error was estimated to be < 3 mm., Conclusion: The algorithm presented in this article requires no user interaction and can be applied to a wide range of registration problems. Quantitative and qualitative evaluations of the algorithm indicate a high degree of accuracy.

Effects of limited spatial resolution of the positron emission tomography (PET) scanner on the quantitative measurement of regional cerebral blood flow (rCBF) was investigated for various tracer kinetic models with use of 15O labeled water and PET. Using a numerical brain phantom consisting of a gray matter, white matter and cerebrospinal fluid components, dynamical tracer distribution images were calculated for the H215O bolus injection and for the C15O2 gas inhalation protocols. The tracer distribution images were convoluted with a 2 dimensional gaussian function with full-width at half maximum (FWHM) of 4, 7, 12 mm to simulate a limited spatial resolution of the PET scanner, and rCBF images were calculated according to some kinetic models. Smoothing the tracer distribution images caused a heterogeneous structure (tissue mixture) in a given volume element. rCBF values calculated by models with use of 15O-water and PET were found to provide rCBF values that were systematically underestimated compared with those obtained by the microsphere model for a mixed tissue region. Moreover, the magnitude of the underestimation was shown to be highly dependent on the tracer kinetic models employed, those errors for mixed tissue of gray and white matter were 20% on steady state, 9% on autoradiography and on weighted integration method, and 2% on non-linear least squares fitting, compared with microsphere model. More errors observed by steady state method and autoradiography method happened for tissue mixture consisting gray matter, white matter and cerebrospinal fluid components. It is important to take into account for difference of the partial volume effect for each models in calculated rCBF.

By means of a high resolution PET scanner, the regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen extraction fraction (rOEF), and metabolic rate of oxygen (rCMRO2) for major cerebral gyri and deep brain structures were studied in eleven normal volunteers during an eye-covered and ear-unplugged resting condition. Regional CBF was measured by the autoradiographic method after intravenous administration of H2(15)O. Regional OEF and rCMRO2 were measured by the single inhalation of 15O2. With MR T1-weighted images as an anatomical reference, thirteen major cerebral gyri, caudate nucleus, lentiform nucleus, thalamus, midbrain, pons, cerebellum and vermis were defined on the CMRO2 images. Values were read by using circular regions of interest 16 mm in diameter. The posterior part of the cingulate gyri had the highest rCBF and rCMRO2 values among brain structures, followed by the lentiform nucleus, the cerebellum, the caudate nucleus, and the thalamus. Parahippocampal gyri had the lowest rCBF and rCMRO2 values among the cortical gyri. Regional OEF for the pontine nuclei (0.34 +/- 0.04), the midbrain (0.35 +/- 0.05), the parahippocampal gyri (0.35 +/- 0.04 for the right and 0.37 +/- 0.05 for the left), and the thalami (0.37 +/- 0.05 for the right and 0.36 +/- 0.04 for the left) were significantly lower than the mean OEF for the cerebral cortices (0.42 +/- 0.04) (p < 0.05 or less). The global CBF and CMRO2 were consistent with those obtained by the Kety-Schmidt method.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: This study investigates the most appropriate protocol for measuring regional myocardial blood flow (MBF) using 15O-water in clinical applications., Methods: Regional MBF, perfusable tissue fraction (PTF) and arterial blood volume (Va) were measured using 15O-water and dynamic PET on five healthy volunteers based on previously published models. Calculated values were compared for the following three tracer administration protocols: 15O-water bolus injection, 15O-water slow (2 min) infusion and 15O-carbon dioxide slow (2 min) inhalation. For the two slow administration protocols, the three parameters MBF, PTF and Va were computed by fitting the model equations to the myocardial regional time-activity curve. For the bolus injection of 15O-water, only two parameters, MBF and PTF, were fitted by using a fixed Va value obtained by a carbon dioxide blood volume scan., Results: All protocols provided consistent MBF values, and the calculated values were homogeneous throughout the whole myocardial segments for all subjects. PTF values were also homogeneous and consistent in the anterior and lateral wall regions, but were significantly greater in the septum (approximately 20%) when the slow 15O-carbon dioxide inhalation protocol was used. MBF and PTF values obtained from the bolus injection protocol showed the smallest intersubject and interregional variations. The simulation study also showed that the magnitude of error was smallest when the bolus injection protocol was employed., Conclusion: The data suggest that the 15O-water bolus injection protocol together with the two-parameter fitting procedure provides the most accurate results for MBF and PTF. However, it requires arterial cannulation and a separate carbon monoxide scan. For clinical studies, however, the 15O-water infusion protocol would be a good alternative, providing MBF and PTF results with an acceptable degree of accuracy and without the need for arterial cannulation.

Stunned myocardium is often observed after unstable angina, myocardial infarction, thrombolysis, angioplasty, and bypass surgery but rarely after coronary vasospasm. A case of stunned myocardium caused by diffuse coronary artery vasospasm and mimicking myocardial infarction is reported. The patient had an emergency coronary angiography, which showed no pathological coronary disease, but the left ventricular ejection fraction showed severe left ventricular dysfunction. Repeat coronary angiography 24 days later after medical treatment (diltiazem and nitrates) showed complete recovery of wall function, and a diffuse vasospasm was induced in both coronary arteries (left anterior and right coronary arteries). Two days later the patient underwent a positron emission tomography study with water labelled with oxygen-15 to evaluate the viable myocardium and oxygen-15 to evaluate oxidative metabolism. The results showed normal myocardial blood flow and perfusable tissue density, confirming that the myocardium was viable, and normal myocardial oxidative metabolism, reflecting the recovery of the left ventricular function.

A mathematical model has been developed to predict the arterial metabolite concentration curve using the whole blood radioactivity curve in positron emission tomography (PET) during 15O2 inhalation. Production of arterial H2 15O due to aerobic metabolism in the body was modeled as a single rate constant, which was determined from 200 steady-state values of plasma and whole blood concentrations recorded during continuous inhalation of 15O2 and C15O2. Comparison of this method in eight 15O2 inhalation studies (four at rest and four during motor stimulation) performed on four subjects resulted in: (1) arterial H2 15O curves that were well matched in shape to those measured by the frequent plasma separation and (2) cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF) were consistent with those obtained by the frequent plasma separation procedure (maximum difference was 3%). An error sensitivity analysis was also performed and demonstrated that errors expected in this modeling approach caused only negligible errors in CMRO2 and CBF estimates. Thus, the arterial H2 15O concentration curve can be accurately predicted using the whole blood time-activity curve; hence, plasma separation can be avoided in 15O2 inhalation PET.

To estimate regional cerebral blood flow (rCBF) and brain-blood partition coefficient (lambda) using a dynamic measurement, a new graphic plot analysis is proposed. By assuming a two-compartment model for tracer kinetics, we derived the linear relationship as Y(t) = K1 - k2 X(t), where Y(t) is the ratio of brain tissue activity-to-time-integrated arterial blood activity and X(t) is the ratio of time-integrated brain tissue activity-to-time-integrated arterial blood activity. A plot of Y(t) against X(t) yields a straight line and the y- and x-intercept of the regression line represent rCBF (K1) and lambda, respectively. The slope is a washout constant (-k2). This method was applied to 14 subjects with N-isopropyl-p-iodine-123 iodoamphetamine ([123I]IMP). The mean values of K1 and lambda for normal subjects were 41.3 +/- 6.7 ml/100 g/min and 29.6 +/- 6.5 ml/g, respectively, in the gray matter. A comparative study with positron emission tomography (PET) using an H2(15)O autoradiographic method revealed good correlation between IMP K1 and PET rCBF [r = 0.822; K1 = 0.842 rCBF + 0.030 (ml/g/min)]. The values of K1 using the graphical method were in excellent agreement with those using a nonlinear least-squares fitting technique (r = 0.992 for K1; r = 0.941 for lambda). The estimated K1 values in the graphical method were not changed when scanning times were varied. We conclude that a two-compartment model is acceptable for IMP kinetics within a scan time of 60 min. The graphical method gives a reliable and rapid estimation of rCBF when applied to dynamic data.

Background: Previous assessments of myocardial viability using positron emission tomography (PET) relied on demonstration of glucose metabolism in hypoperfused asynergic segments using the glucose analogue [18F]2-fluoro-2-deoxyglucose (FDG). Recently, it was shown that myocardial viability could be assessed by calculating the water-perfusable tissue index (PTI) for the asynergic region. PTI represents the proportion of the myocardium that is capable of rapid transsarcolemmal exchange of water and thus perfusable by water. The aim of the present study was to assess myocardial viability by PET using PTI in patients undergoing coronary revascularization., Methods and Results: Twelve patients with chronic coronary artery disease and previous myocardial infarction were studied. Analysis of transmission (tissue density) and 15O-labeled carbon monoxide (blood pool), and 15O-labeled water (myocardial blood flow [MBF]) emission PET data enabled the simultaneous quantification of MBF (ml.min-1.g perfusable tissue-1) and PTI (gram of perfusable tissue per gram of total anatomic tissue). In addition, PET imaging with FDG after 75-g oral glucose load was performed in eight patients. Preoperative echocardiography identified 33 hypocontractile and 26 control segments. Follow-up echocardiography performed 3 to 5 months later demonstrated 26 of 33 segments with improved wall motion (recovery) and seven of 33 segments without improvement (nonrecovery). MBF in the control segments (0.97 +/- 0.22 ml.min-1.g perfusable tissue-1) was significantly higher (p < 0.001) than in both the recovery (0.73 +/- 0.18 ml.min-1.g perfusable tissue-1) and the nonrecovery (0.45 +/- 0.11 ml.min-1.g perfusable tissue-1) segments. PTI in the recovery regions (0.99 +/- 0.15) was > or = 0.7 in all cases and slightly less than in control regions (1.10 +/- 0.15, p < 0.02). FDG uptake in these regions was 92 +/- 17% (n = 13) of the uptake in control segments with normal wall motion. In the nonrecovery group, PTI was 0.62 +/- 0.06 (p < 0.02 versus control and recovery) and always < 0.7. In the one patient in whom a comparison with metabolic imaging was made, FDG uptake was 46% of the uptake in a reference region with normal wall motion., Conclusions: These data showed that contractile recovery occurred only in segments where PTI was > or = 0.7, suggesting that > or = 70% of myocardial tissue in a given asynergic segment should be perfusable by water to enable contractile recovery. There was good agreement between the PTI and FDG methods for predicting improvements in regional wall motion after revascularization. Although further studies should be performed in a larger patient group, the preliminary results are promising and suggest that PTI may be a good predictor of contractile recovery after coronary revascularization.

Noninvasive recording of arterial input functions using regions of interest (ROIs) in the left ventricular (LV) chamber obviates the need for arterial cannulation in PET, but it is compromised by the limited recovery coefficient of the LV chamber and by statistical noise. In the present study, a new mathematical model has been developed, which corrects for the spillover of radioactivity both from the myocardium into the LV ROI and the blood into the myocardial ROI. The method requires the measurement of a time-activity curve in the LV chamber during the dynamic H2(15)O PET study and the measurement of the recovery coefficient of the LV ROI using a 15O-carbon monoxide (C15O) scan and venous blood sampling. This approach was successfully validated against direct measurements of the arterial input function using an on-line beta detector in five greyhounds undergoing dynamic H2(15)O PET imaging. This technique also yielded myocardial blood flow (MBF) values which were not significantly different from those obtained with the beta-probe analyses (maximum difference less than 2%), provided that the LV ROIs were sufficiently large to provide good counting statistics. When this model was not applied for large ROIs (small recovery in LV ROI), systematic overestimations in MBF compared with beta-probe analysis (e.g., a factor by 40% for a recovery coefficient of 0.7) were observed. Thus, this technique enabled the prediction of an accurate input function using the LV time-activity curve, and hence, noninvasive quantification of MBF without arterial cannulation.

Background: We have developed a new measure of myocardial viability, the water-perfusable tissue index (PTI), which is calculated from transmission, C15O, and H2(15)O positron emission tomography (PET) data sets. It is defined as the proportion of the total anatomical tissue within a given region of interest (ROI) that is capable of rapidly exchanging water and has units g (perfusable tissue)/g (total anatomical tissue). The aim of this study was to assess the prognostic value of PTI in predicting improvement in regional wall motion after successful thrombolysis for acute myocardial infarction (AMI) and to measure the myocardial blood flow to the perfusable tissue (MBFp, ml/min/g [perfusable tissue]). Furthermore, PTI was compared with 18FDG metabolic imaging in patients with old myocardial infarction (OMI)., Methods and Results: PET scans were performed in healthy volunteers (group 1, n = 8), patients with OMI (group 2, n = 15), and in patients who were successfully thrombolysed after an AMI (group 3, n = 11). Systolic wall thickening was measured by two-dimensional echocardiography within 2-4 days of AMI and after 4 months to assess contractile recovery. In the healthy volunteers, MBFp was 0.95 +/- 0.13 ml/min/g (perfusable tissue). PTI in these regions was 1.08 +/- 0.07 g (perfusable tissue)/g (total anatomical tissue), which was consistent with all normal myocardium being perfusable by water. In the OMI group, the ratio of the relative 18FDG activity to the relative MBFp defect (metabolism-flow ratio) was calculated for each asynergic segment. Regions in which the metabolism-flow ratio was greater than or equal to 1.20 were considered reversibly injured, whereas those in which the ratio was less than 1.20 were deemed irreversibly injured. PTI in the former group of regions (n = 9) was 0.75 +/- 0.14 g (perfusable tissue)/g (total anatomical tissue) and was significantly higher than in irreversibly injured regions (n = 6) (0.53 +/- 0.12 g [perfusable tissue]/g [total anatomical tissue], p less than 0.01). Values of MBFp were similar in these segments. Seven of 12 segments in the AMI patients showed improved systolic wall thickening on follow-up. PTI in these recovery segments was 0.88 +/- 0.10 g (perfusable tissue)/g (total anatomical tissue) (p = NS versus control). PTI in the nonrecovery regions was 0.53 +/- 0.11 g (perfusable tissue)/g (total anatomical tissue), which was similar to the segments in group 2 in which 18FDG uptake was absent. MBFp was similar in both the recovery and nonrecovery segments in the subacute phase., Conclusions: These data indicate that PTI may be a good prognostic indicator for the recovery of contractile function after successful thrombolysis and show that myocardial viability may be assessed by PET without metabolic imaging.

The transport kinetics of L-[2-18F]-Fluorophenylalanine in the human brain were studied in one normal subject and 6 patients with brain tumor using a dynamic positron emission tomography. The tracer kinetics from blood to brain were described by two compartment model with K1 (influx) and k2 (efflux). The rate constants in normal brain tissue and tumor tissue were K1 = 0.045 ml/g/min, k2 = 0.078 ml/g/min and K1 = 0.122 ml/g/min, k2 = 0.102 ml/g/min, respectively. The Michaelis-Menten constants (Kt and Tmax) for phenylalanine transport in the normal cortex were graphically estimated. The estimated Kt was 35 nmol/ml, whereas the Tmax varied with cerebral blood flow.

We have compared two independent methods of correcting the systematic underestimation in measurements of myocardial radiotracer concentration due to wall motion and small transmural wall thickness in cardiac PET studies. The first technique was based on measurement of the tissue fraction by fitting 15O-labeled water dynamic PET data. The other technique involved the subtraction of the C15O-blood volume scan from the transmission data, producing an image of extravascular density. In normal myocardial regions, both values were observed to be about 60% of myocardial tissue density. The tissue fraction was approximately 10% larger than the extravascular density in normal tissue regions. The ratio of alpha/Dev indicates the proportion of the total extravascular tissue for a given ROI that is perfusable by water--independent of the partial volume effect. This ratio was confirmed to be the expected value in normal tissue regions but was reduced in regions of infarction. The use of 15O-water, C15O and transmission data may aid in the differentiation between perfusable and nonperfusable tissue in the infarcted myocardium.

We investigated the optimal scan time for obtaining the maximal signal-to-noise (S/N) ratio in cerebral blood flow (CBF) measured by PET imaging following 15O-water bolus injection. We performed sequential measurements with dynamic scans of six subjects injected at rest while listening to white noise. Each dynamic data set was edited into images corresponding to different scan times and were calibrated to CBF images by the table look-up method. For each scan time, we evaluated a pixel-by-pixel standard deviation of the CBF for sequential measurements. The S/N-ratio of CBF in the gray matter was 10.2 +/- 1.7 and 13.6 +/- 2.9 at a 40 and 120 sec scan time, respectively. The gain of the 120-sec over 40-sec scan time corresponds to an 80% increase in the number of trials to reach the same S/N-ratio in a stimulation-activation study. The simulation study supported the results, in which the maximal S/N-ratio of the CBF was demonstrated to be 90 and 120 sec at a CBF of 80 and 60 ml/100 ml/min, respectively. It is concluded that the optimal scan time of the 15O-water bolus injection method is in the interval from 90 to 120 sec.

Cardiac PET elicits an accurate relationship between myocardial blood flow (MBF) and tissue viability, which is evaluated by myocardial FDG uptake (MFU). To differentiate reversible tissue from necrotic tissue after the ischemic event, we from necrotic tissue after the ischemic event, we measured absolute MBF and MFU in patients with myocardial infarction. The MBF obtained by O-15 water and dynamic PET was accurately corrected by employing a tissue fraction (a) for the partial volume effect, including wall-motion effect. MFU was also corrected by using the tissue fraction. The subjects consisted of 5 patients with non-Q-wave infarction and 7 patients with Q-wave infarction. The regions of interest were selected from the infarcted area, each corresponding to regions with Q-wave or non-Q-wave. The MBFs in regions with Q wave (0.36 +/- 0.14 ml/min/g) were lower than those without Q wave (0.74 +/- 0.29 ml/min/g) (p less than 0.005). MFUs in regions without Q-wave (0.061 +/- 0.028) were higher than those with Q-wave (0.038 +/- 0.017) (p less than 0.05). The highest threshold of MBF in regions where Q-wave was detected was 0.55 ml/min/g. It is concluded that we will able to find the threshold of electrophysiological dysfunction in the infarcted region with this method.

We developed a new technique of weighted integration for the measurement of local cerebral blood flow (LCBF) and the blood-tissue partition coefficient (p) using dynamic positron emission tomography (PET) and H2(15)O. The weighted integration in the new technique is carried out on the equation of the first time integration of the Kety-Schmidt differential equation. Practically, serially accumulated images with sequentially prolonged accumulation times are weighted by two arbitrary functions. The weighting functions do not have to be differentiated because of the exclusion of the differential term in the starting equation. Consequently, the method does not require data at the end of the scan. The technique was applied to H2(15)O dynamic PET performed on four normal subjects, and was verified to provide a better signal-to-noise ratio than the previously developed integrated projection (IP) technique. Computer simulations were carried out to investigate the effects of statistical noise, tissue heterogeneity, and time delay and dispersion in arterial input function. The simulation showed that the new technique provided about a 1.4 times lower statistical error in both LCBF and p at 50 ml 100 g-1 min-1 compared to the IP technique, and it should be noted that the new technique was less sensitive to the shape of the weighting functions. The new technique provides a new strategy with respect to the statistical error for estimation of LCBF and p.

Background: Oxygen-15-labeled water is a diffusible, metabolically inert myocardial blood flow tracer with a short half-life (2 minutes) that can be used quantitatively with positron emission tomography (PET). The purpose of this study was to validate a new technique to quantify myocardial blood flow (MBF) in animals and to assess its application in patients., Methods and Results: The technique involves the administration of 15O-labeled carbon dioxide (C15O2) and rapid dynamic scanning. Arterial and myocardial time activity curves were fitted to a single tissue compartment tracer kinetic model to estimate MBF in each myocardial region. Validation studies consisted of 52 simultaneous measurements of MBF with PET and gamma-labeled microspheres in nine closed-chest dogs over a flow range of 0.5-6.1 ml/g/min. A good correlation between the two methods was obtained (y = 0.36 + 1.0x, r = 0.91). Human studies consisted of 11 normal volunteers and eight patients with chronic stable angina and single-vessel disease, before and after intravenous dipyridamole infusion. In the normal group, MBF was homogeneous throughout the left ventricle both at rest and after administration of dipyridamole (0.88 +/- 0.08 ml/g/min and 3.52 +/- 1.12 ml/g/min, respectively; p less than or equal to 0.001). In patients, resting MBF was similar in the distribution of the normal and stenotic arteries (1.03 +/- 0.23 and 0.93 +/- 0.21 ml/g/min, respectively). After dipyridamole infusion, MBF in normally perfused areas increased to 2.86 +/- 0.83 ml/g/min, whereas in the regions supplied by stenotic arteries it increased to only 1.32 +/- 0.27 ml/g/min (p less than or equal to 0.001)., Conclusions: PET with C15O2 inhalation provides an accurate noninvasive quantitative method for measuring regional myocardial blood flow in patients.

The intravenous administration of H2(15)O makes possible the quantitative evaluation of regional changes in cerebral blood flow (CBF) during various neuronal activations in man. Many variations on this technique have been proposed. We have compared bolus and slow administration procedures and short and long scan lengths. For a short scan period this study suggests that the bolus injection procedure (with a scan length of 60-120 seconds) provides better CBF count statistics and less sensitivity to errors in the input function than the slow infusion procedure. For a long scan length (greater than 3 min) the slow infusion procedure is recommended. Continuation of H2(15)O infusion allows prolongation of the scan length, which enables us to obtain sufficient CBF statistics (the statistical error may be negligibly small if a sufficient amount of H2(15)O is infused). Another advantage of the slow infusion method may be related to the fluctuation of CBF during the scan period. If CBF fluctuates during this period the slow infusion procedure is expected to provide an average estimate of CBF, whereas the bolus injection procedure provides an estimate (an average over 10 seconds) of CBF which is more sensitive to short-term variations. The feasibility of using 15O2 inhalation to measure regional CBF has also been investigated. By means of a dynamic H2(15)O scan which measures the regional distribution volume of water and a static C15O emission scan which measures blood volume prior to the 15O2 scan, both CBF and cerebral metabolic rate for oxygen (CMRO2) have been accurately measured by the 15O2 scan for various physiological conditions. The application of this technique in a human study confirmed the uncoupling of CBF and CMRO2 during motor and visual activation.

We described theoretical principle and data analysis for PET study using intravenous H2(15)O for measurement of cerebral blood flow (CBF) with emphasis on stimulation study for psychophysiological test. In order to improve signal-to-noise (S/N) ratio in CBF images, we optimized the scan procedures and data analysis. We determined optimal scantime of autoradiographic image to provide minimum S/N ratio as to 90 through 120 sec. Increase of full-width at half-maximum (FWHM) of smoothing filter did reduce the image noise (standard deviation, SD) more rapidly than the partial volume effect. Phantom experiment showed a tendency that a larger FWHM provided a higher statistical t-value.

A simulation study to evaluate the errors in rate constants of the three compartment model using the weighted integral method was performed. Ten combinations of 7 kinds of weight functions, the errors were tested in 18F fluorodeoxyglucose (18FDG) study. The error factors arising in PET measurement were statistical noise, cerebral blood volume, time shift and scanning time of PET measurement. Errors in each rate constant were within the range of 10 percent and those in k1k3/(k2+k3) within 1 percent. The weighted integral method was confirmed to be a faster method than the conventional least squares method within a reasonable error range.

We developed a new technique for fast estimation of local cerebral blood flow and partition coefficient based on time integration of Kety-Schmidt equation. This technique has two advantages concerning statistical noise. Firstly, it does not need a Ci(T) image which contains high statistical noise because of low activity in brain. Secondly, statistical noise is minimized by time integration of Kety-Schmidt equation before multiplied by weighting function. The error analyses in flow and partition coefficient caused by statistical noise were performed using computer simulation, and dynamic PET human study using H(2)15O bolus injection. Both simulation and PET study indicated that uncertainties of flow and partition coefficient were confirmed to be lower in this technique than in the original weighted integration method.