Deep-learning-based attenuation correction in dynamic [15O]H2O studies using PET/MRI in healthy volunteers.

Quantitative [15O]H2O positron emission tomography (PET) is the accepted reference method for regional cerebral blood flow (rCBF) quantification. To perform reliable quantitative [15O]H2O-PET studies in PET/MRI scanners, MRI-based attenuation-correction (MRAC) is required. Our aim was to compare two MRAC methods (RESOLUTE and DeepUTE) based on ultrashort echo-time with computed tomography-based reference standard AC (CTAC) in dynamic and static [15O]H2O-PET. We compared rCBF from quantitative perfusion maps and activity concentration distribution from static images between AC methods in 25 resting [15O]H2O-PET scans from 14 healthy men at whole-brain, regions of interest and voxel-wise levels. Average whole-brain CBF was 39.9 ± 6.0, 39.0 ± 5.8 and 40.0 ± 5.6 ml/100 g/min for CTAC, RESOLUTE and DeepUTE corrected studies respectively. RESOLUTE underestimated whole-brain CBF by 2.1 ± 1.50% and rCBF in all regions of interest (range -2.4%- -1%) compared to CTAC. DeepUTE showed significant rCBF overestimation only in the occipital lobe (0.6 ± 1.1%). Both MRAC methods showed excellent correlation on rCBF and activity concentration with CTAC, with slopes of linear regression lines between 0.97 and 1.01 and R2 over 0.99. In conclusion, RESOLUTE and DeepUTE provide AC information comparable to CTAC in dynamic [15O]H2O-PET but RESOLUTE is associated with a small but systematic underestimation.

Effects of low-dose oxygen ions and protons on cardiac function and structure in male C57BL/6J mice.

PURPOSE: Astronauts traveling beyond low-Earth orbit will be exposed to high linear-energy transfer charged particles. Because there is concern about the adverse effects of space radiation on the cardiovascular system, this study assessed cardiac function and structure and immune cell infiltration in a mouse model of charged-particle irradiation. MATERIALS AND METHODS: Male C57BL/6 J mice were exposed to oxygen ions (16O, 600 MeV/n at 0.25-0.26 Gy/min to a total dose of 0, 0.05, 0.1, 0.25, or 1 Gy), protons (150 MeV, 0.35-0.55 Gy/min to 0, 0.5, or 1 Gy), or protons (150 MeV, 0.5 Gy) followed by 16O (600 MeV/n, 0.1 Gy). Separate groups of mice received 137Cs γ-rays (1 Gy/min to 0, 0.5, 1, or 3 Gy) as a reference. Cardiac function and blood velocity were measured with ultrasonography at 3, 5, 7, and 9 months after irradiation. At 2 weeks, 3 months, and 9 months, cardiac tissue was collected to assess apoptosis, tissue remodeling, and markers of immune cells. RESULTS: Ejection fraction and fractional shortening decreased at 3 and 7 months after 16O. These parameters did not change in mice exposed to γ-rays, protons, or protons followed by 16O. Each of the radiation exposures caused only small increases in cleaved caspase-3 and numbers of apoptotic nuclei. Changes in the levels of α-smooth muscle cell actin and a 75-kDa peptide of collagen type III in the left ventricle suggested tissue remodeling, but there was no significant change in total collagen deposition at 2 weeks, 3 months, and 9 months. Increases in protein amounts of cluster of differentiation (CD)2, CD68, and CD45 as measured with immunoblots at 2 weeks, 3 months, and 9 months after exposure to protons or 16O alone suggested immune cell infiltration. For type III collagen, CD2 and CD68, the efficacy in inducing protein abundance of CD2, CD68, and CD45 was 16O > protons > γ-rays > protons followed by 16O. CONCLUSIONS: Low-dose, high-energy charged-particle irradiation caused mild changes in cardiac function and tissue remodeling in the mouse.

Phase contrast mapping MRI measurements of global cerebral blood flow across different perfusion states - A direct comparison with 15O-H2O positron emission tomography using a hybrid PET/MR system.

Phase-contrast mapping (PCM) magnetic resonance imaging (MRI) provides easy-access non-invasive quantification of global cerebral blood flow (gCBF) but its accuracy in altered perfusion states is not established. We aimed to compare paired PCM MRI and 15O-H2O positron emission tomography (PET) measurements of gCBF in different perfusion states in a single scanning session. Duplicate combined gCBF PCM-MRI and 15O-H2O PET measurements were performed in the resting condition, during hyperventilation and after acetazolamide administration (post-ACZ) using a 3T hybrid PET/MR system. A total of 62 paired gCBF measurements were acquired in 14 healthy young male volunteers. Average gCBF in resting state measured by PCM-MRI and 15O-H2O PET were 58.5 ± 10.7 and 38.6 ± 5.7 mL/100 g/min, respectively, during hyperventilation 33 ± 8.6 and 24.7 ± 5.8 mL/100 g/min, respectively, and post-ACZ 89.6 ± 27.1 and 57.3 ± 9.6 mL/100 g/min, respectively. On average, gCBF measured by PCM-MRI was 49% higher compared to 15O-H2O PET. A strong correlation between the two methods across all states was observed (R2 = 0.72, p < 0.001). Bland-Altman analysis suggested a perfusion dependent relative bias resulting in higher relative difference at higher CBF values. In conclusion, measurements of gCBF by PCM-MRI in healthy volunteers show a strong correlation with 15O-H2O PET, but are associated with a large and non-linear perfusion-dependent difference.

Doppler Flow Velocity and Thermodilution to Assess Coronary Flow Reserve: A Head-to-Head Comparison With [15O]H2O PET.

OBJECTIVES: This study sought to compare Doppler flow velocity reserve (CFRDoppl) and thermodilution-derived coronary flow reserve (CFRthermo) head-to-head with the gold standard for quantification of myocardial perfusion, [15O]H2O positron emission tomography (PET). BACKGROUND: Coronary flow reserve (CFR) is an important parameter for assessing coronary vascular function. To date, 2 techniques are available for invasive assessment of CFR: Doppler flow velocity and thermodilution. Although these techniques have been compared with each other, neither has been compared with [15O]H2O PET perfusion imaging. METHODS: CFR was assessed in 98 vessels of 40 consecutive stable patients with suspected coronary artery disease. Patients underwent [15O]H2O PET, followed by invasive angiography in conjunction with simultaneous measurements of fractional flow reserve, CFRDoppl, and CFRthermo. Both normal and obstructed arteries were included. RESULTS: The quality of Doppler flow velocity traces was significantly lower than that of thermodilution curves (p < 0.001). A moderate correlation was observed between CFRDoppl and CFRthermo (r = 0.59; p < 0.001). CFRDoppl correlated well with PET-derived CFR (CFRPET) (r = 0.82; p < 0.001). In contrast, the correlation between CFRthermo and CFRPET was only modest (r = 0.55; p < 0.001). This difference in correlation with CFRPET was significant (t = 4.9; df = 95; p < 0.001). Bland-Altman analysis revealed a tendency of CFRthermo to overestimate flow reserve at higher values. CONCLUSIONS: Coronary flow reserve, determined using Doppler flow velocity, has superior agreement with [15O]H2O PET in comparison with CFRthermo.

Comparison of Effects between Clopidogrel and Cilostazol on Cerebral Perfusion in Nonsurgical Adult Patients with Symptomatically Ischemic Moyamoya Disease: Subanalysis of a Prospective Cohort.

BACKGROUND AND PURPOSE: Adult patients with symptomatically ischemic moyamoya disease (MMD) initially undergo medical treatment alone including antiplatelet drugs when symptomatic cerebral hemispheres do not exhibit hemodynamic compromise. The purpose of the present study subanalyzing the same patient cohort used in a previous study was to determine which antiplatelet drug, clopidogrel or cilostazol, provides better improvement of cerebral perfusion in such patients. METHODS: All patients without cerebral misery perfusion on 15O gas positron emission tomography (PET) did not undergo revascularization surgery and were treated with medication alone, including antiplatelet therapy. Patients ≥50years and <50years initially received clopidogrel and cilostazol, respectively. When a patient suffered side effects of an antiplatelet drug, they were switched to the other antiplatelet drug. Cerebral blood flow (CBF) in the symptomatic hemisphere was measured at inclusion and at 2years after inclusion using 15O gas PET. RESULTS: Of 68 patients, 31 and 38 were treated with clopidogrel and cilostazol, respectively, for 2years after inclusion. For patients treated with clopidogrel, CBF did not differ between first and second PET. For patients treated with cilostazol, CBF was significantly greater in the second PET than in the first PET. On multivariate analysis, cilostazol administration was an independent predictor of CBF improvement in the symptomatic hemisphere (95% confidence interval, 1.34-139.20; P =.0271). CONCLUSIONS: Cilostazol improves cerebral perfusion better than clopidogrel in adult patients with symptomatically ischemic MMD not accompanied by misery perfusion.

15-O-water myocardial flow reserve PET and CT angiography by full hybrid PET/CT as a potential alternative to invasive angiography.

Combined myocardial flow reserve (MFR) by PET and CT coronary angiography (CTA) is a promising tool for assessment of coronary artery disease. Prior analyses of MFR/CTA has been performed as side-by-side interpretation, not as volume rendered, full hybrid analysis, with fused MFR/CTA. We aimed to: (i) establish a method for full hybrid analysis of MFR/CTA, (ii) validate the inter- and intra-observer reproducibility of MFR values, and (iii) determine the diagnostic value of side-by-side versus full hybrid MFR/CTA with 15-O-water PET. Forty-four outpatients scheduled for invasive coronary angiography (ICA) were enrolled prospectively. All underwent rest/stress 15-O-water PET/CTA with ICA as reference. Within two observers of different experience, the Pearson r at global and territorial level exceeded 0.953 for rest, stress, and MFR values, as determined by Carimas software. Within and between observers, the mean differences between rest, stress, and MFR values were close to zero and the confidence intervals for 95% limits of agreement were narrow. The diagnostic performance of full hybrid PET/CTA did not outperform the side-by-side approach, but performed better than MFR without CTA at vessel level: specificity 93% (95% confidence limits: 89-97%) versus 76% (64-88%), p = 0.0004; positive predictive value 71% (55-86%) versus 51% (37-65%), p = 0.0001; accuracy 90% (84-95%) versus 77% (69-84%), p = 0.0009. MFR showed high reproducibility within and between observers of different experience. The full hybrid model was not superior to side-by-side interpretation of MFR/CTA, but proved better than MFR alone at vessel level with regard to specificity, positive predictive value, and accuracy.

Is Perfusion MRI without Deconvolution Reliable for Mismatch Detection in Acute Stroke? Validation with 15O-Positron Emission Tomography.

BACKGROUND: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions. METHODS: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the -upper PF threshold as defined by PET cerebral blood flow <20 mL/100 g/min. RESULTS: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85-0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84-0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87-0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET. CONCLUSIONS: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke.

Validation of scatter limitation correction to eliminate scatter correction error in oxygen-15 gas-inhalation positron emission tomography images.

OBJECTIVE: High levels of radioactivity inside a facemask cause scatter correction (SC) errors that appear as photopenic artifacts on quantitative oxygen-15 (O) gas-inhalation positron emission tomography (PET) images. The present study aimed to validate the ability of scatter limitation correction (SLC) to eliminate SC errors in O gas-inhalation PET images acquired from patients and a phantom. MATERIALS AND METHODS: We analyzed the SC errors in phantom images and calculated parametric images of the cerebral blood flow (CBF), cerebral blood volume, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2). Phantoms comprised a cylinder and paper with radioactivity to simulate a facemask during (O)O2 gas inhalation. Parametric images were calculated from O gas-inhalation PET images of ten participants. All PET data were reconstructed using conventional SC as model-based SC and SLC. Images acquired from the phantoms and parametric images were assessed visually and quantitatively in the presence and absence of SC error. RESULTS: SC error was evident in images derived from the paper phantom and at the slice level of the cerebellum in CBF, OEF, and CMRO2 images. The radioactivity concentration in the cylindrical phantom with the paper phantom significantly improved with SLC. The SLC also increased the quantitative indices of CBF, OEF, and CMRO2 by 23.8, 42.2, and 44.4%, respectively. CONCLUSION: SLC visually eliminated the SC error and increased the quantitative parameters on O gas-inhalation images derived from a phantom and from patients.

Impact of Revascularization on Absolute Myocardial Blood Flow as Assessed by Serial [15O]H2O Positron Emission Tomography Imaging: A Comparison With Fractional Flow Reserve.

BACKGROUND: The main goal of coronary revascularization is to restore myocardial perfusion in case of ischemia, causing coronary artery disease. Yet, little is known on the effect of revascularization on absolute myocardial blood flow (MBF). Therefore, the present prospective study assesses the impact of coronary revascularization on absolute MBF as measured by [15O]H2O positron emission tomography and fractional flow reserve (FFR) in patients with stable coronary artery disease. METHODS AND RESULTS: Fifty-three patients (87% men, mean age 58.7±9.0 years) with suspected coronary artery disease were included prospectively. All patients underwent serial [15O]H2O positron emission tomography perfusion imaging at baseline and after revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. FFR was routinely measured at baseline and directly post-PCI. After revascularization, regional rest and stress MBF improved from 0.77±0.16 to 0.86±0.25 mL/min/g and from 1.57±0.59 to 2.48±0.91 mL/min/g, respectively, yielding an increase in coronary flow reserve from 2.02±0.69 to 2.94±0.94 (P<0.01 for all). Mean FFR at baseline improved post-PCI from 0.61±0.17 to 0.89±0.08 (P<0.01). After PCI, an increase in FFR paralleled improvement in absolute myocardial perfusion as reflected by stress MBF and coronary flow reserve (r = 0.74 and r = 0.71, respectively, P<0.01 for both). PCI demonstrated a greater improvement of regional stress MBF as compared with coronary artery bypass graft surgery (1.14±1.11 versus 0.66±0.69 mL/min/g, respectively, P=0.02). However, patients undergoing bypass grafting had a more advanced stage of coronary artery disease and more incomplete revascularizations. CONCLUSION: Successful coronary revascularization has a significant and positive impact on absolute myocardial perfusion as assessed by serial quantitative [15O]H2O positron emission tomography. Notably, improvement of FFR after PCI was directly related to the increase in hyperemic MBF.

X-ray angiography perfusion imaging with an intra-arterial injection: comparative study with 15O-gas/water positron emission tomography.

BACKGROUND: X-ray angiography perfusion (XAP) is a perfusion imaging technique based on conventional DSA. OBJECTIVE: In this study, we aimed to validate parameters derived from XAP by comparing them with 15O-gas/water positron emission tomography (PET), using data from patients with chronic ischemic cerebrovascular disease. METHODS: 18 consecutive patients were included. XAP was performed with intra-arterial infusion of contrast media, and a time-density curve was constructed for each cerebral hemisphere. From the curves, the relative values of mean transit time (rMTT) and wash-in rate (rWiR) were obtained by dividing the values of the right hemisphere by those of the left hemisphere. These were then compared with the relative values of cerebral blood flow (rCBF) and rMTT calculated from the PET data. RESULTS: XAP rWiR correlated strongly with PET rCBF (r=0.86, P<0.0001). rMTT measurements from the two modalities were also strongly correlated (r=0.85, P<0.0001). Bland-Altman analysis revealed a bias of 0.14±0.18 (95% limits of agreement -0.22 to 0.51) for PET rCBF versus XAP rWiR, and 0.016±0.093 (95% limits of agreement -0.17 to 0.20) for rMTT between the two modalities. CONCLUSIONS: The relative values obtained from XAP were validated across a population of patients with chronic ischemic cerebrovascular disease.

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

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

PET quantification of cerebral oxygen metabolism in small animals.

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

Estimation of ¹²³I-IMP arterial blood activity using ¹²³I-IMP acquisition data from the lungs and brain without any blood sampling: validation of its usefulness for quantification of regional cerebral blood flow.

OBJECTIVE: The conventional methods for the estimation of regional cerebral blood flow (rCBF) using ¹²³I-labeled N-isopropyl-p-iodoamphetamine (¹²³I IMP) autoradiography (ARG) require continuous or 1-point arterial blood sampling. Patients who need rCBF quantification benefit from the avoidance of arterial puncture. In this study, we attempted to develop a method without any blood sampling to estimate ¹²³I IMP activity in the arterial blood sample at 10 minutes after injection of ¹²³I IMP (Ca10) for the purpose of rCBF quantification. For the evaluation of validity of this method, the mean of rCBFs in various regions of the brain (mean CBF) calculated by ¹²³I IMP ARG method using the estimated Ca10 was compared with that calculated using the Ca10 directly measured with the actual arterial blood sample. Both groups of the mean CBF values were also compared with those measured by O-15 H2O PET ARG method. METHODS: I-123 IMP ARG study was applied to 23 patients, and O-15 H2O PET ARG was applied to 20 patients of them. Dynamic images of the lungs, time series of static images of the brain, and brain SPECT images were acquired after injection of ¹²³I IMP. Arterial blood sampling was done 10 minutes after injection of ¹²³I IMP. Multiple regression analysis was used to estimate Ca10 using 5 parameters from the lung washout counts, time series of brain static counts, and brain SPECT average counts as the explanatory variables and the Ca10 directly measured with the actual arterial blood sample as the objective variable, and the regression equation was calculated. RESULTS: The regression equation was calculated by multiple regression analysis as follows: Estimated Ca10 = (2.09 × 10⁻² · LW3) - (2.29 × 10⁻4 · Cb5) - (9.87 × 10⁻³ · Cbpre-SPECT) + (1.06 · CbSPECTav) + (1.03 × 10⁻² · Cbpost-SPECT) + 165 (counts/s/g), where LW3: lung washout count at 3 minutes after injection, Cb5: brain count at 5 minutes, Cb pre-SPECT: brain count before SPECT, Cb SPECT av: average brain count during SPECT, and Cb post-SPECT: brain count after SPECT. The estimated Ca10 values closely correlated with the directly measured Ca10 values (r = 0.907, P < 0.01). The mean CBF values (mL/min/100 g) calculated by ¹²³I IMP ARG method using the estimated Ca10 also closely correlated with those calculated using the directly measured Ca10 (r = 0.818, P < 0.01). The mean CBF values calculated by the ¹²³I IMP ARG method using either the directly measured or the estimated Ca10 significantly correlated (r = 0.698 and 0.590, respectively; P < 0.01) with those measured by O-15 H2O PET ARG method. CONCLUSIONS: The ¹²³I IMP arterial blood activity can be estimated reliably without any blood sampling using the ¹²³I IMP acquisition data from the lungs and brain. This method can serve for a convenient and noninvasive rCBF quantification technique instead of the conventional methods requiring arterial blood sampling.

Optimization of transmission scan duration for 15O PET study with sequential dual tracer administration using N-index.

PURPOSE: Cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of O(2) (CMRO(2)) can be quantified by PET with the administration of H (2) (15) O and (15)O(2). Recently, a shortening in the duration of these measurements was achieved by the sequential administration of dual tracers of (15)O(2) and H (2) (15) O with PET acquisition and integration method (DARG method). A transmission scan is generally required for correcting photon attenuation in advance of PET scan. Although the DARG method can shorten the total study duration to around 30 min, the transmission scan duration has not been optimized and has possibility to shorten its duration. Our aim of this study was to determine the optimal duration for the transmission scan. We introduced 'N-index', which estimates the noise level on an image obtained by subtracting two statistically independent and physiologically equivalent images. The relationship between noise on functional images and duration of the transmission scan was investigated by N-index. METHODS: We performed phantom studies to test whether the N-index reflects the pixel noise in a PET image. We also estimated the noise level by the N-index on CBF, OEF and CMRO(2) images from DARG method in clinical patients, and investigated an optimal true count of the transmission scan. RESULTS: We found tight correlation between pixel noise and N-index in the phantom study. By investigating relationship between the transmission scan duration and N-index value for the functional images by DARG method, we revealed that the transmission data with true counts of more than 40 Mcounts results in CBF, OEF, and CMRO(2) images of reasonable quantitative accuracy and quality. CONCLUSION: The present study suggests that further shortening of DARG measurement is possible by abridging the transmission scan. The N-index could be used to determine the optimal measurement condition when examining the quality of image.

Automatic labeling method for injectable 15O-oxygen using hemoglobin-containing liposome vesicles and its application for measurement of brain oxygen consumption by PET.

INTRODUCTION: The aim of this study was to develop an injectable (15)O-O(2) system using hemoglobin-containing vesicles (HbV), a type of artificial red blood cell, and to investigate the feasibility of (15)O(2)-labeled HbV ((15)O(2)-HbV) to measure cerebral metabolic rate of oxygen (CMRO(2)) in rats. METHODS: The direct bubbling method was combined with vortexing to enhance labeling efficiency of HbV with (15)O-O(2) gas. L-Cysteine was added as a reductant to protect hemoglobin molecules in HbV from oxidation at different concentrations, and labeling efficiencies were also compared. Measurement of cerebral blood flow (CBF) and CMRO(2) in five normal rats was performed using a small animal PET scanner after the injection of H(2)(15)O and (15)O(2)-HbV to evaluate the precision of hemodynamic parameters quantitatively. RESULTS: The labeling efficiency of HbV was significantly increased when vortexing and bubbling were combined compared with the simple bubbling method (P<.05). The most efficient method for labeling was bubbling of (15)O-O(2) combined with vortexing and the addition of 2.8 mM L-cysteine in HbV solution. The mean radioactivity of 214.4+/-7.8 MBq/mL HbV was obtained using this method. PET scans using (15)O(2)-HbV and H(2)(15)O yielded a mean CMRO(2) value of 6.8+/-1.4 (mL/min per 100 g) in rats with normal CBF of 51.4+/-7.9 (mL/min per 100 g). CONCLUSION: Addition of l-cysteine to HbV and simple direct bubbling of (15)O-O(2) gas combined with vortexing was the most efficient method for preparation of (15)O(2)-HbV. The present injectable system using (15)O(2)-HbV was successfully utilized to measure CMRO(2) in rats, indicating that this new method could be useful for animal models to measure oxygen metabolism in the brain.

Evaluation of utility of asymmetric index for count-based oxygen extraction fraction on dual-tracer autoradiographic method for chronic unilateral brain infarction.

OBJECTIVE: For diagnosing patients with ischemic cerebrovascular disease, non-invasive count-based method with (15)O(2) and H (2) (15) O positron-emission tomography (PET) data is widely used to measure asymmetric increases in oxygen extraction fraction (OEF). For shortening study time, we have proposed dual-tracer autoradiographic (DARG) protocol in which (15)O(2) gas and C(15)O(2) gas are sequentially administrated within short period. In this paper, we evaluated feasibility of the non-invasive count-based method with the DARG protocol. METHODS: Twenty-three patients [67.8 +/- 9.9 (mean +/- SD) years] with chronic unilateral brain infarction were examined by the use of measurements of asymmetric OEF elevation. As DARG protocol, (15)O(2) and C(15)O(2) gases were inhaled with 5-min interval and dynamic PET data were acquired for 8 min. Quantitative OEF (qOEF) image was computed with PET data and arterial input function. Ratio image of (15)O(2) and C(15)O(2) phases of PET data was computed as count-based OEF (cbOEF) image. The asymmetric indices (AI) of qOEF (qOEF-AI) and cbOEF (cbOEF-AI) were obtained from regions of interest symmetric placed on left and right sides of cerebral hemisphere. To optimize the summation time of PET data for the cbOEF image, qOEF and cbOEF images with various summation times were compared. RESULTS: Image quality of cbOEF image was better than that of qOEF image. The best correlation coefficient of 0.94 was obtained when the cbOEF image was calculated from 0 to 180 s of (15)O(2) summed image and 340 to 440 s of C(15)O(2) summed image. CONCLUSION: Using the appropriate summation time, we obtained the cbOEF image with good correlation with qOEF image, which suggests non-invasive cbOEF image can be used for evaluating the degree of misery perfusion in patients with chronic unilateral brain infarction. The count-based method with DARG protocol has a potential to dramatically reduce the examination time of (15)O PET study.

Optimal scan time of oxygen-15-labeled gas inhalation autoradiographic method for measurement of cerebral oxygen extraction fraction and cerebral oxygen metabolic rate.

OBJECTIVE: Regional cerebral blood flow (CBF), cerebral blood volume, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) can be estimated from C15O, H(2)15O, and 15O2 tracers and positron emission tomography (PET) using an autoradiographic (ARG) method. Our objective in this study was to optimize the scan time for 15O2 gas study for accurate estimation of OEF and CMRO2. METHODS: We evaluated statistical noise in OEF by varying the scan time and error caused by the tissue heterogeneity in estimated OEF and CMRO2 using computer simulations. The characteristics of statistical noise were investigated by signal-to-noise (S/N) ratio from repeated tissue time activity curves with noise, which were generated using measured averaged arterial input function and assuming CBF=20, 50, and 80 (ml/100 g per minute). Error caused by tissue heterogeneity was also investigated by estimated OEF and CMRO2 from tissue time activity curve with mixture of gray and white matter varying fraction of mixture. In the simulations, three conditions were assumed (i) CBF in gray and white matter (CBFg and CBFw) was 80 and 20, OEF in gray and white matter (Eg and Ew) was 0.4 and 0.3, (ii) CBFg and CBFw decreased by 50%, and Eg and Ew increased by 50% when compared with conditions (i) and (iii). CBFg and CBFw decreased by 80%, and Eg and Ew increased by 50% when compared with condition (i). RESULTS: The longer scan time produced the better S/N ratio of estimated OEF value from three CBF values (20, 50, and 80). Errors of estimated OEF for three conditions owing to tissue heterogeneity decreased, as scan time took longer. Meanwhile in the case of CMRO2, 3 min of scan time was desirable. CONCLUSIONS: The optimal scan time of 15O2 inhalation study with the ARG method was concluded to be 3 min from taking into account for maintaining the S/N ratio and the quantification of accurate OEF and CMRO2.

Shorter examination method for the diagnosis of misery perfusion with count-based oxygen extraction fraction elevation in 15O-Gas PET.

UNLABELLED: (15)O-Gas PET is useful for evaluating hemodynamic status in patients with ischemic cerebrovascular disease. To reduce examination time and exposure to radioactive gas, we assessed a count-based method with shorter continuous (15)O(2) gas inhalation. METHODS: Twenty-five patients (66 +/- 13 [mean +/- SD] y old) with unilateral cerebrovascular stenoocclusive disease were examined by use of measurements of asymmetric oxygen extraction fraction (OEF) elevation. Dynamic PET scans of 1 min per frame were obtained starting 2 min after the beginning of (15)O(2) inhalation at a constant flow rate (740 MBq/min). Each subject also underwent C(15)O and H(2)(15)O PET with the bolus administration method. To evaluate the effects of different scan start times and durations during (15)O(2) inhalation, we extracted and summed individual (15)O(2) PET data from the dynamic (15)O(2) dataset. Count-based OEF (cbOEF) images were calculated from (15)O(2) and H(2)(15)O PET images. The asymmetric indices (AI) of cbOEF (cbOEF-AI) were obtained from regions of interest drawn on territories of the bilateral middle cerebral artery. These AI were compared with the AI of quantitative OEF (qOEF-AI). RESULTS: The slopes of the regression lines and the coefficients of correlation between qOEF-AI and cbOEF-AI were close to 1.00 and greater than 0.79, respectively, regardless of different scan start times and durations. The cbOEF-AI obtained with a longer scan duration were closer to the qOEF-AI than those obtained with a shorter scan duration. Longer scan durations also provided better coefficients of correlation between cbOEF-AI and qOEF-AI regardless of scan start times. The coefficients of correlation between cbOEF-AI and qOEF-AI were greater than 0.90, except for cbOEF-AI obtained from (15)O(2) images at 2-3 min after (15)O(2) inhalation. CONCLUSION: The cbOEF obtained by (15)O(2) imaging from 4 min after (15)O(2) inhalation to 7 min or longer can correctly diagnose misery perfusion. The less invasive count-based PET method used in this study will be able to reduce examination time, exposure time, and stress for patients with ischemic cerebrovascular disease.

Quantitative measurement of oxygen metabolic rate in the rat brain using microPET imaging of briefly inhaled 15O-labelled oxygen gas.

OBJECTIVE: The quantitative measurement of cerebral metabolic rate of oxygen (CMRO(2)) for rats using positron emission tomography (PET) has been technically difficult. The present study was performed to provide a technique to measure CMRO(2) for rats using a dedicated animal PET technique. METHODS: CMRO(2) in the rat brain was quantitatively measured under alpha-chloralose anaesthesia (30 mg . kg(-1) . h(-1), intravenous infusion) using a PET imaging technique. In our experiment, the (15)O-labelled gas tracer (O(15)O) was administered by a bolus insufflation into the lung through a surgically placed cannula in the trachea. The tracer distribution was then dynamically imaged using the microPET. Unlike other conventional PET methods in which a series of arterial blood samples need to be withdrawn for the measurement of an arterial input function, no arterial blood sampling was employed. Instead, the heart was scanned in dynamic mode at the same time of imaging the brain, and the region of interest drawn over the heart was analysed to obtain an arterial input function. RESULTS: The CMRO(2) value (micromol . 100 g(-1) . min(-1)) from 10 rats was 208 +/- 15 (mean +/- SD). CONCLUSIONS: Our results suggest that the microPET-based CMRO(2) measurement in the rat brain combined with a non-invasive measurement of arterial input function is promising, especially for many applications involving small animals in which repeated measurements of absolute CMRO(2) need to be performed.