Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography - Computed Tomography Scanner.

The authors have developed a paradigm using positron emission tomography (PET) with multiple radiopharmaceutical tracers that combines measurements of cerebral metabolic rate of glucose (CMRGlc), cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV), culminating in estimates of brain aerobic glycolysis (AG). These in vivo estimates of oxidative and non-oxidative glucose metabolism are pertinent to the study of the human brain in health and disease. The latest positron emission tomography-computed tomography (PET-CT) scanners provide time-of-flight (TOF) imaging and critical improvements in spatial resolution and reduction of artifacts. This has led to significantly improved imaging with lower radiotracer doses. Optimized methods for the latest PET-CT scanners involve administering a sequence of inhaled 15O-labeled carbon monoxide (CO) and oxygen (O2), intravenous 15O-labeled water (H2O), and 18F-deoxyglucose (FDG)-all within 2-h or 3-h scan sessions that yield high-resolution, quantitative measurements of CMRGlc, CMRO2, CBF, CBV, and AG. This methods paper describes practical aspects of scanning designed for quantifying brain metabolism with tracer kinetic models and arterial blood samples and provides examples of imaging measurements of human brain metabolism.

Biological washout modelling for in-beam PET: rabbit brain irradiation by 11C and 15O ion beams.

Positron emission tomography (PET) has been used for dose verification in charged particle therapy. The causes of washout of positron emitters by physiological functions should be clarified for accurate dose verification. In this study, we visualized the distribution of irradiated radioactive beams, 11C and 15O beams, in the rabbit whole-body using our original depth-of-interaction (DOI)-PET prototype to add basic data for biological washout effect correction. Time activity curves of the irradiated field and organs were measured immediately after the irradiations. All data were corrected for physical decay before further analysis. We also collected expired gas of the rabbit during beam irradiation and the energy spectrum was measured with a germanium detector. Irradiated radioactive beams into the brain were distributed to the whole body due to the biological washout process, and the implanted 11C and 15O ions were concentrated in the regions which had high blood volume. The 11C-labelled 11CO2 was detected in expired gas under the 11C beam irradiation, while no significant signal was detected under the 15O beam irradiation as a form of C15O2. Results suggested that the implanted 11C ions form molecules that diffuse out to the whole body by undergoing perfusion, then, they are incorporated into the blood-gas exchange in the respiratory system. This study provides basic data for modelling of the biological washout effect.

PET med O-15-vatten påvisade myokard­ischemi där övrig utredning gick bet.

Elevation of troponin reflects myocardial infarction. The underlying causes should be assessed, as treatment and prognosis may differ widely. Myocardial damage with non-obstructive coronary arteries requires further evaluation including magnetic resonance tomography. We report a case of significant myocardial ischemia which was unnoticed by myocardial scintigraphy but detected by positron emission tomography (PET). The 15O-water tracer allows for quantitative assessment of myocardial perfusion including regional abnormalities and may thus diagnose microvascular dysfunction.

Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI.

AIMS: Perfusion of the pancreas and the islets of Langerhans is sensitive to physiological stimuli and is dysregulated in metabolic disease. Pancreatic perfusion can be assessed by both positron emission tomography (PET) and magnetic resonance imaging (MRI), but the methods have not been directly compared or benchmarked against the gold-standard microsphere technique. METHODS: Pigs (n = 4) were examined by [15O]H2O PET and intravoxel incoherent motion (IVIM) MRI technique simultaneously using a hybrid PET/MRI scanner. The pancreatic perfusion was measured both at basal conditions and after intravenous (IV) administration of up to 0.5 g/kg glucose. RESULTS: Pancreatic perfusion increased by 35%, 157%, and 29% after IV 0.5 g/kg glucose compared to during basal conditions, as assessed by [15O]H2O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [15O]H2O PET and IVIM MRI (r = 0.81, R2 = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [15O]H2O PET was within a 15% error of margin of the microsphere technique. CONCLUSION: Pancreatic perfusion by [15O]H2O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [15O]H2O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required.

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.

Relationship between intelligence quotient (IQ) and cerebral metabolic rate of oxygen in patients with neurobehavioural disability after traumatic brain injury.

OBJECTIVE: Cerebral metabolism may play a significant role in neurobehavioural disability following traumatic brain injury (TBI). In this study, we examined the relationship between intelligence quotient (IQ) and the cerebral metabolic rate of oxygen (CMRO2) in the lateral prefrontal cortex, which was measured by 15O-labelled gas positron emission tomography (PET), in patients with TBI. MATERIALS AND METHODS: The subjects were 12 patients (eight males and four females) who suffered from neurobehavioural disability following TBI. Their mean age was 33.3 years. The cause of injury was traffic accidents in all patients and the mean period after injury was 44.8 months. These patients underwent 15O-labelled gas PET and tests using either the Wechsler Adult Intelligence Scale-Revised (WAIS-R) or the Wechsler Intelligence Scale for Children-Revised (WISC-R). Pearson's correlation between CMRO2 and total IQ (TIQ) was calculated. RESULTS: A statistically significant correlation was observed between TIQ and CMRO2 in the right Brodmann areas (BAs) 44 and 45. The lower the WAIS score, the higher the CMRO2 in both areas. CONCLUSION: Neurological function negatively correlated with the metabolism of oxygen. It was possible that changes in brain networks increased the neuronal activity in the undamaged areas and that the increased activity compensated for the function decline.

Loss of inhibition in sensorimotor networks in focal hand dystonia.

OBJECTIVE: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). METHODS: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). RESULTS: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. INTERPRETATION: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [15O]-water and [18F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

Striatal opioid receptor availability is related to acute and chronic pain perception in arthritis: does opioid adaptation increase resilience to chronic pain?

The experience of pain in humans is modulated by endogenous opioids, but it is largely unknown how the opioid system adapts to chronic pain states. Animal models of chronic pain point to upregulation of opioid receptors (OpR) in the brain, with unknown functional significance. We sought evidence for a similar relationship between chronic pain and OpR availability in humans. Using positron emission tomography and the radiotracer (11)C-diprenorphine, patients with arthritis pain (n = 17) and healthy controls (n = 9) underwent whole-brain positron emission tomography scanning to calculate parametric maps of OpR availability. Consistent with the upregulation hypothesis, within the arthritis group, greater OpR availability was found in the striatum (including the caudate) of patients reporting higher levels of recent chronic pain, as well as regions of interest in the descending opioidergic pathway including the anterior cingulate cortex, thalamus, and periaqueductal gray. The functional significance of striatal changes were clarified with respect to acute pain thresholds: data across patients and controls revealed that striatal OpR availability was related to reduced pain perception. These findings are consistent with the view that chronic pain may upregulate OpR availability to dampen pain. Finally, patients with arthritis pain, compared with healthy controls, had overall less OpR availability within the striatum specifically, consistent with the greater endogenous opioid binding that would be expected in chronic pain states. Our observational evidence points to the need for further studies to establish the causal relationship between chronic pain states and OpR adaptation.

Accuracy and precision of pseudo-continuous arterial spin labeling perfusion during baseline and hypercapnia: a head-to-head comparison with ¹5O H2O positron emission tomography.

Measurements of the cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide useful information about cerebrovascular condition and regional metabolism. Pseudo-continuous arterial spin labeling (pCASL) is a promising non-invasive MRI technique to quantitatively measure the CBF, whereas additional hypercapnic pCASL measurements are currently showing great promise to quantitatively assess the CVR. However, the introduction of pCASL at a larger scale awaits further evaluation of the exact accuracy and precision compared to the gold standard. (15)O H2O positron emission tomography (PET) is currently regarded as the most accurate and precise method to quantitatively measure both CBF and CVR, though it is one of the more invasive methods as well. In this study we therefore assessed the accuracy and precision of quantitative pCASL-based CBF and CVR measurements by performing a head-to-head comparison with (15)O H2O PET, based on quantitative CBF measurements during baseline and hypercapnia. We demonstrate that pCASL CBF imaging is accurate during both baseline and hypercapnia with respect to (15)O H2O PET with a comparable precision. These results pave the way for quantitative usage of pCASL MRI in both clinical and research settings.

Oxygen extraction fraction and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Increased oxygen extraction fraction on PET has been considered a risk factor for stroke in patients with carotid stenosis or occlusion, though the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between increased oxygen extraction fraction and ipsilateral stroke risk. MATERIALS AND METHODS: A comprehensive literature search was performed. We included studies with baseline PET oxygen extraction fraction testing, ipsilateral stroke as the primary outcome, and at least 1 year of follow-up. A meta-analysis was performed by use of a random-effects model. RESULTS: After screening 2158 studies, 7 studies with 430 total patients with mean 30-month follow-up met inclusion criteria. We found that 6 of 7 studies were amenable to meta-analysis. Although 4 of the 6 studies independently did not reach statistical significance, meta-analysis revealed a significant positive relationship between abnormal oxygen extraction fraction and future ipsilateral stroke, with a pooled OR of 6.04 (95% CI, 2.58-14.12). There was no statistically significant difference in OR in the subgroup analyses according to testing method or disease site. CONCLUSIONS: Abnormal oxygen extraction fraction remains a powerful predictor of stroke in carotid stenosis or occlusion and is a valuable reference standard to compare and validate MR imaging-based measures of brain oxygen metabolism. However, there is a need for further evaluation of oxygen extraction fraction testing in patients with high-grade but asymptomatic carotid disease.

Impact of subject head motion on quantitative brain (15)O PET and its correction by image-based registration algorithm.

OBJECTIVE: Subject head motion during sequential (15)O positron emission tomography (PET) scans can result in artifacts in cerebral blood flow (CBF) and oxygen metabolism maps. However, to our knowledge, there are no systematic studies examining this issue. Herein, we investigated the effect of head motion on quantification of CBF and oxygen metabolism, and proposed an image-based motion correction method dedicated to (15)O PET study, correcting for transmission-emission mismatch and inter-scan mismatch of emission scans. METHODS: We analyzed (15)O PET data for patients with major arterial steno-occlusive disease (n = 130) to determine the occurrence frequency of head motion during (15)O PET examination. Image-based motion correction without and with realignment between transmission and emission scans, termed simple and 2-step method, respectively, was applied to the cases that showed severe inter-scan motion. RESULTS: Severe inter-scan motion (>3 mm translation or >5° rotation) was observed in 27 of 520 adjacent scan pairs (5.2 %). In these cases, unrealistic values of oxygen extraction fraction (OEF) or cerebrovascular reactivity (CVR) were observed without motion correction. Motion correction eliminated these artifacts. The volume-of-interest (VOI) analysis demonstrated that the motion correction changed the OEF on the middle cerebral artery territory by 17.3 % at maximum. The inter-scan motion also affected CBV, CMRO2 and CBF, which were improved by the motion correction. A difference of VOI values between the simple and 2-step method was also observed. CONCLUSIONS: These data suggest that image-based motion correction is useful for accurate measurement of CBF and oxygen metabolism by (15)O PET.

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.

Quantification of skeletal blood flow and fluoride metabolism in rats using PET in a pre-clinical stress fracture model.

PURPOSE: Blood flow is an important factor in bone production and repair, but its role in osteogenesis induced by mechanical loading is unknown. Here, we present techniques for evaluating blood flow and fluoride metabolism in a pre-clinical stress fracture model of osteogenesis in rats. PROCEDURES: Bone formation was induced by forelimb compression in adult rats. (15)O water and (18)F fluoride PET imaging were used to evaluate blood flow and fluoride kinetics 7 days after loading. (15)O water was modeled using a one-compartment, two-parameter model, while a two-compartment, three-parameter model was used to model (18)F fluoride. Input functions were created from the heart, and a stochastic search algorithm was implemented to provide initial parameter values in conjunction with a Levenberg-Marquardt optimization algorithm. RESULTS: Loaded limbs are shown to have a 26% increase in blood flow rate, 113% increase in fluoride flow rate, 133% increase in fluoride flux, and 13% increase in fluoride incorporation into bone as compared to non-loaded limbs (p < 0.05 for all results). CONCLUSIONS: The results shown here are consistent with previous studies, confirming this technique is suitable for evaluating the vascular response and mineral kinetics of osteogenic mechanical loading.

Quantification of regional myocardial oxygen metabolism in normal pigs using positron emission tomography with injectable (15)O-O (2).

PURPOSE: Although (15)O-O(2) gas inhalation can provide a reliable and accurate myocardial metabolic rate for oxygen by PET, the spillover from gas volume in the lung distorts the images. Recently, we developed an injectable method in which blood takes up (15)O-O(2) from an artificial lung, and this made it possible to estimate oxygen metabolism without the inhalation protocol. In the present study, we evaluated the effectiveness of the injectable (15)O-O(2) system in porcine hearts. METHODS: PET scans were performed after bolus injection and continuous infusion of injectable (15)O-O(2) via a shunt between the femoral artery and the vein in normal pigs. The injection method was compared to the inhalation method. The oxygen extraction fraction (OEF) in the lateral walls of the heart was calculated by a compartmental model in view of the spillover and partial volume effect. RESULTS: A significant decrease of lung radioactivity in PET images was observed compared to the continuous inhalation of (15)O-O(2) gas. Furthermore, the injectable (15)O-O(2) system provides a measurement of OEF in lateral walls of the heart that is similar to the continuous-inhalation method (0.71 +/- 0.036 and 0.72 +/- 0.020 for the bolus-injection and continuous-infusion methods, respectively). CONCLUSION: These results indicate that injectable (15)O-O(2) has the potential to evaluate myocardial oxygen metabolism.

Optimization of the injected activity in dynamic 3D PET: a generalized approach using patient-specific NECs as demonstrated by a series of 15O-H2O scans.

UNLABELLED: The magnitude of the injected activity (A(0)) has a direct impact on the statistical quality of PET images. This study aimed to develop a generalized method for maximizing the statistical quality of dynamic PET images by optimizing A(0). METHODS: Patient-specific noise-equivalent counts (PS-NECs) were used as a metric of the statistical quality of each time frame of a dynamic PET image. Previous methodology developed to extrapolate the NEC as a function of A(0) was extended to dynamic PET, enabling the NEC to be extrapolated as a function of both A(0) and the time after injection. This method allowed A(0) to be optimized after a single scan (at a single A(0)), by maximizing the NEC within the time interval for which the parameter estimation is most sensitive. The extrapolation method was validated by a series of (15)O-H(2)O scans of the body acquired in 3-dimensional mode. Each patient (n = 6) underwent between 3 and 6 scans at 1 bed position. The injected activities were varied over a wide range (140-840 MBq). Noise-equivalent counting rate (NECR) versus A(0) curves and the optimal injected activities were calculated from each injection. RESULTS: PS-NECR versus A(0) curves as extrapolated from different injected activities were consistent (coefficient of variation, typically <5%). The optimal injected activities for an individual, as derived from these curves, were also consistent (maximum coefficient of variation, 4.3%). For abdominal (n = 4) and chest (n = 1) scans, we found optimal injected activities of (15)O-H(2)O in the range of 220-350 MBq for estimating blood perfusion (F) and 660-1,070 MBq for estimating the volume of distribution (V(T)). Higher optimal injected activities were found in the case of a pelvic scan (n = 1; 570 MBq for F and 1,530 MBq for V(T)). CONCLUSION: PS-NECs are a valid and generic method for optimizing the injected activity in PET, allowing scanning protocols to be improved after the collection of an initial, single dynamic dataset. This generic method can be used to estimate the optimal injected activity, which is specific to the patient, tracer, PET scanner, and body region being scanned.

Combination of a mean transit time measurement with an acetazolamide test increases predictive power to identify elevated oxygen extraction fraction in occlusive carotid artery diseases.

UNLABELLED: Reduced cerebral blood flow and cerebrovascular reactivity to acetazolamide have been used as predictors for subsequent ischemic stroke in patients with occlusive carotid artery diseases, called type 3 ischemia. However, recent studies have shown that reduced cerebrovascular reactivity to acetazolamide does not always represent elevated oxygen extraction fraction (OEF). The aim of this study was to establish the methodology to improve the validity of an acetazolamide test identifying elevated OEF. METHODS: This study included 65 patients who developed transient ischemic attack or minor completed stroke attributable to occlusive carotid artery diseases. Hemodynamic and metabolic parameters in the bilateral middle cerebral artery territories were determined in all patients by (15)O-gas PET. RESULTS: Type 3 ischemia alone had 100% sensitivity and 83.2% specificity for identifying elevated OEF, but its positive predictive value and accuracy were low, 47.2% and 0.85, respectively. However, type 3 ischemia and delayed mean transit time combined had an 83.3% positive predictive value and 0.96 accuracy. CONCLUSION: The results strongly suggest that type 3 ischemia and delayed mean transit time together may be powerful predictors in identifying elevated OEF with high sensitivity and specificity, predictive values, and accuracy. SPECT may be able to define the patients with elevated OEF more easily and at lower costs than PET, although further study would be necessary to compare the results by using SPECT.

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.

Nonhuman primate neuroimaging and the neurobiology of psychostimulant addiction.

Neuroimaging techniques have led to significant advances in our understanding of the neurobiology and treatment of drug addiction in humans. The capability to conduct parallel studies in nonhuman primates and human subjects provides a powerful translational approach to link findings in human and animal research. A significant advantage of nonhuman primate models is the ability to use drug-naïve subjects in longitudinal designs that document the neurobiological changes that are associated with chronic drug use. Moreover, experimental therapeutics can be evaluated in subjects with well-documented histories of drug exposure. The in vivo distribution and pharmacokinetics of drug binding in brain have been related to the time-course of behavioral effects associated with the addictive properties of stimulants. Importantly, the characterization of drug interactions with specific protein targets in brain has identified potential targets for medication development. Neuroimaging has proven especially useful in studying the dynamic changes in neuronal function that may be associated with environmental variables. Last, neuroimaging has been used effectively in nonhuman primates to characterize both transient and long-lasting changes in brain chemistry associated with chronic drug exposure. Although there is some evidence to suggest neurotoxicity in humans with long histories of stimulant use, parallel studies in nonhuman primates have not identified consistent long-term changes in such neurochemical markers. Collectively, the results of these studies of nonhuman primates have enhanced our understanding of the neurobiological basis of stimulant addiction and should have a significant impact on efforts to develop medications to treat stimulant abuse.