Monitoring variables affecting positron emission tomography measurements of cerebral blood flow in anaesthetized pigs

Abstract Background Positron emission tomography (PET) imaging of anaesthetized pig brains is a useful tool in neuroscience. Stable cerebral blood flow (CBF) is essential for PET, since variations can affect the distribution of several radiotracers. However, the effect of physiological factors regulating CBF is unresolved and therefore knowledge of optimal anaesthesia and monitoring of pigs in PET studies is sparse. The aim of this study was therefore to determine if and how physiological variables and the duration of anaesthesia affected CBF as measured by PET using [15O]-water in isoflurane–N2O anaesthetized domestic female pigs. First, we examined how physiological monitoring parameters were associated with CBF, and which parameters should be monitored and if possible kept constant, during studies where a stable CBF is important. Secondly, we examined how the duration of anaesthesia affected CBF and the monitoring parameters. Results No significant statistical correlations were found between CBF and the nine monitoring variables. However, we found that arterial carbon dioxide tension (PaCO2) and body temperature were important predictors of CBF that should be observed and kept constant. In addition, we found that long-duration anaesthesia was significantly correlated with high heart rate, low arterial oxygen tension, and high body temperature, but not with CBF. Conclusions The findings indicate that PaCO2 and body temperature are crucial for maintaining stable levels of CBF and thus optimizing PET imaging of molecular mechanisms in the brain of anaesthetized pigs. Therefore, as a minimum these two variables should be monitored and kept constant. Furthermore, the duration of anaesthesia should be kept constant to avoid variations in monitoring variables

Human 13N-ammonia PET studies: the importance of measuring 13N-ammonia metabolites in blood

Dynamic 13N-ammonia PET is used to assess ammonia metabolism in brain, liver and muscle based on kinetic modeling of metabolic pathways, using arterial blood 13N-ammonia as input function. Rosenspire et al. (1990) introduced a solid phase extraction procedure for fractionation of 13N-content in blood into 13N-ammonia, 13N-urea, 13N-glutamine and 13N-glutamate. Due to a radioactive half-life for 13N of 10 min, the procedure is not suitable for blood samples taken beyond 5–7 min after tracer injection. By modifying Rosenspire’s method, we established a method enabling analysis of up to 10 blood samples in the course of 30 min. The modified procedure was validated by HPLC and by 30-min reproducibility studies in humans examined by duplicate 13N-ammonia injections with a 60-min interval. Blood data from a 13N-ammonia brain PET study (from Keiding et al. 2006) showed: (1) time courses of 13N-ammonia fractions could be described adequately by double exponential functions; (2) metabolic conversion of 13N-ammonia to 13N-metabolites were in the order: healthy subjects > cirrhotic patients without HE > cirrhotic patients with HE; (3) kinetics of initial tracer distribution in tissue can be assessed by using total 13N-concentration in blood as input function, whereas assessment of metabolic processes requires 13N-ammonia measurements

Combining compartmental and microvascular models in interpreting dynamic PET data

Measurement of hepatic blood perfusion and of the exchange of substances between blood and cells is a challenge. Long before the development of PET, multiple indicator data were analysed using models based on elaborate capillary theories. Today, PET is a unique modality that allows external quantitative measurements of the regional distribution of intravenously injected radiotracers and their metabolites in tissues, but dynamic PET data are analysed using less physiologically based schemes. The standard compartment model is an inlet equilibration model that does not naturally incorporate blood flow, and a single-uptake model that does not allow substances to re-enter the capillaries. These deficiencies lead to paradoxes when modelling fast blood-cell exchange. We have combined compartmental and capillary theory and developed microvascular models that account for blood flow and concentration gradients in capillaries. The microvascular models can be regarded as revisions of the input function which include more physiological realism and provide a superior description and interpretation of dynamic PET data when compared to the standard compartmental scheme

A microvascular compartment model validated using ¹¹C-methylglucose liver PET in pigs

The standard compartment model (CM) is widely used to analyze dynamic PET data. The CM is fitted to time-activity curves to estimate rate constants that describe the transport of tracer between well-mixed compartments. The aim of this study was to develop and validate a more realistic microvascular compartment model (MCM) that includes capillary tracer concentration gradients, backflux from cells into the perfused capillaries, and multiple re-uptakes during the passage through a capillary. 
 The MCM incorporates only parameters with clear physiological meaning, it is easy to implement and it does not require numerical solution. We compared the MCM and CM for the analysis of 3-min dynamic PET data of pig livers (N=5) following injection of 11C-methylglucose. During PET scans, the tracer concentrations in blood were measured in the hepatic artery, portal vein, and liver vein by manual sampling. We found that the MCM outperformed the CM and that dynamic PET data include information, which cannot be extracted using standard CM. The MCM fitted dynamic PET data better than CM (Akaike values were 46 ± 4 for best MCM fits, and 82 ± 8 for best CM fits; mean ± standard deviation) and extracted physiologically reasonable parameter estimates such as blood perfusion that were in agreement with independent measurements. The difference between model-independent perfusion estimates and the best MCM perfusion estimates was -0.01 ± 0.05 mL/mL/min, whereas the difference was 0.30 ± 0.13 mL/mL/min using CM. In addition, the MCM predicted the time course of concentrations in the liver vein, a prediction fundamentally unobtainable using the CM as it does not return tracer backflux from cells to capillary blood. 
 The results demonstrate the benefit of using models that include more physiology and that models including concentration gradients should be preferred when analyzing the blood-cell exchange of any tracer in any capillary bed

Positron emission tomography of hepatic first-pass metabolism of ammonia in pig

Hepatic first-pass metabolism plays a key role in metabolic regulation and drug metabolism. Metabolic processes can be quantified in vivo by positron emission tomography scanning (PET). We wished to develop a PET technique to measure hepatic first-pass metabolism of ammonia. Seven anaesthetised pigs were given positron-labelled ammonia, NH, into the portal vein and into the vena cava as successive 2-min infusions followed by 22-min dynamic liver scanning. Vena cava infusion data were used to account for recirculation of tracer and metabolites following the portal vein infusion. The scan data were analysed by a model of sinusoidal zonation of ammonia metabolism with periportal urea formation and perivenous formation of glutamine. The hepatic extraction fraction of NH was 0.73±0.16 (mean±SD, n=7 pigs). Values of clearance of ammonia to urea and to glutamine were obtained, as were rate constants for washout of these two metabolites. Overall, the modelling showed half of the ammonia uptake to be converted to urea and half to glutamine. The washout rate constant for glutamine was about one-tenth of that for urea. We conclude that hepatic first-pass metabolism of ammonia was successfully assessed by PET

Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation

Five to 15% of patients with primary sclerosing cholangitis (PSC) develop cholangiocarcinoma (CC) with a median survival of 5 to 7 months, an outcome not significantly improved by liver transplantation. However, if CC is found incidentally during the procedure or in the explanted liver, 5-year survival rates of 35% are reported. A noninvasive method to detect CC small enough to allow for intended curative surgery is needed. Unfortunately, computed tomography (CT) and ultrasonography (US) have poor sensitivity for detection of CC in PSC; however, positron emission tomography (PET) using 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) differentiates well between CC and nonmalignant tissue. We examined whether PET findings are valid using a blinded study design comparing pretransplantation FDG-PET results with histology of explanted livers. Dynamic FDG-PET was performed in 24 consecutive patients with PSC within 2 weeks after listing for liver transplantation and with no evidence of malignancy on CT, magnetic resonance imaging, or ultrasonography. The PET Center staff was blinded to clinical findings, and surgeons and pathologists were blinded to the PET results. Three patients had CC that was correctly identified by PET. PET was negative in I patient with high-grade hilar duct dysplasia. In 20 patients without malignancies, PET was false positive in I patient with epitheloid granulomas in the liver. In conclusion, dynamic FDG-PET appears superior to conventional imaging techniques for both detection and exclusion of CC in advanced PSC. FDG-PET may be useful for screening for CC in the pretransplant evaluation of patients with PSC

Magnetic resonance imaging and computed tomography as tools for the investigation of sperm whale (Physeter macrocephalus) teeth and eye

Abstract Background Scanning techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) are useful tools in veterinary and human medicine. Here we demonstrate the usefulness of these techniques in the study of the anatomy of wild marine mammals as part of a necropsy. MRI and CT scans of sperm whale teeth (n = 4) were performed. The methods were compared and further compared to current standard methods for evaluation of tooth layering. For MRI a zero echo time sequence was used, as previously done for imaging of intact human teeth. For CT two different clinical scanners were used. Results The three scanners did not provide sufficient information to allow age estimation, but both MRI and CT provided anatomical information about the tooth cortex and medulla without the need for sectioning the teeth. MRI scanning was also employed for visualizing the vascularization of an intact eye from one of the stranded sperm whale. Conclusions Clearly, MRI was useful for investigation of the retinal vasculation, but optimum results would require well-preserved tissue. It was not possible to estimate age based on CT scans of tooth growth lines. Further research is needed to clarify the usability of MRI and CT as tools for marine mammal research when samples need to remain intact or when a spatial (three dimensional) arrangement of features needs to be determined