Changes in cerebral oxygenation and cerebral blood flow during hemodialysis - A simultaneous near-infrared spectroscopy and positron emission tomography study

Near-infrared spectroscopy (NIRS) is used to monitor cerebral tissue oxygenation (rSO2) depending on cerebral blood flow (CBF), cerebral blood volume and blood oxygen content. We explored whether NIRS might be a more easy applicable proxy to [15O]H2O positron emission tomography (PET) for detecting CBF changes during hemodialysis. Furthermore, we compared potential determinants of rSO2 and CBF. In 12 patients aged ≥ 65 years, NIRS and PET were performed simultaneously: before (T1), early after start (T2), and at the end of hemodialysis (T3). Between T1 and T3, the relative change in frontal rSO2 (ΔrSO2) was -8 ± 9% ( P = 0.001) and -5 ± 11% ( P = 0.08), whereas the relative change in frontal gray matter CBF (ΔCBF) was -11 ± 18% ( P = 0.009) and -12 ± 16% ( P = 0.007) for the left and right hemisphere, respectively. ΔrSO2 and ΔCBF were weakly correlated for the left (ρ 0.31, P = 0.4), and moderately correlated for the right (ρ 0.69, P = 0.03) hemisphere. The Bland-Altman plot suggested underestimation of ΔCBF by NIRS. Divergent associations of pH, pCO2 and arterial oxygen content with rSO2 were found compared to corresponding associations with CBF. In conclusion, NIRS could be a proxy to PET to detect intradialytic CBF changes, although NIRS and PET capture different physiological parameters of the brain

Dual time-point imaging for post-dose binding potential estimation applied to a [11C]raclopride PET dose occupancy study

Receptor occupancy studies performed with PET often require time-consuming dynamic imaging for baseline and post-dose scans. Shorter protocol approximations based on standard uptake value ratios have been proposed. However, such methods depend on the time-point chosen for the quantification and often lead to overestimation and bias. The aim of this study was to develop a shorter protocol for the quantification of post-dose scans using a dual time-point approximation, which employs kinetic parameters from the baseline scan. Dual time-point was evaluated for a [(11)C]raclopride PET dose occupancy study with the D2 antagonist JNJ-37822681, obtaining estimates for binding potential and receptor occupancy. Results were compared to standard simplified reference tissue model and standard uptake value ratios-based estimates. Linear regression and Bland-Altman analysis demonstrated excellent correlation and agreement between dual time-point and the standard simplified reference tissue model approach. Moreover, the stability of dual time-point-based estimates is shown to be independent of the time-point chosen for quantification. Therefore, a dual time-point imaging protocol can be applied to post-dose [(11)C]raclopride PET scans, resulting in a significant reduction in total acquisition time while maintaining accuracy in the quantification of both the binding potential and the receptor occupancy.status: publishe

18F-FEAnGA for PET of β-glucuronidase activity in neuroinflammation

Activation of microglia is a hallmark of inflammatory, infectious, and degenerative diseases of the central nervous system. Several studies have indicated that there is an increase in release of beta-glucuronidase by activated microglia into the extracellular space at the site of neuroinflammation. beta-glucuronidase is involved in the hydrolysis of glycosaminoglycans on the cell surface and the degradation of the extracellular matrix. Therefore, beta-glucuronidase might be a biomarker for ongoing neurodegeneration induced by neuroinflammation. In this study, we investigated whether the PET tracer F-18-FEAnGA was able to detect beta-glucuronidase release during neuroinflammation in a rat model of herpes encephalitis. Methods: Male Wistar rats were intranasally inoculated with herpes simplex virus 1 (HSV-1) or phosphate-buffered saline as a control. C-11-(R)-PK11195 and F-18-FEAnGA small-animal PET scans were acquired for 60 min. Logan graphical analysis was used to calculate F-18-FEAnGA distribution volumes (DVLogan) in various brain areas. Results: After administration of F-18-FEAnGA, the area under the activity concentration-versus-time curve of the whole brain was 2 times higher in HSV-1-infected rats than in control rats. In addition, the DVLogan of F-18-FEAnGA was most increased in the frontopolar cortex, frontal cortex, bulbus olfactorius, cerebral cortex, cerebellum, and brainstem of HSV-1-infected rats, when compared with control rats. The conversion of F-18-FEAnGA to 4-hydroxy-3-nitrobenzyl alcohol was found to be 1.6 times higher in HSV-1-infected rats than in control rats and correlated with the DVLogan of F-18-FEAnGA in the same areas of the brain. Furthermore, the DVLogan of F-18-FEAnGA also correlated with beta-glucuronidase activity in the same brain regions. In addition, DVLogan of F-18-FEAnGA showed a tendency to correlate with C-11-(R)-PK11195 uptake (marker for activated microglia) in the same brain regions. Conclusion: Despite relatively low brain uptake, F-18-FEAnGA was able to detect an increased release of beta-glucuronidase during neuroinflammation

Induction of β-glucuronidase release by cytostatic agents in small tumors

Extracellular beta-glucuronidase (beta-GUS) in tumors has been investigated as a target enzyme for prodrug therapy. However, despite encouraging preclinical results, animal studies also indicate that the success of prodrug therapy might be limited by the insufficient prodrug-converting enzyme activity, especially in small tumors. We hypothesized that a single dose of a cytostatic drug might induce the release of beta-GUS in small tumors, resulting in increased levels of extracellular beta-GUS and consequently a higher efficacy of the prodrug treatment. Here we examine the extent of beta-GUS release in small C6 glioma tumors after a single treatment of doxorubicin (DOX), carmustine (BCNU) and tumor necrosis factor alpha (TNF-alpha) with positron emission tomography (PET) and the tracer 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-beta-D-glucopyronuronate, [F-18]FEAnGA, which has been proven to be selective for extracellular beta-GUS. Induction of beta-GUS release was first investigated in cultured C6 glioma cells. In addition, a [F-18]FEAnGA PET study was performed in C6 tumor-bearing rats 48 h after a single treatment with different cytostatics to evaluate the extent of beta-glucuronidase release. The cleavage of [F-18]FEAnGA by beta-GUS was analyzed in tumor homogenates. The induction of tumor necrosis and leukocyte infiltration was confirmed by histochemical analysis and flow cytometry. The in vitro studies indicated that all treatments resulted in a decline of viable cells and an increase of extracellular beta-GUS activity. PET studies confirmed that beta-GUS was released in vivo and the distribution volume of the PET tracer [F-18]FEAnGA in C6 gliomas was increased significantly by 15-70%, depending on the treatment. Histochemical analysis of the tumors indicated that carmustine and TNF-alpha treatment caused a larger necrotic area with the absence of infiltrating immune cells, whereas doxorubicin induced an increase in leukocyte infiltration. These results were confirmed by flow cytometry. In conclusion, the present study demonstrates that a single dose of a cytostatic agent is able to increase the release of beta-GUS. The release in beta-GUS can be monitored by [F-18]FEAnGA PET in a noninvasive manner. This study may open the way to a two-step chemotherapy prodrug approach, in which tumors are treated with a single dose of a cytostatic drug prior to prodrug treatment

Small-animal PET study of adenosine A1 receptors in rat brain: blocking receptors and raising extracellular adenosine

Activation of adenosine A(1) receptors (A(1)R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A(1)R can be visualized using 8-dicyclopropylmethyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX) and PET. This study aims to test whether (11)C-MPDX can be used for quantitative studies of cerebral A1R in rodents. Methods: (11)C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A(1)R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A1R, whereas ethanol and ABT-702 increase extracellular adenosine. Results: In groups 1 and 3, the brain was clearly visualized. High uptake of (11)C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2-tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K(1)/k(2) from the model fit) was not altered under the study conditions. Conclusion: (11)C-MPDX shows a regional distribution in rat brain consistent with binding to A(1)R. Tracer binding is blocked by the selective A(1)R antagonist DPCPX. Pretreatment of animals with ethanol and adenosine kinase inhibitor increases (11)C-MPDX uptake. This increase may reflect an increased availability of A(1)R after acute exposure to ethanol