Douglass Vines

Effects of Early Life Stress on [11C]DASB Positron Emission Tomography Imaging of Serotonin Transporters in Adolescent Peer- and Mother-Reared Rhesus Monkeys

Peer-reared (PR) rhesus monkeys with early maternal separation later exhibit aggressiveness, impaired impulse control, alcohol abuse, and low CSF 5-hydroxyindoleacetic acid. This study compared regional brain serotonin transporter (SERT) binding between nine PR and seven mother-reared rhesus monkeys with [11C]DASB positron emission tomography (PET) imaging. Parametric images of binding potential (BP) (which is proportional to Bmax/KD, in which Bmax is transporter density and KD is dissociation constant) and relative blood flow (R1) were generated by the two-parameter multilinear reference tissue model. R1 images were used for coregistration and normalization of PET parametric data to the magnetic resonance imaging template space. Group BP differences were analyzed voxelwise by Students t test in SPM2. Region of interest-based parameter values were also calculated to obtain the magnitude of regional BP differences between the two groups. For the PR group, SERT BP was decreased by 10–23% across a range of brain areas consisting of the raphe, thalamus, hypothalamus, caudate and putamen, globus pallidum, anterior cingulate gyrus, and medial temporal regions, including amygdala and hippocampus (cluster-level corrected p = 0.002). For the latter three regions, BP was decreased in the right hemisphere. These results agree with the hypothesis that early maternal deprivation affects the development of the serotonergic system and suggest that decreased serotonergic innervations in the critical brain regions may explain some of the behavioral and biochemical abnormalities in PR monkeys.

Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET

This study evaluates effects of anesthesia on (18)F-FDG (FDG) uptake in mouse brain and heart to establish the basic conditions of small animal PET imaging. Prior to FDG injection, 12 mice were anesthetized with isoflurane gas; 11 mice were anesthetized with an intraperitoneal injection of a ketamine/xylazine mixture; and 11 mice were awake. In isoflurane and ketamine/xylazine conditions, FDG brain uptake (%ID/g) was significantly lower than in controls. Conversely, in the isoflurane condition, %ID/g in heart was significantly higher than in controls, whereas heart uptake in ketamine/xylazine mice was significantly lower. Results suggest that anesthesia impedes FDG uptake in mouse brain and affects FDG uptake in heart; however, the effects in the brain and heart differ depending on the type of anesthesia used.

Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease

Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects.

Quantitative PET Comparing Gated with Nongated Acquisitions Using a NEMA Phantom with Respiratory-Simulated Motion

This study evaluated the use of gated versus nongated PET acquisitions for absolute quantification of radioisotope concentration (RC) in a respiratory motion–simulated moving phantom filled with radioactive spheres and background for both 2-dimensional (2D) and 3-dimensional (3D) acquisitions. Methods: An image-quality phantom with all 6 spheres filled with the same 18F RC (range, 19–62 kBq/mL) was scanned with PET/CT at rest and in motion with and without gating. The background was filled with 18F solution to yield sphere-to-background ratios of approximately 5, 10, 15, and 20 to 1. Both 2D and 3D acquisitions were used for all combinations. Respiratory motion was simulated by using a motor-driven plastic platform to move the phantom periodically with a displacement of 2 cm and a cycle time of 5.8 s. For gated acquisitions, the phantom was tracked using a real-time position management system. Images were reconstructed, and regions of interest with the same sizes as the actual spheres were manually placed on axial slices to determine maximum and mean pixel RC. A threshold method (70% and 94% for 2D and 3D modes) was also used to determine a mean voxel RC. All values were compared with the expected RC; percentage differences were calculated for each sphere. To reduce partial-volume effects, only data for the 4 largest spheres were analyzed. Results: The mean pixel method was the only method with linear responses for all 3 scan types, enabling direct comparisons. The ranges of RC percentage differences were underestimated for all scan types (using the mean pixel method). The overall mean percentage differences were 37, 49, and 41 in 2D mode and 40, 51, and 41 in 3D mode for static, nongated, and gated acquisitions, respectively. Gated acquisitions improved quantification (by reducing underestimation) over nongated acquisitions by 8% and 10% for 2D and 3D modes. Conclusion: In the presence of motion, the use of gated PET acquisitions appears to improve quantification accuracy over nongated acquisitions, almost restoring the results to those observed when the phantom is static.

Liposome contrast agent for CT‐based detection and localization of neoplastic and inflammatory lesions in rabbits: validation with FDG‐PET and histology

PURPOSE This study was aimed at assessing the performance of a liposome-based computed tomography (CT) contrast agent to detect tumor and inflammatory lesions in a rabbit model relative to (18)F-fluorodeoxyglucose- positron emission tomography (FDG-PET). MATERIALS AND METHODS Nine New Zealand White rabbits were inoculated with a cell suspension obtained from the tumor tissue of a donor rabbit bearing VX2 carcinoma. Spontaneously formed inflammatory lesions were identified in the skeletal muscles of six of the nine animals. The CT liposome agent (185 +/- 37 mg/kg of iodine) was administered intravenously 7 days following tumor inoculation. The PET/CT imaging session took place five days post-liposome contrast administration and 1 h post (18)F-FDG injection (30.3 +/- 5.1 MBq/kg). Approximately 20 h post-imaging, the tumor and inflammatory lesions were excised for histo-pathology assessment. RESULTS Liposome-CT identified the same number of primary tumors as FDG-PET (nine lesions, volumes = 0.07-7.01 cm(3), SUV(max) = 1.5-10.9, HU(mean) = 103.0-140.6). It also detected 25 inflammatory lesions (volumes = 0.01-2.73 cm(3), HU(mean) = 114.5-268.6), while FDG-PET identified seven (volumes = 0.05-1.04 cm(3), SUV(max) = 2.7-7.1). Differences in the mean CT signal (HU(mean)) between the tumor and inflammatory lesions were statistically significant (p < 0.0001). Partial volume adjusted SUV(max) values for the two lesion types calculated from the FDG-PET data set did not yield a significant difference (p > 0.15). CONCLUSION These results demonstrate that liposome-CT can be considered for effective screening of neoplastic and inflammatory diseases, as well as subsequent image-guided biopsy. Moreover, the differential accumulation of the liposomal agent at tumor and inflammatory sites highlights its potential role in increasing the specificity of image-based diagnosis.

A Novel Minimally Invasive Technique to Create a Rabbit VX2 Lung Tumor Model for Nano-Sized Image Contrast and Interventional Studies

Background The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung cancer imaging and interventional studies. However, previously reported models had issues in terms of invasiveness of tumor inoculation, control of tumor aggressiveness and incidence of complications. Purpose We aimed to develop a minimally invasive rabbit VX2 lung cancer model suitable for imaging and transbronchial interventional studies. Methods New Zealand white rabbits and VX2 tumors were used in the study. An ultra-thin bronchoscope was inserted through a miniature laryngeal mask airway into the bronchus. Different numbers of VX2 tumor cells were selectively inoculated into the lung parenchyma or subcarinal mediastinum to create a uniform tumor with low incidence of complications. The model was characterized by CT, FDG-PET, and endobronchial ultrasound (EBUS). Liposomal dual-modality contrast agent was used to evaluate liposome drug delivery system in this model. Results Both peripheral and mediastinal lung tumor models were created. The tumor making success rate was 75.8% (25/33) in the peripheral lung tumor model and 60% (3/5) in the mediastinal tumor model. The group of 1.0×106 of VX2 tumor cells inoculation showed a linear growth curve with less incidence of complications. Radial probe EBUS visualized the internal structure of the tumor and the size measurement correlated well with CT measurements (r2 = 0.98). Over 7 days of continuous enhancement of the lung tumor by liposomal contrast in the lung tumor was confirmed both CT and fluorescence imaging. Conclusion Our minimally invasive bronchoscopic rabbit VX2 lung cancer model is an ideal platform for lung cancer imaging and preclinical bronchoscopic interventional studies.

Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake

Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. Methods: We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer 18F-fluoroazomycin arabinoside (or 18F-1-α-d-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [18F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. Results: Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. Conclusion: Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents.

Molecular Alterations in the Hippocampus after Experimental Subarachnoid Hemorrhage

Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.

Evaluation of Mouse Tail-Vein Injections Both Qualitatively and Quantitatively on Small-Animal PET Tail Scans

Quantitative small-animal PET of mice requires successful delivery of radiotracers into the venous system. Intravenous injection of radiotracers via lateral tail veins is the most commonly used method of administration and can be technically challenging. Evaluation of the quality of an intravenous injection is necessary to determine whether small-animal PET is quantitatively accurate. The purpose of this study was to evaluate and compare the quality of 50 consecutive intravenous injections into mouse tail veins using both quantitative and qualitative methods. Methods: During 18F-FDG intravenous injection, qualitative assessment of the injection was performed and classified according to specific criteria as good, intermediate, or poor. Small-animal PET scans of the body and tail were acquired, and tail injection sites were quantitatively assessed in terms of percentage injected dose per gram and classified as low, medium, or high uptake of 18F-FDG. Qualitative and quantitative methods were compared. To assess baseline amounts of 18F-FDG in the tail without a tail injection, 3 additional mice were injected by the intraperitoneal method, imaged, and quantitatively assessed in the same manner. The in vivo imaging data were validated on 7 additional mice by sacrificing them after scans, removing their tails, rescanning the tails, and then measuring the tail radioactivity ex vivo in a γ-counter and correlating it with the in vivo amount. Results: Validation of in vivo imaging to ex vivo data yielded an excellent correlation, with an r2 value of 0.95. Comparison of qualitative and quantitative methods yielded 45 matching results (42 good and low, 2 intermediate and medium, and 1 poor and high). There were 5 cases of mismatching results (1 false-negative and 4 false-positive) between qualitative and quantitative methods. Low-uptake tail injections were comparable to the intraperitoneal injection values. Using qualitative methods, accuracy was true 90% (45/50) of the time. The overall rate of successful intravenous injections was 92% (46/50) using quantitative methods. Conclusion: Qualitative assessment is all that is necessary if the intravenous injection is classified as good. In intermediate, poor, or uncertain classifications, a scan of the tail should be performed for quantitative assessment.

Predicting Radiation Esophagitis Using 18F-FDG PET During Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer.

Introduction: Treatment of locally advanced non–small cell lung cancer with chemoradiotherapy (CRT) is limited by development of toxicity in normal tissue, including radiation esophagitis (RE). Increasingly, 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is being used for adaptive planning. Our aim was to assess changes in esophageal FDG uptake during CRT and relate the changes to the onset and severity of RE. Methods: This prospective study in patients with stage II–III non–small cell lung cancer involved serial four‐dimensional computed tomography and PET scans during CRT (60–74Gy). RE was recorded weekly using the Common Terminology Criteria for Adverse Events (v4.0), and imaging was performed at weeks 0, 2, 4, and 7. Changes in the esophaguss peak standard uptake value (SUVpeak) were analyzed for each time point and correlated with grade of RE using the Wilcoxon rank‐sum test. The volume of esophagus receiving 50 Gy (V50) and volume of esophagus receiving 60 Gy (V60) were correlated with the development of RE, and the C‐statistic (area under the curve [AUC]) was calculated to measure predictivity of grade 3 RE. Results: RE developed in 20 of 27 patients (74%), with grade 3 reached in 6 (22%). A significant percentage increase in SUVpeak in the patients with RE was noted at week 4 (p = 0.01) and week 7 (p = 0.03). For grade 3 RE, a significant percentage increase in SUVpeak was noted at week 2 (p = 0.01) and week 7 (p = 0.03) compared with that for less than grade 3 RE. Median V50 (46.3%) and V60 (33.4%) were significantly higher in patients with RE (p = 0.04). The AUC measurements suggested that the percentage change in SUVpeak at week 2 (AUC = 0.69) and V50 (AUC = 0.67) and V60 (AUC = 0.66) were similarly predictive of grade 3 RE. Conclusions: Serial FDG‐PET images during CRT show significant increases in SUVpeak for patients in whom RE develops. The changes at week 2 may predict those at risk for the development of grade 3 RE and may be informative for adaptive planning and early intervention.