Mirwais Wardak

Discriminant Analysis of 18F-Fluoro-Thymidine Kinetic Parameters to Predict Survival in Patients with Recurrent High-Grade Glioma

Purpose: The primary objective of this study was to investigate whether changes in 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) kinetic parameters, taken early after the start of therapy, could predict overall survival (OS) and progression-free survival (PFS) in patients with recurrent malignant glioma undergoing treatment with bevacizumab and irinotecan. Experimental Design: High-grade recurrent brain tumors were investigated in 18 patients (8 male and 10 female), ages 26 to 76 years. Each had 3 dynamic positron emission tomography (PET) studies as follows: at baseline and after 2 and 6 weeks from the start of treatment, 18F-FLT (2.0 MBq/kg) was injected intravenously, and dynamic PET images were acquired for 1 hour. Factor analysis generated factor images from which blood and tumor uptake curves were derived. A three-compartment, two-tissue model was applied to estimate tumor 18F-FLT kinetic rate constants using a metabolite- and partial volume–corrected input function. Different combinations of predictor variables were exhaustively searched in a discriminant function to accurately classify patients into their known OS and PFS groups. A leave-one-out cross-validation technique was used to assess the generalizability of the model predictions. Results: In this study population, changes in single parameters such as standardized uptake value or influx rate constant did not accurately classify patients into their respective OS groups (<1 and ≥1 year; hit ratios ≤78%). However, changes in a set of 18F-FLT kinetic parameters could perfectly separate these two groups of patients (hit ratio = 100%) and were also able to correctly classify patients into their respective PFS groups (<100 and ≥100 days; hit ratio = 88%). Conclusions: Discriminant analysis using changes in 18F-FLT kinetic parameters early during treatment seems to be a powerful method for evaluating the efficacy of therapeutic regimens. Clin Cancer Res; 17(20); 6553–62. ©2011 AACR.

Movement Correction Method for Human Brain PET Images: Application to Quantitative Analysis of Dynamic [18F]-FDDNP Scans

Head movement during a PET scan (especially a dynamic scan) can affect both the qualitative and the quantitative aspects of an image, making it difficult to accurately interpret the results. The primary objective of this study was to develop a retrospective image-based movement correction (MC) method and evaluate its implementation on dynamic 2-(1-{6-[(2-18F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (18F-FDDNP) PET images of cognitively intact controls and patients with Alzheimers disease (AD). Methods: Dynamic 18F-FDDNP PET images, used for in vivo imaging of β-amyloid plaques and neurofibrillary tangles, were obtained from 12 AD patients and 9 age-matched controls. For each study, a transmission scan was first acquired for attenuation correction. An accurate retrospective MC method that corrected for transmission–emission and emission–emission misalignments was applied to all studies. No restriction was assumed for zero movement between the transmission scan and the first emission scan. Logan analysis, with the cerebellum as the reference region, was used to estimate various regional distribution volume ratio (DVR) values in the brain before and after MC. Discriminant analysis was used to build a predictive model for group membership, using data with and without MC. Results: MC improved the image quality and quantitative values in 18F-FDDNP PET images. In this subject population, no significant difference in DVR value was observed in the medial temporal (MTL) region of controls and patients with AD before MC. However, after MC, significant differences in DVR values in the frontal, parietal, posterior cingulate, MTL, lateral temporal (LTL), and global regions were seen between the 2 groups (P < 0.05). In controls and patients with AD, the variability of regional DVR values (as measured by the coefficient of variation) decreased on average by more than 18% after MC. Mean DVR separation between controls and patients with AD was higher in frontal, MTL, LTL, and global regions after MC. Group classification by discriminant analysis based on 18F-FDDNP DVR values was markedly improved after MC. Conclusion: The streamlined and easy-to-use MC method presented in this work significantly improves the image quality and the measured tracer kinetics of 18F-FDDNP PET images. The proposed MC method has the potential to be applied to PET studies on patients having other disorders (e.g., Down syndrome and Parkinsons disease) and to brain PET scans with other molecular imaging probes.

Movement correction of [ 18 F]FDDNP PET studies for brain amyloid imaging

2-(l-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naph- thyl}ethylidene)malononitrile ([18F]FDDNP) PET studies for imaging neuronal concentration of beta-amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimers disease (AD), usually requires a 1-2 hour dynamic scan to measure the kinetics of the tracer in brain tissue. It is difficult for the subject to keep his or her head stationary during the entire data acquisition period. Thus, the reliability of the acquired kinetic data could be severely compromised. Furthermore, misalignment between transmission (TX) and emission (EM) scans due to head movement could introduce errors in attenuation correction (AC) and physiological parameters. In this study, we have developed an image-based procedure for head movement correction that takes a TX image and coregisters it to its corresponding non-AC EM frame before reconstruction of the dynamic image and then realigns all the now proper AC EM frames to a common reference frame. Effects of head movement on tracer time-activity curves and distribution volume ratio (DVR) parametric images are also investigated. The proposed movement correction procedure is done with [18F]FDDNP as a case in point but has the potential to be used in a wide variety of dynamic brain PET studies.

Automated movement correction for dynamic PET/CT images: Evaluation with phantom and patient data

Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC methods performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.

Specific Imaging of Bacterial Infection Using 6″-18F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria

6″-18F-fluoromaltotriose is a PET tracer that can potentially be used to image and localize most bacterial infections, much like 18F-FDG has been used to image and localize most cancers. However, unlike 18F-FDG, 6″-18F-fluoromaltotriose is not taken up by inflammatory lesions and appears to be specific to bacterial infections by targeting the maltodextrin transporter that is expressed in gram-positive and gram-negative strains of bacteria. Methods: 6″-18F-fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in cultures and in living mice. Results: 6″-18F-fluoromaltotriose was taken up in both gram-positive and gram-negative bacterial strains. 6″-18F-fluoromaltotriose was also able to detect Pseudomonas aeruginosa in a clinically relevant mouse model of wound infection. The utility of 6″-18F-fluoromaltotriose to help monitor antibiotic therapies was also evaluated in rats. Conclusion: 6″-18F-fluoromaltotriose is a promising new tracer that has significant diagnostic utility, with the potential to change the clinical management of patients with infectious diseases of bacterial origin.

A bootstrap method for identifying image regions affected by intra-scan body movement during a PET/CT scan

Intra-scan body movement (IBM) during a PET/CT study can degrade the image quality in subtle ways that are not easy for physicians to detect and can thus affect the diagnostic value of the images. In this study, we propose a method for identifying regions on a PET/CT image that are affected by IBM. The method is based on bootstrapping the sinogram data of short sub-frames of a scan to form multiple sets of sinograms of original scan length, from which multiple images are reconstructed. High voxel-wise percent standard variation among these images would indicate image regions that are compromised by IBM and should be interpreted with caution. Both computer simulation and real human PET/CT data were used in this study to demonstrate the validity of the proposed method for identifying IBM.

Correction to: Molecular Imaging of Inflammation in Ischemic Heart Disease

The original version of this article unfortunately contained mistakes in the abbreviations and body of the text. The Authors had correctly pointed out these errors at the proof stage but were regretfully not implemented at the production level.

The Gift of Light: Using Multiplexed Optical Imaging to Probe Cardiac Metabolism in Health and Disease

Heart failure (HF) resulting from impaired left ventricular (LV) function is associated with significant morbidity and mortality in the United States and worldwide.1 In the failing heart, there are changes in energy substrate metabolism whose causes and effects are poorly understood.2 These changes may contribute to deterioration in cardiac contractility and to increasing LV remodeling that are the hallmarks of the failing heart. In HF following cardiac hypertrophy, there is a major metabolic switch in myocardial substrate metabolism from fatty acid to glucose oxidation.2–5 A key marker of this switch is the coordinated downregulation of fatty acid oxidation enzymes (eg, medium-chain acyl-CoA dehydrogenase and carnitine palmitoyltransferase-I β) and mRNA levels in the human LV with a concomitant increase in glucose uptake and oxidation.2,6 This switch is thought to represent a metabolic reprogramming toward substrate metabolism that is more commonly seen in the fetal heart.7 The fetus in a womb uses glucose from the mother as the major substrate for energy production; in fact, ≈80% of fetal energy comes from glucose oxidation. See Article by Panagia et al Moreover, recent studies have suggested that brown adipose tissue (BAT) may play an important role in obesity, type 2 diabetes mellitus, and HF.8–13 BAT regulates basal and inducible energy expenditure in humans and is composed of cells that contain numerous lipid droplets, dense packing of mitochondria, and the expression of the mitochondria-associated UCP1 (uncoupling protein 1).11 UCP1 mediates the biochemical uncoupling of electron transport by allowing proton leakage across the inner mitochondrial membrane into the mitochondrial matrix, thus short-circuiting the usual linkage of electron transport to adenosine triphosphate production that is catalyzed by ATP synthase.11 Instead, the chemical energy generated by cellular respiration in brown adipocytes is dissipated in …