Robust nonlinear parameter estimation in tracer kinetic analysis using infinity norm regularization and particle swarm optimization

In positron emission tomography (PET) studies, the voxel-wise calculation of individual rate constants describing the tracer kinetics is quite challenging because of the nonlinear relationship between the rate constants and PET data and the high noise level in voxel data. Based on preliminary simulations using a standard two-tissue compartment model, we can hypothesize that it is possible to reduce errors in the rate constant estimates when constraining the overestimation of the larger of two exponents in the model equation. We thus propose a novel approach based on infinity-norm regularization for limiting this exponent. Owing to the non-smooth cost function of this regularization scheme, which prevents the use of conventional Jacobian-based optimization methods, we examined a proximal gradient algorithm and the particle swarm optimization (PSO) through a simulation study. Because it exploits multiple initial values, the PSO method shows much better convergence than the proximal gradient algorithm, which is susceptible to the initial values. In the implementation of PSO, the use of a Gamma distribution to govern random movements was shown to improve the convergence rate and stability compared to a uniform distribution. Consequently, Gamma-based PSO with regularization was shown to outperform all other methods tested, including the conventional basis function method and Levenberg–Marquardt algorithm, in terms of its statistical properties.     

In vivo blind‐deconvolution photoacoustic ophthalmoscopy with total variation regularization

Photoacoustic ophthalmoscopy (PAOM) is capable of noninvasively imaging anatomic and functional information of the retina in living rodents. However, the strong ocular aberration in rodent eyes and limited ultrasonic detection sensitivity affect PAOM's spatial resolution and signal‐to‐noise ratio (SNR) in in vivo eyes. In this work, we report a computational approach to combine blind deconvolution (BD) algorithm with a regularizing constraint based on total variation (BDTV) for PAOM imaging restoration. We tested the algorithm in retinal and choroidal microvascular images in albino rat eyes. The algorithm improved PAOM's lateral resolution by around 2‐fold. Moreover, it enabled the improvement in imaging SNR for both major vessels and capillaries, and realized the well‐preserved blood vessels' edges simultaneously, which surpasses conventional Richardson‐Lucy BD algorithm. The reported results indicate that the BDTV algorithm potentially facilitate PAOM in extracting retinal pathophysiological information by enhancing in vivo imaging quality without physically modifying PAOM's optical configuration.      

Machine learning in quantitative PET: A review of attenuation correction and low-count image reconstruction methods

The rapid expansion of machine learning is offering a new wave of opportunities for nuclear medicine. This paper reviews applications of machine learning for the study of attenuation correction (AC) and low-count image reconstruction in quantitative positron emission tomography (PET). Specifically, we present the developments of machine learning methodology, ranging from random forest and dictionary learning to the latest convolutional neural network-based architectures. For application in PET attenuation correction, two general strategies are reviewed: 1) generating synthetic CT from MR or non-AC PET for the purposes of PET AC, and 2) direct conversion from non-AC PET to AC PET. For low-count PET reconstruction, recent deep learning-based studies and the potential advantages over conventional machine learning-based methods are presented and discussed. In each application, the proposed methods, study designs and performance of published studies are listed and compared with a brief discussion. Finally, the overall contributions and remaining challenges are summarized.     

Non-local means improves total-variation constrained photoacoustic image reconstruction

Photoacoustic/Optoacoustic tomography aims to reconstruct maps of the initial pressure rise induced by the absorption of light pulses in tissue. This reconstruction is an ill-conditioned and under-determined problem, when the data acquisition protocol involves limited detection positions. The aim of the work is to develop an inversion method which integrates denoising procedure within the iterative model-based reconstruction to improve quantitative performance of optoacoustic imaging. Among the model-based schemes, total-variation (TV) constrained reconstruction scheme is a popular approach. In this work, a two-step approach was proposed for improving the TV constrained optoacoustic inversion by adding a non-local means based filtering step within each TV iteration. Compared to TV-based reconstruction, inclusion of this non-local means step resulted in signal-to-noise ratio improvement of 2.5 dB in the reconstructed optoacoustic images.     

3D immuno-confocal image reconstruction of fibroblast cytoskeleton and nucleus architecture

Computational models of cellular structures generally rely on simplifying approximations and assumptions that limit biological accuracy. This study presents a comprehensive image processing pipeline for creating unified three-dimensional (3D) reconstructions of the cell cytoskeletal networks and nuclei. Confocal image stacks of these cellular structures were reconstructed to 3D isosurfaces (Imaris), then tessellations were simplified to reduce the number of elements in initial meshes by applying quadric edge collapse decimation with preserved topology boundaries (MeshLab). Geometries were remeshed to ensure uniformity (Instant Meshes) and the resulting 3D meshes exported (ABAQUS) for downstream application. The protocol has been applied successfully to fibroblast cytoskeletal reorganisation in the scleral connective tissue of the eye, under mechanical load that mimics internal eye pressure. While the method herein is specifically employed to reconstruct immunofluorescent confocal imaging data, it is also more widely applicable to other biological imaging modalities where accurate 3D cell structures are required.     

Optimization-based region-of-interest reconstruction for X-ray computed tomography based on total variation and data derivative

Region-of-interest (ROI) and interior reconstructions for computed tomography (CT) have drawn much attention and can be of practical value for potential applications in reducing radiation dose and hardware cost. The conventional wisdom is that the exact reconstruction of an interior ROI is very difficult to be obtained by only using data associated with lines through the ROI. In this study, we propose and investigate optimization-based methods for ROI and interior reconstructions based on total variation (TV) and data derivative. Objective functions are built by the image TV term plus the data finite difference term. Different data terms in the forms of L1-norm, L2-norm, and Kullback–Leibler divergence are incorporated and investigated in the optimizations. Efficient algorithms are developed using the proximal alternating direction method of multipliers (ADMM) for each program. All sub-problems of ADMM are solved by using closed-form solutions with high efficiency. The customized optimizations and algorithms based on the TV and derivative-based data terms can serve as a powerful tool for interior reconstructions. Simulations and real-data experiments indicate that the proposed methods can be of practical value for CT imaging applications.     

Radiosynthesis and preclinical evaluation of [18F]FEM as a potential novel PET probe for tumor imaging

In the 21st century, the incidence and mortality of cancer, one of the most challenging diseases in the world, have rapidly increased. The purpose of this study was to develop 2-(2-[¹⁸F]fluoroethoxy)ethyl 4-methylbenzenesulfonate ([¹⁸F]FEM) as a positron emission tomography (PET) agent for tumor imaging. In this study, [¹⁸F]FEM was synthesized with a good radiochemical yield (45.4 ± 5.8%), high specific radioactivity (over 25 GBq/μmol), and commendable radiochemical purity (over 99%). The octanol/water partition coefficient of [¹⁸F]FEM was 1.44 ± 0.04. The probe demonstrated good stability in vitro (phosphate-buffered saline (PBS) and mouse serum (MS)), and binding specificity to five different tumor cell lines (A549, PC-3, HCC827, U87, and MDA-MB-231). PET imaging of tumor-bearing mice showed that [¹⁸F]FEM specifically accumulated at the tumor site of the five different tumor cell lines. The average tumor-to-muscle (T/M) ratio was over 2, and the maximum T/M values reached about 3.5. The biodistribution and dynamic PET imaging showed that most probes were metabolized by the liver, whereas a small part was metabolized by the kidney. Moreover, dynamic brain images and quantitative data showed [¹⁸F]FEM can quickly cross the blood brain barrier (BBB) and quickly fade out, thereby suggesting it may be a promising candidate probe for the imaging of brain tumors. The presented results demonstrated that [¹⁸F]FEM is a promising probe for tumor PET imaging.     

The 68Ge phantom-based FDG-PET site qualification program for clinical trials adopted by FIL (Italian Foundation on Lymphoma)

PurposeThe quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life.MethodsWe set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of ¹⁸F and ⁶⁸Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR).ResultsThe use of a ⁶⁸Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the ¹⁸F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with ⁶⁸Ge and ¹⁸F respectively.ConclusionsThe ⁶⁸Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement.     

A review of GPU-based medical image reconstruction

Tomographic image reconstruction is a computationally demanding task, even more so when advanced models are used to describe a more complete and accurate picture of the image formation process. Such advanced modeling and reconstruction algorithms can lead to better images, often with less dose, but at the price of long calculation times that are hardly compatible with clinical workflows. Fortunately, reconstruction tasks can often be executed advantageously on Graphics Processing Units (GPUs), which are exploited as massively parallel computational engines. This review paper focuses on recent developments made in GPU-based medical image reconstruction, from a CT, PET, SPECT, MRI and US perspective. Strategies and approaches to get the most out of GPUs in image reconstruction are presented as well as innovative applications arising from an increased computing capacity. The future of GPU-based image reconstruction is also envisioned, based on current trends in high-performance computing.     

Production of 64Cu-labeled monobody for imaging of human EphA2-expressing tumors

We previously reported on the monobody E1, which specifically targets the tumor marker hEphA2. In this study, we labeled NOTA-conjugated E1 with ⁶⁴Cu (⁶⁴Cu-NOTA-E1) and evaluated biologic characteristics. The uptake of ⁶⁴Cu-NOTA-E1 in PC3 cells (a human prostate cancer cell line) with high expression of hEphA2 increased in a time-dependent manner. In PC3 xenograft mice, ⁶⁴Cu-NOTA-E1 injected via the tail vein allowed visualization of tumors on positron emission tomography after 1 h and the highest uptake measured at 24 h post-injection. By contrast, the radioactivity of other tissues either did not increase or decreased over 24 h. This indicates that ⁶⁴Cu-NOTA-E1 has high tumor uptake and retention, with rapid clearance, and low background values in other tissues. Therefore, ⁶⁴Cu-NOTA-E1 should be suitable as a novel PET imaging agent for hEphA2-expressing tumors.     

18F]azadibenzocyclooctyne ([18F]ADIBO): a biocompatible radioactive labeling synthon for peptides using catalyst free [3+2] cycloaddition

N-Terminally azido-modified peptides were labeled with the novel prosthetic labeling synthon [(18)F]azadibenzocyclooctyne ([(18)F]ADIBO) using copper-free azide-alkyne [3+2]-dipolar cycloaddition in high radiochemical yields (RCYs). (18)F-Labeled [(18)F]ADIBO was prepared by nucleophilic substitution of the corresponding tosylate in 21% overall RCY (EOB) in a fully automated synthesis unit within 55 min. [(18)F]ADIBO was incubated with azide-containing peptides at room temperature in the absence of toxic metal catalysts and the formation of the triazole conjugate was confirmed. Finally, the azide-alkyne [3+2]-dipolar cycloaddition was shown to proceed with 95% radiochemical yield in ethanol within 30 min, allowing for a development of a kit-like peptide labeling approach with [(18)F]ADIBO.     

Synthesis and evaluation of NLRP3-inhibitory sulfonylurea [11C]MCC950 in healthy animals

The diaryl sulfonylurea MCC950/CRID3 is a potent NLRP3 inhibitor (IC₅₀ = 8 nM) and, in animal models, MCC950 protects against numerous NLRP3-related neurodegenerative disorders. To evaluate the brain uptake and investigate target engagement of MCC950, we synthesised [¹¹C-urea]MCC950 via carrier added [¹¹C]CO₂ fixation chemistry (activity yield = 237 MBq; radiochemical purity >99%; molar activity = 7 GBq/µmol; radiochemical yield (decay-corrected from [¹¹C]CO₂) = 1.1%; synthesis time from end-of-bombardment = 31 min; radiochemically stable for >1 h). Despite preclinical efficacy in neurodegeneration studies, preclinical positron emission tomography (PET) imaging studies in mouse, rat and rhesus monkey revealed poor brain uptake of low molar activity [¹¹C]MCC950 and rapid washout. In silico prediction tools suggest efflux transporter liabilities for MCC950 at microdoses, and this information should be taken into account when developing next generation NLRP3 inhibitors and/or PET radiotracers.     

An efficient and expedient method for the synthesis of 11C-labeled α-aminoisobutyric acid: a tumor imaging agent potentially useful for cancer diagnosis

We describe the synthesis of ¹¹C-labeled α-aminoisobutyric acid 2 from iodo[¹¹C]methane and methyl N-(diphenylmethylen)-d,l-alaniate (5). The tetrabutylammonium fluoride (TBAF)-promoted α-[¹¹C]methylation of sterically hindered analog 5 was a key step in our synthesis process. Total radiochemical conversion of 2 was high and a remote-controlled synthesis was carried out. A comparative tumor positron emission tomography (PET) imaging study using the same model mouse showed higher uptake of 2 than with ¹¹C-labeled methionine and [¹⁸F] fluorodeoxyglucose (FDG).     

A statistical measure of tissue heterogeneity with application to 3D PET sarcoma data

In vivo measurement of local tissue characteristics by modern bioimaging techniques such as positron emission tomography (PET) provides the opportunity to analyze quantitatively the role that tissue heterogeneity may play in understanding biological function. This paper develops a statistical measure of the heterogeneity of a tissue characteristic that is based on the deviation of the distribution of the tissue characteristic from a unimodal elliptically contoured spatial pattern. An efficient algorithm is developed for computation of the measure based on volumetric region of interest data. The technique is illustrated by application to data from PET imaging studies of fluorodeoxyglucose utilization in human sarcomas. A set of 74 sarcoma patients (with five-year follow-up survival information) were evaluated for heterogeneity as well as a number of other potential prognostic indicators of survival. A Cox proportional hazards analysis of these data shows that the degree of heterogeneity of the sarcoma is the major risk factor associated with patient death. Some theory is developed to analyze the asymptotic statistical behavior of the heterogeneity estimator. In the context of data arising from Poisson deconvolution (PET being the prime example), the heterogeneity estimator, which is a non-linear functional of the PET image data, is consistent and converges at a rate that is parametric in the injected dose.     

Segmentation improvement through denoising of PET images with 3D-context modelling in wavelet domain

Positron emission tomography (PET) images have been incorporated into the radiotherapy process as a powerful tool to assist in the contouring of lesions, leading to the emergence of a broad spectrum of automatic segmentation schemes for PET images (PET-AS). However, not all proposed PET-AS algorithms take into consideration the previous steps of image preparation. PET image noise has been shown to be one of the most relevant affecting factors in segmentation tasks. This study demonstrates a nonlinear filtering method based on spatially adaptive wavelet shrinkage using three-dimensional context modelling that considers the correlation of each voxel with its neighbours. Using this noise reduction method, excellent edge conservation properties are obtained. To evaluate the influence in the segmentation schemes of this filter, it was compared with a set of Gaussian filters (the most conventional) and with two previously optimised edge-preserving filters. Five segmentation schemes were used (most commonly implemented in commercial software): fixed thresholding, adaptive thresholding, watershed, adaptive region growing and affinity propagation clustering. Segmentation results were evaluated using the Dice similarity coefficient and classification error. A simple metric was also included to improve the characterisation of the filters used for induced blurring evaluation, based on the measurement of the average edge width. The proposed noise reduction procedure improves the results of segmentation throughout the performed settings and was shown to be more stable in low-contrast and high-noise conditions. Thus, the capacity of the segmentation method is reinforced by the denoising plan used.     

A high-yield route to synthesize the P-glycoprotein radioligand [11C]N-desmethyl-loperamide and its parent radioligand [11C]loperamide

N-Desmethyl-loperamide and loperamide were synthesized from α,α-diphenyl-γ-butyrolactone and 4-(4-chlorophenyl)-4-hydroxypiperidine in five and four steps with 8% and 16% overall yield, respectively. The amide precursor was synthesized from 4-bromo-2,2-diphenylbutyronitrile and 4-(4-chlorophenyl)-4-hydroxypiperidine in 2 steps with 21–57% overall yield. [¹¹C]N-Desmethyl-loperamide and [¹¹C]loperamide were prepared from their corresponding amide precursor and N-desmethyl-loperamide with [¹¹C]CH₃OTf through N-[¹¹C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 20–30% and 10–15% radiochemical yields, respectively, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB.     

Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography

Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with ⁸⁹Zr for positron emission tomography imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, respectively. Trastuzumab conjugates of 3 and 4 were efficiently labeled with ⁸⁹Zr (>95% radiochemical yield). The in vitro plasma stability of ⁸⁹Zr-4-Trastuzumab and especially ⁸⁹Zr-3-Trastuzumab was greatly improved over previously reported ⁸⁹Zr-1-Trastuzumab and ⁸⁹Zr-2-Trastuzumab, but their demetalation remained higher and faster than ⁸⁹Zr-deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for ⁸⁹Zr-4-Trastuzumab, followed by ⁸⁹Zr-3-Trastuzumab, and to a lesser extent for ⁸⁹Zr-DFO-Trastuzumab. Molecular modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr-complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability.