QUANTITATIVE NUCLEAR MEDICINE IMAGING USING ADVANCED IMAGE RECONSTRUCTION AND RADIOMICS

Our aim is to help put nuclear medicine at the forefront of quantitation on the path to the realization of personalized medicine. We propose and evaluate (Part I) advanced image reconstruction and (Part II) robust radiomics (large-scale data-oriented study of radiological images). The goal is to attain significantly improved diagnostic, prognostic and treatment-response assessment capabilities. Part I presents a new paradigm in point-spread function (PSF)-modeling, a partial volume correction method in PET imaging where resolution-degrading phenomena are modeled within the reconstruction framework. PSF-modeling improves resolution and enhances contrast, but significantly alters noise properties and induces edge-overshoots. Past efforts involve a dichotomy of PSF vs. no-PSF modeling; by contrast, we focus on a wide-spectrum of PSF models, including under- and over-estimation of the true PSF, for the potential of enhanced quantitation in standardized uptake values (SUVs). We show for the standard range of iterations employed in clinic (not excessive), edge enhancement due to overestimation actually lower SUV bias in small regions, while inter-voxel correlations suppress image roughness and enhance uniformity. An overestimated PSF yields improved contrast and limited edge-overshoot effects at lower iterations, enabling enhanced SUV quantitation. Overall, our framework provides an effective venue for quantitative task-based optimization. Part II proposes robust and reproducible radiomics methods. Radiomics workflows are complex, generating hundreds of features, which can lead to high variability and overfitting, and ultimately hampering performance. We developed and released a Standardized Environment for Radiomics Analysis (SERA) solution to enable robust radiomics analyses. We conduct studies on two unique imaging datasets – renal cell carcinoma SPECT and prostate cancer PET – identifying robust and reproducible radiomic features. In addition, we evaluate a novel hypothesis that radiomic features extracted from clinically normal (non-ischemic) myocardial perfusion SPECT (MPS) can predict coronary artery calcification (CAC; as extracted from CT). This has important implications, since CAC assessment is not commonly-performed nor reimbursed in wide community settings. SERA-derived radiomic features were utilized in a multi-step feature selection framework, followed by the application of machine learning to radiomic features. Our results show the potential to predict CAC from normal MPS, suggesting added usage and value for routine standard MPS

Quantitative PET and SPECT

Since the introduction of personalized medicine, the primary focus of imaging has moved from detection and diagnosis to tissue characterization, the determination of prognosis, prediction of treatment efficacy, and measurement of treatment response. Precision (personalized) imaging heavily relies on the use of hybrid technologies and quantitative imaging biomarkers. The growing number of promising theragnostics require accurate quantification for pre- and post-treatment dosimetry. Furthermore, quantification is required in the pharmacokinetic analysis of new tracers and drugs and in the assessment of drug resistance. Positron Emission Tomography (PET) is, by nature, a quantitative imaging tool, relating the time–activity concentration in tissues and the basic functional parameters governing the biological processes being studied. Recent innovations in single photon emission computed tomography (SPECT) reconstruction techniques have allowed for SPECT to move from relative/semi-quantitative measures to absolute quantification. The strength of PET and SPECT is that they permit whole-body molecular imaging in a noninvasive way, evaluating multiple disease sites. Furthermore, serial scanning can be performed, allowing for the measurement of functional changes over time during therapeutic interventions. This Special Issue highlights the hot topics on quantitative PET and SPECT

Theoretical Analysis of Penalized Maximum-Likelihood Patlak Parametric Image Reconstruction in Dynamic PET for Lesion Detection

Detecting cancerous lesions is a major clinical application of emission tomography. In a previous work, we studied penalized maximum-likelihood (PML) image reconstruction for lesion detection in static PET. Here we extend our theoretical analysis of static PET reconstruction to dynamic PET. We study both the conventional indirect reconstruction and direct reconstruction for Patlak parametric image estimation. In indirect reconstruction, Patlak parametric images are generated by first reconstructing a sequence of dynamic PET images, and then performing Patlak analysis on the time activity curves (TACs) pixel-by-pixel. In direct reconstruction, Patlak parametric images are estimated directly from raw sinogram data by incorporating the Patlak model into the image reconstruction procedure. PML reconstruction is used in both the indirect and direct reconstruction methods. We use a channelized Hotelling observer (CHO) to assess lesion detectability in Patlak parametric images. Simplified expressions for evaluating the lesion detectability have been derived and applied to the selection of the regularization parameter value to maximize detection performance. The proposed method is validated using computer-based Monte Carlo simulations. Good agreements between the theoretical predictions and the Monte Carlo results are observed. Both theoretical predictions and Monte Carlo simulation results show the benefit of the indirect and direct methods under optimized regularization parameters in dynamic PET reconstruction for lesion detection, when compared with the conventional static PET reconstruction

Molecular Imaging

The present book gives an exceptional overview of molecular imaging. Practical approach represents the red thread through the whole book, covering at the same time detailed background information that goes very deep into molecular as well as cellular level. Ideas how molecular imaging will develop in the near future present a special delicacy. This should be of special interest as the contributors are members of leading research groups from all over the world

Factor analysis of dynamic PET images

Thanks to its ability to evaluate metabolic functions in tissues from the temporal evolution of a previously injected radiotracer, dynamic positron emission tomography (PET) has become an ubiquitous analysis tool to quantify biological processes. Several quantification techniques from the PET imaging literature require a previous estimation of global time-activity curves (TACs) (herein called \textit{factors}) representing the concentration of tracer in a reference tissue or blood over time. To this end, factor analysis has often appeared as an unsupervised learning solution for the extraction of factors and their respective fractions in each voxel. Inspired by the hyperspectral unmixing literature, this manuscript addresses two main drawbacks of general factor analysis techniques applied to dynamic PET. The first one is the assumption that the elementary response of each tissue to tracer distribution is spatially homogeneous. Even though this homogeneity assumption has proven its effectiveness in several factor analysis studies, it may not always provide a sufficient description of the underlying data, in particular when abnormalities are present. To tackle this limitation, the models herein proposed introduce an additional degree of freedom to the factors related to specific binding. To this end, a spatially-variant perturbation affects a nominal and common TAC representative of the high-uptake tissue. This variation is spatially indexed and constrained with a dictionary that is either previously learned or explicitly modelled with convolutional nonlinearities affecting non-specific binding tissues. The second drawback is related to the noise distribution in PET images. Even though the positron decay process can be described by a Poisson distribution, the actual noise in reconstructed PET images is not expected to be simply described by Poisson or Gaussian distributions. Therefore, we propose to consider a popular and quite general loss function, called the $\beta$-divergence, that is able to generalize conventional loss functions such as the least-square distance, Kullback-Leibler and Itakura-Saito divergences, respectively corresponding to Gaussian, Poisson and Gamma distributions. This loss function is applied to three factor analysis models in order to evaluate its impact on dynamic PET images with different reconstruction characteristics

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)