Kinetic modeling and parameter estimation of TSPO PET imaging in the human brain

PURPOSE: Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model. METHODS: This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed. RESULTS AND CONCLUSIONS: Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods

A non-rigid registration method for mouse whole body skeleton registration

Micro-CT/PET imaging scanner provides a powerful tool to study tumor in small rodents in response to therapy. Accurate image registration is a necessary step to quantify the characteristics of images acquired in longitudinal studies. Small animal registration is challenging because of the very deformable body of the animal often resulting in different postures despite physical restraints. In this paper, we propose a non-rigid registration approach for the automatic registration of mouse whole body skeletons, which is based on our improved 3D shape context non-rigid registration method. The whole body skeleton registration approach has been tested on 21 pairs of mouse CT images with variations of individuals and time-instances. The experimental results demonstrated the stability and accuracy of the proposed method for automatic mouse whole body skeleton registration

An improved 3D shape context registration method for non-rigid surface registration

3D shape context is a method to define matching points between similar shapes as a pre-processing step to non-rigid registration. The main limitation of the approach is point mismatching, which includes long geodesic distance mismatch and neighbors crossing mismatch. In this paper, we propose a topological structure verification method to correct the long geodesic distance mismatch and a correspondence field smoothing method to correct the neighbors crossing mismatch. A robust 3D shape context model is proposed and further combined with thin-plate spline model for non-rigid surface registration. The method was tested on phantoms and rat hind limb skeletons from micro CT images. The results from experiments on mouse hind limb skeletons indicate that the approach is robust

Longitudinal mouse-PET imaging: a reliable method for estimating binding parameters without a reference region or blood sampling

International audienceLongitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging.METHODS:Using dynamic, whole-body 18F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (VT) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The VT and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against VT and %ID parameters.RESULTS:The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the VT estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans.CONCLUSION:We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling

Modelling [18F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain

PURPOSE: To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [(18)F]LW223, kinetics in the heart and brain when using a simplified imaging approach. METHODS: Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [(18)F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (V(T)) and binding potential transfer corrected (BP(TC)) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40–120 min) were estimated. RESULTS: PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [(18)F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BP(TC) more stable in the heart and V(T) more stable in the brain. CONCLUSION: Modelling of [(18)F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05482-1

Advanced quantitative evaluation of PET systems using the ACR phantom and NiftyPET software

Purpose: A novel phantom-imaging platform, a set of software tools, for automated and high-precision imaging of the American College of Radiology (ACR) positron emission tomography (PET) phantom for PET/magnetic resonance (PET/MR) and PET/computed tomography (PET/CT) systems is proposed. Methods: The key feature of this platform is the vector graphics design that facilitates the automated measurement of the knife-edge response function and hence image resolution, using composite volume of interest templates in a 0.5 mm resolution grid applied to all inserts of the phantom. Furthermore, the proposed platform enables the generation of an accurate μ -map for PET/MR systems with a robust alignment based on two-stage image registration using specifically designed PET templates. The proposed platform is based on the open-source NiftyPET software package used to generate multiple list-mode data bootstrap realizations and image reconstructions to determine the precision of the two-stage registration and any image-derived statistics. For all the analyses, iterative image reconstruction was employed with and without modeled shift-invariant point spread function and with varying iterations of the ordered subsets expectation maximization (OSEM) algorithm. The impact of the activity outside the field of view (FOV) was assessed using two acquisitions of 30 min each, with and without the activity outside the FOV. Results: The utility of the platform has been demonstrated by providing a standard and an advanced phantom analysis including the estimation of spatial resolution using all cylindrical inserts. In the imaging planes close to the edge of the axial FOV, we observed deterioration in the quantitative accuracy, reduced resolution (FWHM increased by 1–2 mm), reduced contrast, and background uniformity due to the activity outside the FOV. Although it slows convergence, the PSF reconstruction had a positive impact on resolution and contrast recovery, but the degree of improvement depended on the regions. The uncertainty analysis based on bootstrap resampling of raw PET data indicated high precision of the two-stage registration. Conclusions: We demonstrated that phantom imaging using the proposed methodology with the metric of spatial resolution and multiple bootstrap realizations may be helpful in more accurate evaluation of PET systems as well as in facilitating fine tuning for optimal imaging parameters in PET/MR and PET/CT clinical research studies

Impact of cerebral blood flow and amyloid load on SUVR bias

BACKGROUND: Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aβ burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [18F]flutemetamol (N = 90) or [18F]florbetaben (N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland-Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region. RESULTS: Despite high correlations (GCA: R2 ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVRbias and R1, albeit non-significant. CONCLUSION: The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aβ burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018

Quantification of macrophage-driven inflammation during myocardial infarction with 18F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion: 18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI

Biological parameter estimation for longitudinal imaging in the rodent brain

The thesis investigates kinetic modelling and parameter estimation techniques for longitudinal imaging studies in pre-clinical PET (positron emission tomography) of the rodent brain. Pre-clinical PET imaging is useful for investigating animal models of disease, and it is possible to follow evolution toward pathology with longitudinal imaging studies. Longitudinal studies require experimental methods that avoid blood sampling. It's also necessary to have methods that will allow the generation of parametric maps and give statistically robust and accurate parameter estimates. The work presented in this thesis aimed to develop, explore and validate parameter estimation methods for longitudinal studies using extensive kinetic modelling and simulation based approaches. Two biological targets were investigated, the D2 dopamine system, and the translocator protein (TSPO), useful for PET imaging as an indicator of neuroinflammation. The first part of the work achieved a robust and accurate data driven method for following changes in parameter estimates or creating parametric maps of the D2 dopamine system with 11C-raclopride. The method was validated for estimating Bavail and appKD in a broad range of experimental conditions. The second part of the thesis focused on the characterisation of TSPO ligands. The binding properties of two lead radiotracers (18F-PBR111 and 18F-PBR102) were compared in a well validated model of neuroinflammation, and found to be similar. The binding parameters of 18F-PBR111 were further characterised in an animal model of epileptogenesis. The studies presented in this thesis explored, developed and validated extensive kinetic modelling techniques and image processing tools for longitudinal imaging studies. The techniques will reliably estimate stable and accurate kinetic parameters, create parametric maps, and be able to detect small changes locally. This will allow researchers to study the progression through all stages of neurodegenerative diseases

Imaging translocator protein expression with positron emission tomography.

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