Image-derived Input Function Research Articles

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

Longitudinal 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.MethodsUsing 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.ResultsThe 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.ConclusionWe 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.

Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer

BackgroundHigh expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with 68Ga-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between 68Ga-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of 68Ga-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.MethodsDynamic 68Ga-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K1) and irreversible binding (Ki) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to Ki.ResultsCharacterization of HER2 expression in smaller liver metastases was improved using parametric images. Ki values from parametric images agreed very well with VOI-based gold standard (R2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with Ki values from both the two-tissue compartment model and Patlak method (R2 = 0.87 and 0.95, both p < 0.001). 68Ga-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).Conclusion68Ga-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein Ki highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.

Quantification of PD-L1 Expression with 18F-BMS-986192 PET/CT in Patients with Advanced-Stage Non-Small Cell Lung Cancer.

The aim of this work was to quantify the uptake of 18F-BMS-986192, a programmed cell death ligand 1 (PD-L1) adnectin PET tracer, in patients with non-small cell lung cancer. To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as SUV was investigated. Methods: Data from a study with 18F-BMS-986192 in patients with advanced-stage non-small cell lung cancer eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of 18F-BMS-986192, a 60-min dynamic PET/CT scan was started, followed by a 30-min whole-body PET/CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time-activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor-to-blood ratio as well as several SUV measures. Results: Twenty-two tumors in 9 patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 of 18 tumor time-activity curves. The distribution volume (VT ) ranged from 0.4 to 4.8 mL⋅cm-3 Similar values were obtained with an image-derived input function. From the simplified measures, SUV normalized for body weight at 50 and 67 min after injection correlated best with VT , with an R2 of more than 0.9. Conclusion: A single-tissue reversible model can be used to quantify tumor uptake of the PD-L1 PET tracer 18F-BMS-986192. SUV at 60 min after injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. To assess its predictive value for response evaluation during programmed cell death protein 1 or PD-L1 immune checkpoint inhibition, further validation of SUV against VT based on an image-derived input function is recommended.

Comparison of different kinetic models for dynamic 18F-FDG PET/CT imaging of hepatocellular carcinoma with various, also dual-blood input function

A kinetic modeling analysis was performed on hepatocellular carcinoma (HCC) as well as healthy liver tissue regions from dynamic FDG positron emission tomographys/computer tomography (PET/CT) cans. On basis of image derived input function from hepatic artery and portal vein, various kinetic models were compared among each other in order to check whether HCC can be classified and differ from healthy tissue within the kinetic parameters.14 HCC and 10 healthy liver regions from FDG PET/CT scans of ten patients were analyzed from their time activity curves (TACs) were extracted from the PET dynamic images. Also the hepatic artery and the portal vein were delineated in the fused PET/CT images, which were used as input functions. Four kinetic models were applied to the TACs, using both or only one input function. Results were analyzed with several information criteria according to Akaike and Schwartz as well as be the F-Test. The paired student’s t-test was used to determine the differences between HCC and healthy regions.All applied models revealed significant differences of p < 0.01 of k3 between HCC and healthy liver and three out of four models produced almost identical values for k3 = 0.03 min−1 and Ki = 0.03 min−1. According to the information criteria tests, a simple two-tissue model with only a venous input function is clearly preferred in case of HCC TACs. After dividing all HCC regions into two groups having a low and a high HCC-to-healthy ratio, respectively, this model also showed significant differences of k3 between these two groups.In conclusion, results indicate that the portal vein is sufficient to describe kinetic FDG processes in HCC and healthy liver regions.

Utility of Absolute Quantification in Non-lesional Extratemporal Lobe Epilepsy Using FDG PET/MR Imaging.

The purpose of this study was to establish a non-invasive clinical PET/MR protocol using [18F]-labeled deoxyglucose (FDG) that provides physicians with regional metabolic rate of glucose (MRGlc) values and to clarify the contribution of absolute quantification to clinical management of patients with non-lesional extratemporal lobe epilepsy (ETLE). The study included a group of 15 patients with non-lesional ETLE who underwent a dynamic FDG PET study using a fully-integrated PET/MRI system (Siemens Biograph). FDG tracer uptake images were converted to MRGlc (μmol/100 g/min) maps using an image derived input function that was extracted based on the combined analysis of PET and MRI data. In addition, the same protocol was applied to a group of healthy controls, yielding a normative database. Abnormality maps for ETLE patients were created with respect to the normative database, defining significant hypo- or hyper-metabolic regions that exceeded ±2 SD of normal regional mean MRGlc values. Abnormality maps derived from MRGlc images of ETLE patients contributed to the localization of hypo-metabolic areas against visual readings in 53% and increased the confidence in the original clinical readings in 33% of all cases. Moreover, quantification allowed identification of hyper-metabolic areas that are associated with frequently spiking cortex, rarely acknowledged in clinical readings. Overall, besides providing some confirmatory information to visual readings, quantitative PET imaging demonstrated only a moderate impact on clinical management of patients with complex pathology that leads to epileptic seizures, failing to provide new decisive information that would have changed classification of patients from being rejected to being considered for surgical intervention.

Image-Derived Input Functions for Quantification of A1 Adenosine Receptors Availability in Mice Brains Using PET and [18F]CPFPX.

PurposeIn vivo imaging for the A1 adenosine receptors (A1ARs) with positron emission tomography (PET) using 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxan- thine ([18F]CPFPX) has become an important tool for studying physiological processes quantitatively in mice. However, the measurement of arterial input functions (AIFs) on mice is a method with restricted applicability because of the small total blood volume and the related difficulties in withdrawing blood. Therefore, the aim of this study was to extract an appropriate [18F]CPFPX image-derived input function (IDIF) from dynamic PET images of mice.ProceduresIn this study, five mice were scanned with [18F]CPFPX for 60 min. Arterial blood samples (n = 7 per animal) were collected from the femoral artery and corrected for metabolites. To generate IDIFs, three different approaches were selected: (A) volume of interest (VOI) placed over the heart (cube, 10 mm); (B) VOI set over abdominal vena cava/aorta region with a cuboid (5 × 5 × 15 mm); and (C) with 1 × 1 × 1 mm voxels on five consecutive slices. A calculated scaling factor (α) was used to correct for partial volume effect; the method of obtaining the total metabolite correction of [18F]CPFPX for IDIFs was developed. Three IDIFs were validated by comparison with AIF. Validation included the following: visual performance; computing area under the curve (AUC) ratios (IDIF/AIF) of whole-blood curves and parent curves; and the mean distribution volume (VT) ratios (IDIF/AIF) of A1ARs calculated by Logan plot and two-tissue compartment model.ResultsCompared with the AIF, the IDIF with VOI over heart showed the best performance among the three IDIFs after scaling by 1.77 (α) in terms of visual analysis, AUC ratios (IDIF/AIF; whole-blood AUC ratio, 1.03 ± 0.06; parent curve AUC ratio, 1.01 ± 0.10) and VT ratios (IDIF/AIF; Logan VT ratio, 1.00 ± 0.17; two-tissue compartment model VT ratio, 1.00 ± 0.13) evaluation. The A1ARs distribution of average parametric images was in good accordance to autoradiography of the mouse brain.ConclusionThe proposed study provides evidence that IDIF with VOI over heart can replace AIF effectively for quantification of A1ARs using PET and [18F]CPFPX in mice brains.

Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington\u2019s Disease: a Longitudinal PET Study

Impairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington’s Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [11C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (VT (IDIF)) and voxel-wise parametric VT (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [11C]ITDM VT (IDIF) quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [11C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [11C]ITDM PET imaging demonstrated higher [11C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.

In vitro and In vivo Assessment of Suitable Reference Region and Kinetic Modelling for the mGluR1 Radioligand [11C]ITDM in Mice

PurposeThis study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [11C]ITDM in mice.ProceduresWe performed in vivo blocking as well as displacement of [11C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [3H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [11C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches.ResultsIn vivo blocking with YM-202074 resulted in a decreased [11C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition, in vitro [3H]ITDM binding could be blocked in a dose-dependent manner. The volume of distribution (VT) based on the noninvasive IDIF (VT (IDIF)) showed excellent agreement with the VT values based on the metabolite-corrected plasma input function regardless of the metabolite correction (r2 > 0.943, p < 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r2 > 0.960, p < 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r2 = 0.379, p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach.ConclusionsNo suitable reference region could be identified for [11C]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [11C]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain.

MNGI-13. DYNAMIC IMAGING OF MENINGIOMA WITH 3’-DEOXY-3’-[18F]-FLUOROTHYMIDINE USING POSITRON EMISSION TOMOGRAPHY: A POSSIBLE PREDICTOR OF TUMOR GROWTH

Abstract BACKGROUND Positron emission tomography (PET) with 3’-deoxy-3’-[18F]-fluorothymidine (18F-FLT) provides a non-invasive assessment of in vivo tumor proliferation that could be useful for predicting growth potential in meningiomas. We aimed to study static and dynamic 18F-FLT PET metrics prospectively to assess metabolic activity of meningioma, and their associations to potential tumor growth on subsequent MRI scans. METHODS Between April 2017 and December 2018, 44 patients harboring MRI-suspected (n = 37) and histologically-verified residual meningiomas (n = 7) underwent a 60-minute dynamic 18F-FLT PET prior to imaging surveillance. Maximum and mean standardized uptake values (SUVmax, SUVmean) with/without normalisation to blood radioactivity obtained from a 40-60-minute static PET image and a 60-minute venous blood sampling were calculated. Total volume of distribution (VT) was estimated by kinetic modeling using a two-tissue reversible compartmental model with a fractional blood volume and metabolite-corrected image-derived input function. Tumor growth rate was calculated by volumetric analysis of subsequent MRI scans. RESULTS At the time of this writing, a total of 53 follow-up MRI scans from 33 patients were available for review, with a median follow-up time of 11 months (range, 4–22.5 months). Tumor growth/progression was observed in 12 cases with a monthly median growth rate of 0.10 cm3 (range, 0.03–3.41 cm3). All 18F-FLT metrics were significantly higher in patients with radiological progression compared to patients with stable findings with maximum tumor-to-blood-ratio (TBRmax) as the most promising imaging biomarker (4.9 ± 1.4 vs. 3.4 ± 1.0, P = .003; Mann-Whitney) and the strongest predictor for tumor progression (hazard ratio, 3.125; 95% confidence interval, 1.390–7.028; P = .006; univariate binary logistic regression). Age, gender, previous residual remnant(s) and initial tumor volume (median, 3.1 cm3; range, 0.2–55.3 cm3) had no influence. CONCLUSION 18F-FLT PET imaging could be a valuable tool in designing a patient-tailored surveillance strategy for patients with asymptomatic meningiomas.

In vivo imaging of synaptic loss in Alzheimer’s disease with [18F]UCB-H positron emission tomography

Loss of brain synapses is an early pathological feature of Alzheimer's disease. The current study assessed synaptic loss in vivo with positron emission tomography and an 18F-labelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. Twenty-four patients with mild cognitive impairment or Alzheimer's disease and positive [18F]Flutemetamol amyloid-PET were compared to 19 healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an image-derived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients' cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer's disease and to relate them to patients' cognitive impairment.

Assessment of acute bone loading in humans using [18F]NaF PET/MRI

PurposeThe acute effect of loading on bone tissue and physiology can offer important information with regard to joint function in diseases such as osteoarthritis. Imaging studies using [18F]-sodium fluoride ([18F]NaF) have found changes in tracer kinetics in animals after subjecting bones to strain, indicating an acute physiological response. The aim of this study is to measure acute changes in NaF uptake in human bone due to exercise-induced loading.MethodsTwelve healthy subjects underwent two consecutive 50-min [18F]NaF PET/MRI examinations of the knees, one baseline followed by one post-exercise scan. Quantification of tracer kinetics was performed using an image-derived input function from the popliteal artery. For both scans, kinetic parameters of KiNLR, K1, k2, k3, and blood volume were mapped parametrically using nonlinear regression with the Hawkins model. The kinetic parameters along with mean SUV and SUVmax were compared between the pre- and post-exercise examinations. Differences in response to exercise were analysed between bone tissue types (subchondral, cortical, and trabecular bone) and between regional subsections of knee subchondral bone.ResultsExercise induced a significant (p < <0.001) increase in [18F]NaF uptake in all bone tissues in both knees, with mean SUV increases ranging from 47% in trabecular bone tissue to 131% in subchondral bone tissue. Kinetic parameters involving vascularization (K1 and blood volume) increased, whereas the NaF extraction fraction [k3/(k2 + k3)] was reduced.ConclusionsBone loading induces an acute response in bone physiology as quantified by [18F]NaF PET kinetics. Dynamic imaging after bone loading using [18F]NaF PET is a promising diagnostic tool in bone physiology and imaging of biomechanics.

Promise of Fully Integrated PET/MRI: Noninvasive Clinical Quantification of Cerebral Glucose Metabolism.

We describe a fully automated processing pipeline to support the noninvasive absolute quantification of the cerebral metabolic rate for glucose (CMRGlc) in a clinical setting. This pipeline takes advantage of “anatometabolic” information associated with fully integrated PET/MRI. Methods: Ten healthy volunteers (5 men and /5 women; 27 ± 7 y old; 70 ± 10 kg) underwent a test-retest 18F-FDG PET/MRI examination of the brain. The imaging protocol consisted of a 60-min PET list-mode acquisition with parallel MRI acquisitions, including 3-dimensional time-of-flight MR angiography, MRI navigators, and a T1-weighted MRI scan. State-of-the-art MRI-based attenuation correction was derived from T1-weighted MRI (pseudo-CT [pCT]). For validation purposes, a low-dose CT scan was also performed. Arterial blood samples were collected as the reference standard (arterial input function [AIF]). The developed pipeline allows the derivation of an image-derived input function (IDIF), which is subsequently used to create CMRGlc maps by means of a Patlak analysis. The pipeline also includes motion correction using the MRI navigator sequence as well as a novel partial-volume correction that accounts for background heterogeneity. Finally, CMRGlc maps are used to generate a normative database to facilitate the detection of metabolic abnormalities in future patient scans. To assess the performance of the developed pipeline, IDIFs extracted by both CT-based attenuation correction (CT-IDIF) and MRI-based attenuation correction (pCT-IDIF) were compared with the reference standard (AIF) using the absolute percentage difference between the areas under the curves as well as the absolute percentage difference in regional CMRGlc values. Results: The absolute percentage differences between the areas under the curves for CT-IDIF and pCT-IDIF were determined to be 1.4% ± 1.0% and 3.4% ± 2.6%, respectively. The absolute percentage difference in regional CMRGlc values based on CT-IDIF and pCT-IDIF differed by less than 6% from the reference values obtained from the AIF. Conclusion: By taking advantage of the capabilities of fully integrated PET/MRI, we developed a fully automated computational pipeline that allows the noninvasive determination of regional CMRGlc values in a clinical setting. This methodology might facilitate the proliferation of fully quantitative imaging into the clinical arena and, as a result, might contribute to improved diagnostic efficacy.

MRI-Driven PET Image Optimization for Neurological Applications.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are established imaging modalities for the study of neurological disorders, such as epilepsy, dementia, psychiatric disorders and so on. Since these two available modalities vary in imaging principle and physical performance, each technique has its own advantages and disadvantages over the other. To acquire the mutual complementary information and reinforce each other, there is a need for the fusion of PET and MRI. This combined dual-modality (either sequential or simultaneous) could generate preferable soft tissue contrast of brain tissue, flexible acquisition parameters, and minimized exposure to radiation. The most unique superiority of PET/MRI is mainly manifested in MRI-based improvement for the inherent limitations of PET, such as motion artifacts, partial volume effect (PVE) and invasive procedure in quantitative analysis. Head motion during scanning significantly deteriorates the effective resolution of PET image, especially for the dynamic scan with lengthy time. Hybrid PET/MRI device can offer motion correction (MC) for PET data through MRI information acquired simultaneously. Regarding the PVE associated with limited spatial resolution, the process and reconstruction of PET data can be further optimized by using acquired MRI either sequentially or simultaneously. The quantitative analysis of dynamic PET data mainly relies upon an invasive arterial blood sampling procedure to acquire arterial input function (AIF). An image-derived input function (IDIF) method without the need of arterial cannulization, can serve as a potential alternative estimation of AIF. Compared with using PET data only, combining anatomical or functional information from MRI for improving the accuracy in IDIF approach has been demonstrated. Yet, due to the interference and inherent disparity between the two modalities, these methods for optimizing PET image based on MRI still have many technical challenges. This review discussed upon the most recent progress, current challenges and future directions of MRI-driven PET data optimization for neurological applications, with either sequential or simultaneous acquisition approach.

Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

Kinetic modelling and quantification bias in small animal PET studies with [18F]AB5186, a novel 18 kDa translocator protein radiotracer.

IntroductionPositron Emission Tomography (PET) imaging with selective 18 kDa translocator protein (TSPO) radiotracers has contributed to our understanding on the role of inflammation in disease development and progression. With an increasing number of rodent models of human disease and expansion of the preclinical PET imaging base worldwide, accurate quantification of longitudinal rodent TSPO PET datasets is necessary. This is particularly relevant as TSPO PET quantification relies on invasive blood sampling due to lack of a suitable tissue reference region. Here we investigate the kinetics and quantification bias of a novel TSPO radiotracer [18F]AB5186 in rats using automatic, manual and image derived input functions.Methods[18F]AB5186 was administered intravenously and dynamic PET imaging was acquired over 2 hours. Arterial blood was collected manually to derive a population based input function or using an automatic blood sampler to derive a plasma input function. Manually sampled blood was also used to analyze the [18F]AB5186 radiometabolite profile in plasma and applied to all groups as a population based dataset. Kinetic models were used to estimate distribution volumes (VT) and [18F]AB5186 outcome measure bias was determined.Results[18F]AB5186 distribution in rats was consistent with TSPO expression and at 2 h post-injection 50% of parent compound was still present in plasma. Population based manual sampling methods and image derived input function (IDIF) underestimated VT by ~50% and 88% compared with automatic blood sampling, respectively. The VT variability was lower when using IDIF versus arterial blood sampling methods and analysis of the Bland-Altman plots showed a good agreement between methods of analysis.ConclusionQuantification of TSPO PET rodent data using image-derived methods, which are more amenable for longitudinal scanning of small animals, yields outcome measures with reduced variability and good agreement, albeit biased, compared with invasive blood sampling methods.

Kinetic [18F]-Fluoride of the Knee in Normal Volunteers.

[F]-sodium fluoride ([F]NaF) is a well-established bone-seeking agent that has shown promise to assess bone turnover in a variety of disorders, but its distribution in healthy knee joints has not been explored. This study aimed to investigate parametric values for [F]NaF uptake in various bone tissues types of the knee and their spatial distributions. Twelve healthy subjects were hand-injected with 92.5 MBq of [F]NaF and scanned on a 3-T PET/MRI system. Listmode PET data for both knees were acquired for 50 minutes from injection simultaneously with MRI Dixon and angiography data. The image-derived input function was determined from the popliteal artery. Using the Hawkins model, Patlak analysis was performed to obtain Ki (Ki) values and nonlinear regression analysis to obtain Ki, K1, k3/(k2 + k3), and blood volume. Comparisons for the measured kinetic parameters, SUV, and SUVmax were made between tissue types (subchondral, cortical, and trabecular bone) and between regional subsections of subchondral bone. Cortical bone had the highest [F]NaF uptake differing significantly in all measured parameters when compared with trabecular bone and significantly higher SUVmax and K1 than subchondral bone. Subchondral bone also had significantly higher SUV, SUVmax, and Ki than trabecular bone tissue. Regional differences were observed in K1 and k3/(k2 + k3) values. Quantitative [F]NaF PET is sensitive to variations in bone vascularization and metabolism in the knee joint.

No significant difference found in PET/MRI CBF values reconstructed with CT-atlas-based and ZTE MR attenuation correction

BackgroundAccurate attenuation correction (AC) is one of the most important issues to be addressed in quantitative brain PET/MRI imaging. Atlas-based MRI AC (AB-MRAC), one of the representative MRAC methods, has been used to estimate the skull attenuation in brain scans. The zero echo time (ZTE) pulse sequence is also expected to provide a better MRAC estimation in brain PET scans. The difference in quantitative measurements of cerebral blood flow (CBF) using H215O-PET/MRI was compared between the two MRAC methods, AB and ZTE.MethodTwelve patients with cerebrovascular disease (4 males, 43.2 ± 11.7 years) underwent H215O-PET/MRI studies with a 3-min PET scan and MRI scans including the ZTE sequence. Eleven of them were also studied under the conditions of baseline and 10 min after acetazolamide administration, and 2 of them were followed up after several months interval. A total of 25 PET images were reconstructed as dynamic data using 2 sets of reconstruction parameters to obtain the image-derived input function (IDIF), the time-activity curves of the major cerebral artery extracted from images, and CBF images. The CBF images from AB- and ZTE-MRAC were then compared for global and regional differences.ResultsThe mean differences of IDIF curves at each point obtained from AB- and ZTE-MRAC dynamic data were less than 5%, and the differences in time-activity curves were very small. The means of CBF from AB- and ZTE-MRAC reconstructions calculated using each IDIF showed differences of less than 5% for all cortical regions. CBF images from AB-MRAC tended to show greater values in the parietal region and smaller values in the skull base region.ConclusionThe CBF images from AB- and ZTE-MRAC reconstruction showed no significant differences in regional values, although the parietal region tended to show greater values in AB-MRAC reconstruction. Quantitative values in the skull base region were very close, and almost the same IDIFs were obtained.

Assessment of Simplified Methods for Quantification of 18F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer.

18F-fluorodihydrotestosterone (18F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying 18F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these 18F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic 18F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic 15O-H2O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUVBW), lean body mass (SUVLBM), whole blood (SUVWB), parent plasma activity concentration (SUVPP), area under the parent plasma curve (SUVAUC,PP), and area under the whole-blood input curve (SUVAUC,WB); and SUVBW corrected for sex hormone-binding globulin levels (SUVSHBG). Results were correlated with parameters derived from full pharmacokinetic 18F-FDHT and 15O-H2O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven 18F-FDHT-avid lesions were evaluated. 18F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar Ki results (R2 = 0.98). Patlak Ki and SUVAUC,PP showed an excellent correlation (R2 > 0.9). SUVBW showed a moderate correlation to Ki (R2 = 0.70, presumably due to fast 18F-FDHT metabolism. When calculating SUVSHBG, correlation to Ki improved (R2 = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). 18F-FDHT uptake showed minimal blood flow dependency. Conclusion:18F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUVAUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of 18F-FDHT uptake in whole-body PET/CT scans. In addition, SUVSHBG could potentially be used as an even simpler method to quantify 18F-FDHT uptake when less complex scanning protocols and accuracy are required.

Partial-volume correction in dynamic PET-CT: effect on tumor kinetic parameter estimation and validation of simplified metrics

BackgroundPartial-volume effects generally result in an underestimation of tumor tracer uptake on PET-CT for small lesions, necessitating partial-volume correction (PVC) for accurate quantification. However, investigation of PVC in dynamic oncological PET studies to date is scarce. The aim of this study was to investigate PVC’s impact on tumor kinetic parameter estimation from dynamic PET-CT acquisitions and subsequent validation of simplified semi-quantitative metrics. Ten patients with EGFR-mutated non-small cell lung cancer underwent dynamic 18F-fluorothymidine PET-CT before, 7 days after, and 28 days after commencing treatment with a tyrosine kinase inhibitor. Parametric PVC was applied using iterative deconvolution without and with highly constrained backprojection (HYPR) denoising, respectively. Using an image-derived input function with venous parent plasma calibration, we estimated full kinetic parameters VT, K1, and k3/k4 (BPND) using a reversible two-tissue compartment model, and simplified metrics (SUV and tumor-to-blood ratio) at 50–60 min post-injection.ResultsPVC had a non-linear effect on measured activity concentrations per timeframe. PVC significantly changed each kinetic parameter, with a median increase in VT of 11.8% (up to 25.1%) and 10.8% (up to 21.7%) without and with HYPR, respectively. Relative changes in kinetic parameter estimates vs. simplified metrics after applying PVC were poorly correlated (correlations 0.36–0.62; p < 0.01). PVC increased correlations between simplified metrics and VT from 0.82 and 0.81 (p < 0.01) to 0.90 and 0.88 (p < 0.01) for SUV and TBR, respectively, albeit non-significantly. PVC also increased correlations between treatment-induced changes in simplified metrics vs. VT at 7 (SUV) and 28 (SUV and TBR) days after treatment start non-significantly. Delineation on partial-volume corrected PET images resulted in a median decrease in metabolic tumor volume of 14.3% (IQR − 22.1 to − 7.5%), and increased the effect of PVC on kinetic parameter estimates.ConclusionPVC has a significant impact on tumor kinetic parameter estimation from dynamic PET-CT data, which differs from its effect on simplified metrics. However, it affected validation of these simplified metrics both as single measurements and as biomarkers of treatment response only to a small extent. Future dynamic PET studies should preferably incorporate PVC.Trial registrationDutch Trial Register, NTR3557.

Hybrid PET/MR Kernelised Expectation Maximisation Reconstruction for Improved Image-Derived Estimation of the Input Function from the Aorta of Rabbits.

Positron emission tomography (PET) provides simple noninvasive imaging biomarkers for multiple human diseases which can be used to produce quantitative information from single static images or to monitor dynamic processes. Such kinetic studies often require the tracer input function (IF) to be measured but, in contrast to direct blood sampling, the image-derived input function (IDIF) provides a noninvasive alternative technique to estimate the IF. Accurate estimation can, in general, be challenging due to the partial volume effect (PVE), which is particularly important in preclinical work on small animals. The recently proposed hybrid kernelised ordered subsets expectation maximisation (HKEM) method has been shown to improve accuracy and contrast across a range of different datasets and count levels and can be used on PET/MR or PET/CT data. In this work, we apply the method with the purpose of providing accurate estimates of the aorta IDIF for rabbit PET studies. In addition, we proposed a method for the extraction of the aorta region of interest (ROI) using the MR and the HKEM image, to minimise the PVE within the rabbit aortic region—a method which can be directly transferred to the clinical setting. A realistic simulation study was performed with ten independent noise realisations while two, real data, rabbit datasets, acquired with the Biograph Siemens mMR PET/MR scanner, were also considered. For reference and comparison, the data were reconstructed using OSEM, OSEM with Gaussian postfilter and KEM, as well as HKEM. The results across the simulated datasets and different time frames show reduced PVE and accurate IDIF values for the proposed method, with 5% average bias (0.8% minimum and 16% maximum bias). Consistent results were obtained with the real datasets. The results of this study demonstrate that HKEM can be used to accurately estimate the IDIF in preclinical PET/MR studies, such as rabbit mMR data, as well as in clinical human studies. The proposed algorithm is made available as part of an open software library, and it can be used equally successfully on human or animal data acquired from a variety of PET/MR or PET/CT scanners.