Parametric [11C]flumazenil images

Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [18F]flumazenil ([18F]FMZ). Here, [18F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABAA receptor binding capacity revealing regional differences and age-related changes. Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5-6months) and 11 old (range 39-42months) gerbils, starting simultaneously with the injection of [18F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses. BPnd differed significantly between models (p < 0.0005), showing the smallest mean difference between 2TCM as reference and SRTM as simplified procedure. SRTM revealed the lowest AIC values. Both volume of distribution (r2 = 0.8793, p = 0.018) and BPnd (r2 = 0.8216, p = 0.034) correlated with in vitro autoradiography data. A significant age-related decrease of receptor binding was observed in auditory (AC, IC, MGB) and other brain regions (SC and CB) (p < 0.0001, unpaired t test) being confirmed by SPM using pons as reference (p < 0.0001, uncorrected). Imaging of GABAA receptor binding capacity in gerbils using [18F]FMZ PET revealed SRTM as a simple and robust quantification method of GABAA receptors. Comparison of BPnd in young and old gerbils demonstrated an age-related decrease of GABAA receptor binding.

Patlak slope (PS) images have the potential to improve lesion conspicuity compared with standardized uptake value (SUV) images but may be more artifact-prone. This study compared PS versus SUV image quality and hepatic tumor-to-background ratios (TBRs) at matched time points. Early and late SUV and PS images were reconstructed from dynamic positron emission tomography (PET) data. Two independent, blinded readers scored image quality metrics (a four-point Likert scale) and counted tracer-avid lesions. Hepatic lesions and parenchyma were segmented and quantitatively analyzed. Differences were assessed via the Wilcoxon signed-rank test (alpha, 0.05). Forty-three subjects were included. For overall quality and lesion detection, early PS images were significantly inferior to other reconstructions. For overall quality, late PS images (reader 1 [R1]: 3.95, reader 2 [R2]: 3.95) were similar (p > 0.05) to early SUV images (R1: 3.88, R2: 3.84) but slightly superior (p ≤ 0.002) to late SUV images (R1: 2.97, R2: 3.44). For lesion detection, late PS images were slightly inferior to late SUV images (R1 only) but slightly superior to early SUV images (both readers). PS-based TBRs were significantly higher than SUV-based TBRs at the early time point, with opposite findings at the late time point. In conclusion, late PS images are similar to early/late SUV images in image quality and lesion detection; the superiority of SUV versus PS hepatic TBRs is time-dependent.

To explore the potential for simplified measures of [11 C]PIB uptake to serve as a surrogate for cerebral blood flow (CBF) measures, thereby, providing both pathological and functional information in the same scan. Participants (N = 24, 16 M, 8 F, 57-87 years) underwent quantitative [15 O]water imaging and dynamic [11 C]PIB imaging. Time-activity curves were created for each participant's regional [11 C]PIB data scaled in standardized uptake values (SUVs). The frame in which maximal uptake occurred was defined for each subject (ie, "peak"). The concentration (SUV) for each region at the individual's peak, during the 3.5-4 minute time interval and for the initial 6 minute sum, was determined. R1 (ie, relative delivery using cerebellum as reference tissue) from the simplified reference tissue model 2 was determined for each region. PIB SUVs were compared to the absolute CBF global and regional values (in mL/minute/100 mL) and the R1 values were compared to the cerebellar-normalized rCBF. Significant linear relationships were found for all SUV measures with measures of absolute global and regional CBF that were comparable to the relationship between normalized CBF and R1. The individual SUVpeak exhibited the strongest relationship both regionally and globally. All individuals and all regions had highly significant regression slopes. Age, gender, or amyloid burden did not influence the relationship. Early PIB uptake has the potential to effectively serve as a surrogate for global and regional CBF measures. The simple and readily obtainable individual's SUVpeak value was the strongest predictor regionally and globally of CBF.

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates

Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues. Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7-2.9min) and late phase (SUVRLP, 80-105min) to approximate R1 and DVR, respectively. The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals. Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study.

Reduced signal on [(11)C]]flumazenil (FMZ) positron emission tomography (PET) is associated with epileptogenic foci. Linear correlations within individuals between parametric and nonparametric images of FMZ binding have been shown, and various methods have been used, without comparison of diagnostic usefulness. Using hippocampal sclerosis (HS) as a test case, we formally compare the diagnostic yield of parametric images obtained either with a parent tracer arterial plasma input function and spectral analysis (yielding volume-of-distribution (VD) images), or with an image-based input function and the simplified reference tissue model (binding potential images, BP-SRTM) with the diagnostic yield of semiquantitative-integrated (ADD) images from 10 to 20 or 20 to 40 mins (ADD1020 and ADD2040). Dynamic 90-min [(11)C]FMZ PET datasets and arterial plasma input functions were available for 15 patients with medically refractory medial temporal lobe epilepsy (TLE) and histologically verified unilateral HS and for 13 control subjects. SPM2 was used for analysis. ADD1020 and ADD2040 images showed decreased FMZ uptake ipsilateral to the epileptogenic hippocampus in 13/15 cases; 6/13 had bilateral decreases in the ADD1020 analysis and 5/13 in the ADD2040 analysis. BP-SRTM images detected ipsilateral decreases in 12/15 cases, with bilateral decreases in three. In contrast, VD images showed ipsilateral hippocampal decreases in all 15 patients, with bilateral decreases in three patients. Bilateral decreases in the ADD images tended to be more symmetrical and in one case were more marked contralaterally. Full quantification with an image-independent input should ideally be used in the evaluation of FMZ PET; at least in TLE, intrasubject correlations do not predict equivalent clinical usefulness.

18F-Fludeoxyglucose (FDG) PET/CT is an effective tool for detecting active cardiac sarcoidosis (CS), but often has difficulty distinguishing CS lesions from physiological myocardial accumulation. We investigated the potential of the glucose metabolic rate (MRglc, mg/min/100mL) from four-dimensional FDG PET/CT in distinguishing between CS and physiological accumulation. Additionally, we compared CS delineation between MRglc and standardized uptake value (SUV). A total of 192 individuals with CS or suspected CS who underwent four-dimensional FDG PET/CT after 18 h fasting was enrolled. Ultimately, 45 individuals with CS and 14 patients with physiological accumulation, with SUVmean ≥ 2.7 accumulation in the left ventricular myocardium, were analyzed. The SUV, MRglc, and the ratio of MRglc to SUV (MRglc/SUV) were calculated for each lesion with SUVmean ≥ 2.7 using data acquired between 30 and 50min on four-dimensional FDG PET/CT. In the CS group, lesion-to-normal myocardium contrast ratios on MRglc and SUV images were compared. A total of 127 lesions from 45 individuals with CS and 43 physiological accumulations from 14 individuals were analyzed. The SUV, MRglc, and MRglc/SUV for CS lesions were significantly lower than those for physiological accumulations (SUV, 4.26±1.35 vs. 6.06±3.28; MRglc, 1.91±1.02 vs. 3.78±2.11; MRglc/SUV, 0.43±0.14 vs. 0.63±0.14; p<0.0001). Receiver operating characteristic analysis revealed that the ability to discriminate CS lesions from physiological accumulations yielded areas under the curves of 0.656, 0.808, and 0.849; sensitivities of 68, 76, and 73%; and specificities of 61, 72, and 84%, for SUV 4.525, MRglc 2.41, and MRglc/SUV 0.518. In the CS group, the contrast ratio of lesions was significantly greater on MRglc images than on SUV images (6.36±6.17 vs. 2.54±1.03, p<0.0001). MRglc from four-dimensional FDG PET/CT is a useful quantitative measure to distinguish CS lesions from physiological accumulation and enables better visualization of CS lesion contrast than SUV.

This work assesses the one-step late maximum likelihood expectation maximization (OSL-MLEM) 4D PET reconstruction algorithm for direct estimation of parametric images from raw PET data when using the simplified reference tissue model with the basis function method (SRTM-BFM) for the kinetic analysis. To date, the OSL-MLEM method has been evaluated using kinetic models based on two-tissue compartments with an irreversible component. We extend the evaluation of this method for two-tissue compartments with a reversible component, using SRTM-BFM on simulated 3D + time data sets (with use of [11C]raclopride time-activity curves from real data) and on real data sets acquired with the high resolution research tomograph. The performance of the proposed method is evaluated by comparing voxel-level binding potential (BPND) estimates with those obtained from conventional post-reconstruction kinetic parameter estimation. For the commonly chosen number of iterations used in practice, our results show that for the 3D + time simulation, the direct method delivers results with lower %RMSE at the normal count level (decreases of 9–10 percentage points, corresponding to a 38–44% reduction), and also at low count levels (decreases of 17–21 percentage points, corresponding to a 26–36% reduction). As for the real 3D data set, the results obtained follow a similar trend, with the direct reconstruction method offering a 21% decrease in %CV compared to the post reconstruction method at low count levels. Thus, based on the results presented herein, using the SRTM-BFM kinetic model in conjunction with the OSL-MLEM direct 4D PET MLEM reconstruction method offers an improvement in performance when compared to conventional post reconstruction methods.

PET analysis is conventionally performed as a two-stage process of quantification followed by analysis. We recently introduced SiMBA (Simultaneous Multifactor Bayesian Analysis), a hierarchical model that performs quantification and analysis for all brain regions of all individuals at once, and in so doing improves both the accuracy of parameter estimation and inferential efficiency. However until now, SiMBA has only been implemented for the two-tissue compartment model. We have now extended this general approach to also allow a non-invasive reference tissue implementation that includes both the full reference tissue model (FRTM) and the simplified reference tissue model (SRTM). Although the FRTM did not successfully converge and gave rise to unlikely parameter estimates for this application, the SRTM described the data well. In simulated data, SiMBA improves quantitative parameter estimation accuracy, reducing error by, on average, 57% for binding potential () using SRTM. In considerations of statistical power, our simulation studies indicate that the efficiency of SiMBA modeling approximately corresponds to improvements that would require doubling the sample size if using conventional methods, with no increase in the false-positive rate. We applied the model to PET data measured with [11C]AZ10419369, which binds selectively to the serotonin 1B receptor, in datasets collected at three different PET centres (n = 139, n = 44 and n = 39). We show that SiMBA yields replicable inferences by comparing associations between PET parameters and age in the different datasets. Moreover, we show that time activity curve data from different centres can be combined in a single SiMBA model using covariates to control between-centre parameter differences, in order to harmonise data between centres. In summary, we present a novel approach for non-invasive quantification and analysis of PET time activity curve data which improves quantification and inferences, enables effective between-centre data harmonisation, and also yields replicable outcomes. This method has the potential to significantly expand the range of research questions which can be meaningfully tested using conventional sample sizes with PET imaging.

BackgroundDifferences between on‐ and off‐target retention characteristics between [18F]MK6240 and [18F]Flortaucipir (FTP) complicate the harmonization across tracers. Our objective here was to separate the impact of the reference region by evaluating correlations between [18F]MK6240 (MK) and [18F]FTP standard uptake values (SUVs).MethodParticipants (Figure 1, n=90) received an amyloid‐β (Aβ) PET scan ([11C]PIB or [18F]NAV4694) and two tau‐PET scans: [18F]MK (90‐110 minutes post‐injection) and [18F]FTP (80‐100 minutes post‐injection). For all PET scans, the individual frames were realigned, averaged, and co‐registered to a Freesurfer 7.1‐segmented T1‐MPRAGE. SUVs were calculated in the reference region (inferior cerebellar gray), on‐target regions (entorhinal cortex, hippocampus, Braak III, Braak IV, Braak V, Braak VI) and off‐target regions (caudate, pallidum, putamen, thalamus, cerebellar white matter, choroid plexus, meninges, eroded white matter). We examined correlations between [18F]MK and [18F]FTP SUV values as a function of Aβ status, as well as their associations with age.ResultAll correlations (Figure 2) were significant at p&lt;0.001. The interaction with Aβ status was significant for hippocampus, BraakIII‐V and the metatemporal region. In Aβ+ participants, [18F]FTP and [18F]MK6240 have similar SUVs in on‐target regions with a slope close to 1 except for in hippocampus and Braak VI. However, [18F]FTP SUVs, on average, were greater than [18F]MK SUVs in Aβ+ and Aβ‐ subjects in the reference region and all off‐target regions except for meninges, and in Aβ‐ subjects in the on‐target regions. Age correlated with [18F]FTP SUVs in Aβ‐ subjects in all regions (except the reference region, Braak VI and meninges) and [18F]MK SUVs in putamen and pallidum, but this correlation was only significant (p&lt;0.01) when young and old subjects were included.ConclusionDespite [18F]MK’s higher affinity for tau and SUVR dynamic range being twice that of [18F]FTP, the SUVs in on‐target regions are similar. The higher [18F]FTP signal in the reference region appears to be the contributing factor to the lower dynamic range. The higher [18F]FTP signal in on‐target regions for Aβ‐ subjects may reflect the presence of off‐target signals in these subjects. Taking off‐target signals into account should improve correlations between the two tracers, especially when measuring the earliest deposition of tau.

[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test–retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer’s disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were –2.2% ± 8.5, 0.4% ± 12.0 and –8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(18F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V T). The regional nondisplaceable binding potential (BP ND) was calculated from 1TC V T, using the centrum semiovale (CS) as the reference region. Results: 18F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18F-SynVesT-2 is faster than the kinetics of 11C-UCB-J and 18F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

BackgroundIn non-small cell lung cancer (NSCLC) patients off erlotinib therapy, positron emission tomography (PET) using [11C]erlotinib distinguished epidermal growth factor receptor (EGFR) mutations from wild-type EGFR. However, tumor uptake of [11C]erlotinib during erlotinib therapy is unknown. Therefore, the aims of this study were to evaluate tumor [11C]erlotinib uptake in NSCLC patients both on and off erlotinib therapy, to evaluate the effect of erlotinib therapy on tumor perfusion and its correlation to tumor [11C]erlotinib uptake, and also, to investigate simplified uptake parameters using arterial and venous blood samples.MethodsTen patients were to be scanned twice with a 1–2-week interval, i.e., on (E+) and off (E−) erlotinib therapy. Each procedure consisted of a low-dose CT scan, a 10-min dynamic [15O]H2O PET scan, and a 60-min dynamic [11C]erlotinib PET scan with arterial and venous sampling at six time points. In patients(E+), the optimal compartment model was analyzed using Akaike information criterion. In patients(E−), the uptake parameter was the volume of distribution (VT), estimated by using metabolite-corrected plasma input curves based on image-derived input functions and discrete arterial and venous blood samples. Tumor blood flow (TBF) was determined by rate constant of influx (K1) of [15O]H2O using the 1T2k model and correlated with VT and K1 values of [11C]erlotinib. The investigated simplified parameters were standardized uptake value (SUV) and tumor-to-blood ratio (TBR) at 40–60 min pi interval.ResultsOf the 13 patients included, ten were scanned twice. In patients(E+), [11C]erlotinib best fitted the 2T4k model with VT. In all patients, tumor VT(E+) was lower than VT(E−) (median VT(E−) = 1.61, range 0.77–3.01; median VT(E+) = 1.17, range 0.53–1.74; P = 0.004). Using [15O]H2O, five patients were scanned twice. TBF did not change with erlotinib therapy, TBF showed a positive trend towards correlation with [11C]erlotinib K1, but not with VT. TBR40–50 and TBR50–60, using both arterial and venous sampling, correlated with VT(E−) (all rs >0.9, P < 0.001), while SUV did not. In patients off and on therapy, venous TBR underestimated arterial TBR by 26 ± 12 and 9 ± 9 %, respectively.ConclusionsIn patients on erlotinib in therapeutic dose, tumor VT decreases with high variability, independent of tumor perfusion. For simplification of [11C]erlotinib PET scanning protocols, both arterial and venous TBR 40–60 min post injection can be used; however, arterial and venous TBR values should not be interchanged as venous values underestimate arterial values.Trial registrationRegistered at the Netherlands Trial Registry: NTR3670.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0169-8) contains supplementary material, which is available to authorized users.

The aim of the present study is to evaluate the validity of the simplified reference tissue model (SRTM) and of Logan graphical analysis with reference tissue (LGAR) for quantification of histamine H1 receptors (H1Rs) by using positron emission tomography (PET) with [11C]doxepin. These model-based analytic methods (SRTM and LGAR) are compared to Logan graphical analysis (LGA) and to the one-tissue model (1TM), using complete datasets obtained from 5 healthy volunteers. Since HIR concentration in the cerebellum can be regarded as negligibly small, the cerebellum was selected as the reference tissue in the present study. The comparison of binding potential (BP) values estimated by LGAR and 1TM showed good agreement; on the other hand, SRTM turned out to be unstable concerning parameter estimation in several regions of the brain. By including the results of noise analysis, LGAR became a reliable method for parameter estimation of [11C]doxepin data in the cortical regions.

A regularized full reference tissue model for PET neuroreceptor mapping