[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer’s disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson’s disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.

[F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer’s disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically-based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n=6), intermediate Braak (III-IV, n=7) and high Braak (V-VI, n=9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging–pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.

18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurological disorders including Alzheimer's disease (AD) and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods Nine subjects (4 control, 3 with history of TBI, 2 mild cognitive impairment (MCI) due to suspected AD) underwent dynamic PET imaging for up to 120 minutes after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (one- and two-tissue configurations) and graphical analysis techniques (Logan and MA1 regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static standardized uptake value ratio (SUVR) utilizing the cerebellum as a reference tissue. Results Percent unmetabolized 18F-T807 in plasma followed a single exponential with T1/2 of 17.0±4.2 minutes. Metabolite corrected plasma radioactivity concentration fit a bi-exponential (T1/2: 18.1±5.8; 2.4±0.5 minutes). 18F-T807 in gray matter peaked quickly (SUV >2 at ∼5 minutes). Compartmental modeling resulted in good fits and the two-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in MCI subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 minutes, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high quality parametric maps when applied in voxelwise fashion. Reference region based approaches including Logan DVR (t*=55 min) and SUVR (80-100 min interval) were highly correlated with DVR estimated using 2Tv (R2=0.97, p<0.0001). Conclusions 18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches utilizing DVR (t*=55 minutes) and static SUVR (80-100 minutes) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.

Purpose: Recently, updated EARL specifications (EARL2) have been developed and announced. This study aims at investigating the impact of the EARL2 specifications on the quantitative reads of clinical PET-CT studies and testing a method to enable the use of the EARL2 standards whilst still generating quantitative reads compliant with current EARL standards (EARL1). Methods: Thirteen non-small cell lung cancer (NSCLC) and seventeen lymphoma PET-CT studies were used to derive four image datasets-the first dataset complying with EARL1 specifications and the second reconstructed using parameters as described in EARL2. For the third (EARL2F6) and fourth (EARL2F7) dataset in EARL2, respectively, 6 mm and 7 mm Gaussian post-filtering was applied. We compared the results of quantitative metrics (MATV, SUVmax, SUVpeak, SUVmean, TLG, and tumorto-liver and tumor-to-blood pool ratios) obtained with these 4 datasets in 55 suspected malignant lesions using three commonly used segmentation/volume of interest (VOI) methods (MAX41, A50P, SUV4). Results: We found that with EARL2 MAX41 VOI method, MATV decreases by 22%, TLG remains unchanged and SUV values increase by 23-30% depending on the specific metric used. The EARL2F7 dataset produced quantitative metrics best aligning with EARL1, with no significant differences between most of the datasets (p>0.05). Different VOI methods performed similarly with regard to SUV metrics but differences in MATV as well as TLG were observed. No significant difference between NSCLC and lymphoma cancer types was observed. Conclusions: Application of EARL2 standards can result in higher SUVs, reduced MATV and slightly changed TLG values relative to EARL1. Applying a Gaussian filter to PET images reconstructed using EARL2 parameters successfully yielded EARL1 compliant data.

BackgroundThe aim of this pilot study was to evaluate whether the uptake of 89Zr-bevacizumab in non-small cell lung cancer (NSCLC) tumors could be visualized and quantified. The correlation between tumor 89Zr-bevacizumab uptake and tumor response to antitumor therapy with a bevacizumab-based regimen was explored.MethodsSeven NSCLC patients underwent static PET scans at days 4 and 7 after injection of 36.4 ± 0.9 MBq (mean ± SD) 89Zr-bevacizumab, prior to commencing carboplatin-paclitaxel-bevacizumab chemotherapy (CPB). Overall survival (OS) and progression-free survival (PFS) to CPB followed by bevacizumab maintenance therapy was correlated to tumor tracer uptake, quantified using peak standardized uptake values (SUVpeak).ResultsZr-bevacizumab uptake (SUVpeak) was approximately four times higher in tumor tissues (primary tumor and metastases) than in non-tumor tissues (healthy muscle, lung, and fat) on days 4 and 7. A positive trend but no significant correlation could be found between SUVpeak and OS or PFS.ConclusionsThis pilot study shows that 89Zr-bevacizumab PET imaging in NSCLC is feasible. Further investigation to validate this technique as a predictive biomarker for selecting patients for bevacizumab treatment is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0035-5) contains supplementary material, which is available to authorized users.

Purpose In order to achieve comparability of image quality, harmonisation of PET system performance is imperative. In this study, prototype harmonisation criteria for PET brain studies were developed. Methods Twelve clinical PET/CT systems (4 GE, 4 Philips, 4 Siemens, including SiPM-based “digital” systems) were used to acquire 30-min PET scans of a Hoffman 3D Brain phantom filled with ~ 33 kBq·mL−1 [18F]FDG. Scan data were reconstructed using various reconstruction settings. The images were rigidly coregistered to a template (voxel size 1.17 × 1.17 × 2.00 mm3) onto which several volumes of interest (VOIs) were defined. Recovery coefficients (RC) and grey matter to white matter ratios (GMWMr) were derived for eroded (denoted in the text by subscript e) and non-eroded grey (GM) and white (WM) matter VOIs as well as a mid-phantom cold spot (VOIcold) and VOIs from the Hammers atlas. In addition, left-right hemisphere differences and voxel-by-voxel differences compared to a reference image were assessed. Results Systematic differences were observed for reconstructions with and without point-spread-function modelling (PSFON and PSFOFF, respectively). Normalising to image-derived activity, upper and lower limits ensuring image comparability were as follows: for PSFON, RCGMe = [0.97–1.01] and GMWMre = [3.51–3.91] for eroded VOI and RCGM = [0.78–0.83] and GMWMr = [1.77–2.06] for non-eroded VOI, and for PSFOFF, RCGMe = [0.92–0.99] and GMWMre = [3.14–3.68] for eroded VOI and RCGM = [0.75–0.81] and GMWMr = [1.72–1.95] for non-eroded VOI. Conclusions To achieve inter-scanner comparability, we propose selecting reconstruction settings based on RCGMe and GMWMre as specified in “Results”. These proposed standards should be tested prospectively to validate and/or refine the harmonisation criteria.

The 2T4k+VB model provided the best fit to the dynamic [(18)F]FAZA data. IDIF with venous blood samples can be used as input function. Further data are needed to validate the use of simplified methods.

IntroductionChronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.ObjectiveTo study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.MethodsWe performed [18F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.ResultsDespite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.ConclusionAV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.