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In ALK-positive advanced NSCLC, crizotinib has a high response rate and effectively increases quality of life and survival. CT measurement of the tumor may insufficiently reflect the actual tumor load changes during targeted therapy with crizotinib. We explored whether 18F-FDG PET measured metabolic changes are different from CT based changes and studied the impact of these changes on disease progression. 18F-FDG PET/CT was performed prior to and after 6 weeks of crizotinib treatment. Tumor response on CT was classified with RECIST 1.1, while 18F-FDG PET response was assessed according to the 1999 EORTC recommendations and PERCIST criteria. Agreement was assessed using McNemars test. During follow-up, patients received additional PET/CT during crizotinib treatment and second generation ALK inhibition. We assessed whether PET was able to detect progression earlier then CT. In this exploratory study 15 patients were analyzed who were treated with crizotinib. There was a good agreement in the applicability of CT and 18F-FDG PET/CT using the EORTC recommendations. During first line crizotinib and subsequent second line ALK inhibitors, PET was able to detect progression earlier then CT in 10/22 (45%) events of progression and in the others disease progression was detected simultaneously. In advanced ALK positive NSCLC PET was able to detect progressive disease earlier than with CT in nearly half of the assessments while both imaging tests performed similar in the others.

•Cortical synaptic density is not influenced by aging over the adult life span up to 85 years.•The caudate nucleus may have a small age-dependent decrease of synaptic density of 1.7% per decade but residual spatial normalization and partial volume effects may contribute to this.•Synaptic density is not sex-dependent in healthy adults. 11C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as in vivo proxy of synaptic density. There are discrepancies in postmortem data on stability of synaptic density with healthy aging. In this study, healthy aging and sex as potential modifiers of 11C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex. 80 healthy volunteers underwent 11C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric 11C-UCB-J standardized uptake value ratio (SUVR) images were calculated using the centrum semiovale as reference tissue. To correct for atrophy-related partial volume effects, a region-based voxel-wise type partial volume correction (PVC) was applied in FreeSurfer. The correlations of 11C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging. Full results were available for 78 participants (19–85y; 33 M/45 F). VBM grey matter concentration changes with aging were most predominant in the perisylvian and frontal regions. After PVC, no significantly decreased 11C-UCB-J SUVR with aging was found in the voxel-based analysis, whereas the VOI-based analysis showed a slight decrease in the caudate nucleus (−1.7% decrease per decade, p= 0.0025) only. There was no association between sex and 11C-UCB-J SUVR, nor an interaction between aging and sex for this parameter. In vivo, PET using 11C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes.

Purpose Next-generation SPECT/CT systems with CdZnTe (CZT) digital detectors in a ring-like setup are emerging to perform quantitative Lu-177 SPECT imaging in clinical routine. It is essential to assess how the shorter acquisition time might affect the image quality and uncertainty on the mean absorbed dose of the tumors and organs at risk compared to a conventional system. Methods A NEMA Image Quality phantom was scanned with a 3D CZT SPECT/CT system (Veriton, by Spectrum Dynamics) using 6 min per bed position and with a conventional SPECT/CT system (Symbia T16, by Siemens) using 16 min per bed position. The sphere-to-background ratio was 12:1 and the background activity concentration ranged from 0.52 to 0.06 MBq/mL. A clinical reconstruction protocol for dosimetry purposes was determined for both systems by maximizing the sphere-to-background ratio while keeping the coefficient of variation of the background as low as possible. The corresponding image resolution was determined by the matching filter method and used for a dose uncertainty assessment of both systems following an established uncertainty model.. Results The optimized iterative reconstruction protocol included scatter and attenuation correction for both systems and detector response modeling for the Siemens system. For the 3D CZT system, 6 iterations and 8 subsets were combined with a Gaussian post-filter of 3 mm Full Width Half Maximum (FWHM) for post-smoothing. For the conventional system, 16 iterations and 16 subsets were applied with a Gaussian post-smoothing filter of 1 mm FWHM. For these protocols, the sphere-to-background ratio was 18.5% closer to the true ratio for the conventional system compared to the 3D CZT system when considering the four largest spheres. Meanwhile, the background coefficient of variation was very similar for both systems. These protocols resulted in SPECT image resolution of 14.8 mm and 13.6 mm for the 3D CZT and conventional system respectively. Based on these resolution estimates, a 50% dose uncertainty corresponded to a lesion volume of 28 mL for the conventional system and a lesion volume of 33 mL for the 3D CZT system. Conclusions An optimized reconstruction protocol for a Veriton system with 6 min of acquisition time per bed position resulted in slightly higher dose uncertainties than a conventional Symbia system using 16 min of acquisition time per bed position. Therefore, a 3D CZT SPECT/CT allows to significantly reduce the acquisition times with only a very limited impact on dose uncertainties such that quantitative Lu-177 SPECT/CT imaging becomes much more accessible for treatment concurrent dosimetry. Nevertheless, the uncertainty of SPECT-based dose estimates remains high.

Purpose This study aimed to assess the imaging performance of a 3D CZT SPECT/CT system for Tb-161 and compare its quantitative accuracy and image quality with those of a conventional [NaI(Tl)]-based SPECT/CT system. Methods A NEMA Image Quality (IQ) phantom was scanned with a 3D CZT SPECT/CT (Veriton, Spectrum Dynamics) for 8 min per bed position and with a conventional SPECT/CT (Symbia T16, by Siemens) for 16 min per bed position. The 3D CZT SPECT acquisition time was virtually shortened by reparsing the listmode data. The NEMA IQ phantom was scanned with a cold background and with a sphere-to-background ratio (SBR) of 20:1 and 10:1, with 0.71 MBq/mL in the spheres. Clinical reconstruction protocols were chosen by maximizing the SBR (for the four largest spheres) while minimizing the background noise. Results The optimal SBR-to-noise trade-off was achieved at 48 updates for the Symbia and 50 updates for the Veriton. The Veriton exhibited a 20% and 34% higher SBR with a 19% and 10% lower CoV compared to the Symbia for the 10:1 and 20:1 spheres to background ratios, respectively. The calibration factors were determined as 15.17 and 4.8  cps/MBq for the Symbia and Veriton, respectively. Reducing the scan time had minimal effect on SBR, but a twofold count reduction increased background noise by 11%. Conclusion Quantitative Tb-161 SPECT imaging can be performed using both a conventional and a 3D CZT SPECT/CT. Given its higher sensitivity, the 3D CZT system is preferred, as it achieved better image quality with an 8-min acquisition compared to a conventional system with a 16-min acquisition.

Background Accurate cellular dosimetry is essential to investigate fundamental mechanisms of targeted radionuclide therapy. The aim of this study was to assess how morphological cellular geometry models influence cellular dosimetry estimates, in comparison to simplified spherical models that do not properly represent an adherent cell geometry. Methods Virtual cell models of the CA20948 cell line were generated by confocal microscopy of SSTR2 and DAPI staining and served as input to derive morphological S-values for 177 Lu and 161 Tb. Absorbed dose–response relationships were established for [ 177 Lu]Lu-DOTA-TATE, [ 161 Tb]Tb-DOTA-TATE, [ 177 Lu]Lu-DOTA-LM3 and [ 161 Tb]Tb-DOTA-LM3 using S-values from both morphological and spherical cell geometries. Results Thirty-four cell geometries were modeled and a spherical model with equivalent volume was generated with a radius for the cell and nucleus of 8.6(7) µm and 5.5(6) µm, respectively. Compared to spherical cell models, morphological cell models significantly changed the S-value with an increase of 13% ( 177 Lu) and 22% ( 161 Tb) with the cell membrane as source region and a decrease of 11% ( 177 Lu) and 12% ( 161 Tb) with the cytoplasm as source region. Absorbed dose-response relationships based on morphological cell geometries showed a linear dose-response model for [ 177 Lu]Lu-DOTA-TATE and [ 161 Tb]Tb-DOTA-TATE with α = 0.22[0.18,0.26] Gy-1, and a linear-quadratic dose-response model for [ 177 Lu]Lu-DOTA-LM3 and [ 161 Tb]Tb-DOTA-LM3 with α = 0.000[0.000,0.022] Gy-1 and β = 0.064[0.055,0.072] Gy-2. The assumption of a spherical cell model did not significantly affect the dose-response models, while underestimating the cell dimensions did induce a rescaling of the dose-response models. Conclusion These findings validate the use of simplified spherical models for CA20948 cells but highlight the importance of a correct estimation of the cell dimensions.

Contrary to group-based brain connectivity analyses, the aim of this study was to construct individual brain metabolic networks to determine age-related effects on brain metabolic connectivity. Static 40-60 minutes [18F]FDG PET images of 67 healthy subjects between 20-82 years were acquired with an integrated PET-MR system. Network nodes were defined by brain parcellation using the Schaefer atlas, while connectivity strength between two nodes was determined by comparing the distribution of PET uptake values within each node using a Kullback-Leibler divergence similarity estimation. After constructing individual brain networks, a linear and quadratic regression analysis of metabolic connectivity strengths within- and between networks was performed to model age-dependency. In addition, the age dependency of metrics for network integration (characteristic path length), segregation (clustering coefficient and local efficiency) and centrality (number of hubs) were assessed within the whole brain and within predefined functional subnetworks. Overall, a decrease of metabolic connectivity strength with healthy ageing was found within the whole brain network and several subnetworks except within the somatomotor, limbic and visual network. The same decrease of metabolic connectivity was found between several networks across the whole brain network and the functional subnetworks. In terms of network topology, a less integrated and less segregated network was observed with ageing, while the distribution and the number of hubs did not change with ageing, suggesting that brain metabolic networks are not reorganized during the adult lifespan. In conclusion, using an individual brain metabolic network approach, a decrease in metabolic connectivity strength was observed with healthy ageing, both within the whole brain and within several predefined networks. These findings can be used in a diagnostic setting to differentiate between age-related changes in brain metabolic connectivity strength and changes caused by early development of neurodegeneration.

Background Tau pathology in Alzheimer’s disease (AD) propagates trans-synaptically along structurally connected brain networks and in synergy with amyloid pathology it induces synaptic damage. However, the in vivo relationship of amyloid, tau and synaptic density with white matter (WM) structural changes has been studied rather limitedly. Recent advances in diffusion MRI processing allow quantification of apparent fibre density and fibre cross-section on the fixel level, i.e., individual fibre populations within one voxel. The aim of this study was to investigate the hypothesis of axonal loss due to tau propagation and amyloid pathology and its association with synaptic density in early disease stages. Methods Twenty-four patients with amnestic mild cognitive impairment (aMCI) and 23 healthy controls (HC) underwent baseline amyloid ( 11 C-PiB/ 18 F-NAV4694), tau ( 18 F-MK-6240) and synaptic density ( 11 C-UCB-J binding to SV2A) PET/MR in combination with diffusion MRI and cognitive assessments. A subset of 14 aMCI patients underwent follow-up visits after 2 years. First, a whole-brain fixel-based analysis was performed to identify differences in fibre density and fibre cross-section between HC and aMCI and longitudinally in the aMCI group. Next, a tract-of-interest analysis was performed, focusing on the temporal-cingulum bundle where most alterations have been shown in early AD. Tau and SV2A PET were quantified in the connected regions, i.e., hippocampus and posterior cingulate/precuneus (PCC-P). Amyloid PET centiloids were measured in the commonly used cortical composite volume-of-interest. Results At baseline, multiple WM tracts showed lower fibre density and lower fibre cross-section in aMCI compared to HC, and these parameters further decreased longitudinally in the aMCI group. In the temporal cingulum bundle, reduced fibre density was significantly associated with reduced hippocampal synaptic density while increased hippocampal and PCC-P tau specifically correlated with reduced fibre cross-section. Increased global amyloid burden was associated with reduced fibre density and fibre cross-section in the temporal cingulum bundle. Conclusions Our results suggest that WM degeneration already occurs in the aMCI stage of AD and alterations in apparent fibre density and fibre cross-section of the temporal cingulum bundle are associated with AD hallmark pathology.

Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.

Late-life depression has been consistently associated with lower gray matter volume, the origin of which remains largely unexplained. Recent in-vivo PET findings in early-onset depression and Alzheimer’s Disease suggest that synaptic deficits contribute to the pathophysiology of these disorders and may therefore contribute to lower gray matter volume in late-life depression. Here, we investigate synaptic density in vivo for the first time in late-life depression using the synaptic vesicle glycoprotein 2A receptor radioligand 11 C-UCB-J. We included 24 currently depressed adults with late-life depression (73.0 ± 6.2 years, 16 female, geriatric depression scale = 19.5 ± 6.8) and 36 age- and gender-matched healthy controls (70.4 ± 6.2 years, 21 female, geriatric depression scale = 2.7 ± 2.9) that underwent simultaneous 11 C-UCB-J positron emission tomography (PET) and 3D T1- and T2-FLAIR weighted magnetic resonance (MR) imaging on a 3-tesla PET-MR scanner. We used analyses of variance to test for 11 C-UCB-J binding and gray matter volumes differences in regions implicated in depression. The late-life depression group showed a trend in lower gray matter volumes in the hippocampus ( p  = 0.04), mesial temporal ( p  = 0.02) and prefrontal cortex ( p  = 0.02) compared to healthy control group without surviving correction for multiple comparison. However, no group differences in 11 C-UCB-J binding were found in these regions nor were any associations between 11 C-UCB-J and depressive symptoms. Our data suggests that, in contrast to Alzheimer’s Disease, lower gray matter volume in late-life depression is not associated with synaptic density changes. From a therapeutic standpoint, preserved synaptic density in late-life depression may be an encouraging finding.

PurposeHistone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer’s disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [18F]EKZ-001 ([18F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects.MethodsBiodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (VT) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. VT differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches.ResultsThe effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA VT were in agreement with 2TCM VT, however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional VT values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher VT than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported.Conclusion[18F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.