Pharmacokinetic analysis and simplified uptake measures for tumour lesion [18F]F-AraG PET imaging in patients with non-small cell lung cancer.

INTRODUCTION: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter. METHODS: Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals. RESULTS: Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60-70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01). CONCLUSION: Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.

Performance of simplified methods for quantification of [18F]NaF uptake in fibrodysplasia ossificans progressiva.

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a rare, genetic disease in which heterotopic bone is formed in muscles, tendons and ligaments throughout the body. Disease progression is variable over time and between individuals. 18F-fluoride uptake in newly formed bone can be evaluated using [18F]NaF (i.e., sodiumfluoride) PET/CT, identifying active areas of bone formation in FOP. The purpose of this study was to assess the performance of various semi-quantitative methods with full kinetic analysis. Results: Seven patients (age range: 20-31 years) with FOP underwent dynamic [18F]NaF scans at baseline and after one year. [18F]NaF uptake was measured in aorta descendens, vertebrae, heterotopic bone lesions and metabolically active regions on PET, and quantified using nonlinear regression (NLR) analysis together with standardized uptake value (SUV) and target-to-blood ratio (TBR). SUV was on measured the 40-45 min frame of the dynamic sequence (SUV40-45) and on the subsequent static sweep (SUVStatic). Correlations between and SUV40-45 and NLR-derived Ki were comparable when normalized to body weight (r = 0.81, 95% CI 0.64-0.90), lean body mass (r = 0.79, 95% CI 0.61-0.89) and body surface area (r = 0.84, 95% CI 0.70-0.92). Correlation between TBR40-45 and NLR-derived Ki (r = 0.92, 95% CI 0.85-0.96) was higher than for SUV40-45. Correlation between TBR40-45 and NLR-derived Ki was similar at baseline and after one year (r = 0.93 and 0.94). The change in TBR40-45 between baseline measurement and after one year correlated best with the change in NLR-derived Ki in the PET-active lesions (r = 0.87). Conclusion: The present data supports the use of TBR for assessing fluoride uptake in PET-active lesions in FOP. Clinical trial registration: Sub-study of the Lumina-1 trial (clinicaltrials.gov, NCT03188666, registered 13-06-2017).

The Early Perfusion Image Is Useful to Support the Visual Interpretation of Brain Amyloid-PET With 18F-Flutemetamol in Borderline Cases.

PURPOSE: Visual interpretation of brain amyloid-ß (Aß) PET can be difficult in individuals with borderline Aß burden. Coregistration with individual MRI is recommended in these cases, which, however, is not always available. This study evaluated coregistration with the early perfusion frames acquired immediately after tracer injection to support the visual interpretation of the late Aß-frames in PET with 18F-flutemetamol (FMM). PATIENTS AND METHODS: Fifty dual-time-window FMM-PET scans of cognitively normal subjects with 0 to 60 Centiloids were included retrospectively (70.1 ± 6.9 years, 56% female, MMSE score 28.9 ± 1.3, 42% APOE ɛ4 carrier). Regional Aß load was scored with respect to a 6-point Likert scale by 3 independent raters in the 10 regions of interest recommended for FMM reading using 3 different settings: Aß image only, Aß image coregistered with MRI, and Aß image coregistered with the perfusion image. The impact of setting, within- and between-readers variability, region of interest, and Aß-status was tested by repeated-measure analysis of variance of the Likert score. RESULTS: The Centiloid scale ranged between 2 and 52 (interquartile range, 7-19). Support of visual scoring by the perfusion image resulted in the best discrimination between Aß-positive and Aß-negative cases, mainly by improved certainty of excluding Aß plaques in Aß-negative cases (P = 0.030). It also resulted in significantly higher between-rater agreement. The setting effect was most pronounced in the frontal lobe and in the posterior cingulate cortex/precuneus area (P = 0.005). CONCLUSIONS: The early perfusion image is a suitable alternative to T1-weighted MRI to support the visual interpretation of the late Aß image in FMM-PET.

Ultra-low foetal radiation exposure in 18F-FDG PET/CT imaging with a long axial field-of-view PET/CT system.

PURPOSE: Long axial field-of-view (LAFOV) PET/CT systems enable PET/CT scans with reduced injected activities because of improved sensitivity. With this study, we aimed to examine the foetal radiation dose from an 18F-FDG PET/CT scan on a LAFOV PET/CT system with reduced injected activity. METHODS: Two pregnant women were retrospectively included and received an 18F-FDG PET/CT scan on a LAFOV PET/CT system with an intravenous bolus injection of 0.30 MBq/kg. Foetal radiation exposure from the PET was estimated using dose conversion factors from three published papers. Radiation exposure from the CT scans was estimated using CT-Expo. RESULTS: Foetal radiation dose from the PET scan ranged between 0.11 and 0.44 mGy. Foetal radiation exposure from the CT scan ranged between < 0.10 - 0.90 mGy depending if the foetus was included in the field-of-view. CONCLUSION: Foetal radiation dose could be reduced to < 1.5 mGy when scanning pregnant patients on a LAFOV PET/CT system. The radiation dose to the foetus was reduced significantly in our study due to the increased sensitivity of the LAFOV PET/CT system.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Validation of image-derived input function using a long axial field of view PET/CT scanner for two different tracers.

BACKGROUND: Accurate image-derived input function (IDIF) from highly sensitive large axial field of view (LAFOV) PET/CT scanners could avoid the need of invasive blood sampling for kinetic modelling. The aim is to validate the use of IDIF for two kinds of tracers, 3 different IDIF locations and 9 different reconstruction settings. METHODS: Eight [18F]FDG and 10 [18F]DPA-714 scans were acquired respectively during 70 and 60 min on the Vision Quadra PET/CT system. PET images were reconstructed using various reconstruction settings. IDIFs were taken from ascending aorta (AA), descending aorta (DA), and left ventricular cavity (LV). The calibration factor (CF) extracted from the comparison between the IDIFs and the manual blood samples as reference was used for IDIFs accuracy and precision assessment. To illustrate the effect of various calibrated-IDIFs on Patlak linearization for [18F]FDG and Logan linearization for [18F]DPA-714, the same target time-activity curves were applied for each calibrated-IDIF. RESULTS: For [18F]FDG, the accuracy and precision of the IDIFs were high (mean CF ≥ 0.82, SD ≤ 0.06). Compared to the striatum influx (Ki) extracted using calibrated AA IDIF with the updated European Association of Nuclear Medicine Research Ltd. standard reconstruction (EARL2), Ki mean differences were < 2% using the other calibrated IDIFs. For [18F]DPA714, high accuracy of the IDIFs was observed (mean CF ≥ 0.86) except using absolute scatter correction, DA and LV (respectively mean CF = 0.68, 0.47 and 0.44). However, the precision of the AA IDIFs was low (SD ≥ 0.10). Compared to the distribution volume (VT) in a frontal region obtained using calibrated continuous arterial sampler input function as reference, VT mean differences were small using calibrated AA IDIFs (for example VT mean difference = -5.3% using EARL2), but higher using calibrated DA and LV IDIFs (respectively + 12.5% and + 19.1%). CONCLUSIONS: For [18F]FDG, IDIF do not need calibration against manual blood samples. For [18F]DPA-714, AA IDIF can replace continuous arterial sampling for simplified kinetic quantification but only with calibration against arterial blood samples. The accuracy and precision of IDIF from LAFOV PET/CT system depend on tracer, reconstruction settings and IDIF VOI locations, warranting careful optimization.

Endocannabinoid levels in plasma and neurotransmitters in the brain: a preliminary report on patients with a psychotic disorder and healthy individuals.

BACKGROUND: Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. METHODS: Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [18F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. RESULTS: A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients (p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. CONCLUSIONS: Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.

Mitigating SUV uncertainties using total body PET imaging.

PURPOSE: Standardised uptake values (SUV) are commonly used to quantify 18F-FDG lesion uptake. However, SUVs may suffer from several uncertainties and errors. Long-axial field-of-view (LAFOV) PET/CT systems might enable image-based quality control (QC) by deriving 18F-FDG activity and weight from total body (TB) 18F-FDG PET images. In this study, we aimed to develop these image-based QC to reduce errors and mitigate SUV uncertainties. METHODS: Twenty-five out of 81 patient scans from a LAFOV PET/CT system were used to determine regression fits for deriving of image-derived activity and weight. Thereafter, the regression fits were applied to 56 independent 18F-FDG PET scans from the same scanner to determine if injected activity and weight could be obtained accurately from TB and half-body (HB) scans. Additionally, we studied the impact of image-based values on the precision of liver SUVmean and lesion SUVpeak. Finally, 20 scans were acquired from a short-axial field-of-view (SAFOV) PET/CT system to determine if the regression fits also applied to HB scans from a SAFOV system. RESULTS: Both TB and HB 18F-FDG activity and weight significantly predicted reported injected activity (r = 0.999; r = 0.984) and weight (r = 0.999; r = 0.987), respectively. After applying the regression fits, 18F-FDG activity and weight were accurately derived within 4.8% and 3.2% from TB scans and within 4.9% and 3.1% from HB, respectively. Image-derived values also mitigated liver and lesion SUV variability compared with reported values. Moreover, 18F-FDG activity and weight obtained from a SAFOV scanner were derived within 6.7% and 4.5%, respectively. CONCLUSION: 18F-FDG activity and weight can be derived accurately from TB and HB scans, and image-derived values improved SUV precision and corrected for lesion SUV errors. Therefore, image-derived values should be included as QC to generate a more reliable and reproducible quantitative uptake measurement.

Harmonization of brain PET images in multi-center PET studies using Hoffman phantom scan.

BACKGROUND: Image harmonization has been proposed to minimize heterogeneity in brain PET scans acquired in multi-center studies. However, standard validated methods and software tools are lacking. Here, we assessed the performance of a framework for the harmonization of brain PET scans in a multi-center European clinical trial. METHOD: Hoffman 3D brain phantoms were acquired in 28 PET systems and reconstructed using site-specific settings. Full Width at Half Maximum (FWHM) of the Effective Image Resolution (EIR) and harmonization kernels were estimated for each scan. The target EIR was selected as the coarsest EIR in the imaging network. Using "Hoffman 3D brain Analysis tool," indicators of image quality were calculated before and after the harmonization: The Coefficient of Variance (COV%), Gray Matter Recovery Coefficient (GMRC), Contrast, Cold-Spot RC, and left-to-right GMRC ratio. A COV% ≤ 15% and Contrast ≥ 2.2 were set as acceptance criteria. The procedure was repeated to achieve a 6-mm target EIR in a subset of scans. The method's robustness against typical dose-calibrator-based errors was assessed. RESULTS: The EIR across systems ranged from 3.3 to 8.1 mm, and an EIR of 8 mm was selected as the target resolution. After harmonization, all scans met acceptable image quality criteria, while only 13 (39.4%) did before. The harmonization procedure resulted in lower inter-system variability indicators: Mean ± SD COV% (from 16.97 ± 6.03 to 7.86 ± 1.47%), GMRC Inter-Quartile Range (0.040-0.012), and Contrast SD (0.14-0.05). Similar results were obtained with a 6-mm FWHM target EIR. Errors of ± 10% in the DRO activity resulted in differences below 1 mm in the estimated EIR. CONCLUSION: Harmonizing the EIR of brain PET scans significantly reduced image quality variability while minimally affecting quantitative accuracy. This method can be used prospectively for harmonizing scans to target sharper resolutions and is robust against dose-calibrator errors. Comparable image quality is attainable in brain PET multi-center studies while maintaining quantitative accuracy.

PET Imaging and Protein Expression of Prostate-Specific Membrane Antigen in Glioblastoma: A Multicenter Inventory Study.

Upregulation of prostate-specific membrane antigen (PSMA) in neovasculature has been described in glioblastoma multiforme (GBM), whereas vasculature in nonaffected brain shows hardly any expression of PSMA. It is unclear whether PSMA-targeting tracer uptake on PET is based on PSMA-specific binding to neovasculature or aspecific uptake in tumor. Here, we quantified uptake of various PSMA-targeting tracers in GBM and correlated this with PSMA expression in tumor biopsy samples from the same patients. Methods: Fourteen patients diagnosed with de novo (n = 8) or recurrent (n = 6) GBM underwent a preoperative PET scan after injection of 1.5 MBq/kg [68Ga]Ga-PSMA-11 (n = 7), 200 MBq of [18F]DCFpyl (n = 3), or 200 MBq of [18F]PSMA-1007 (n = 4). Uptake in tumor and tumor-to-background ratios, with contralateral nonaffected brain as background, were determined. In a subset of patients, PSMA expression levels from different regions in the tumor tissue samples (n = 40), determined using immunohistochemistry (n = 35) or RNA sequencing (n = 13), were correlated with tracer uptake on PET. Results: Moderate to high (SUVmax, 1.3-20.0) heterogeneous uptake was found in all tumors irrespective of the tracer type used. Uptake in nonaffected brain was low, resulting in high tumor-to-background ratios (6.1-359.0) calculated by dividing SUVmax of tumor by SUVmax of background. Immunohistochemistry showed variable PSMA expression on endothelial cells of tumor microvasculature, as well as on dispersed individual cells (of unknown origin), and granular staining of the neuropil. No correlation was found between in vivo uptake and PSMA expression levels (for immunohistochemistry, r = -0.173, P = 0.320; for RNA, r = -0.033, P = 0.915). Conclusion: Our results indicate the potential use of various PSMA-targeting tracers in GBM. However, we found no correlation between PSMA expression levels on immunohistochemistry and uptake intensity on PET. Whether this may be explained by methodologic reasons, such as the inability to measure functionally active PSMA with immunohistochemistry, tracer pharmacokinetics, or the contribution of a disturbed blood-brain barrier to tracer retention, should still be investigated.

Cognitive performance in multiple sclerosis: what is the role of the gamma-aminobutyric acid system?

Cognitive impairment occurs in 40-65% of persons with multiple sclerosis and may be related to alterations in glutamatergic and GABAergic neurotransmission. Therefore, the aim of this study was to determine how glutamatergic and GABAergic changes relate to cognitive functioning in multiple sclerosis in vivo. Sixty persons with multiple sclerosis (mean age 45.5 ± 9.6 years, 48 females, 51 relapsing-remitting multiple sclerosis) and 22 age-matched healthy controls (45.6 ± 22.0 years, 17 females) underwent neuropsychological testing and MRI. Persons with multiple sclerosis were classified as cognitively impaired when scoring at least 1.5 standard deviations below normative scores on ≥30% of tests. Glutamate and GABA concentrations were determined in the right hippocampus and bilateral thalamus using magnetic resonance spectroscopy. GABA-receptor density was assessed using quantitative [11C]flumazenil positron emission tomography in a subset of participants. Positron emission tomography outcome measures were the influx rate constant (a measure predominantly reflecting perfusion) and volume of distribution, which is a measure of GABA-receptor density. Twenty persons with multiple sclerosis (33%) fulfilled the criteria for cognitive impairment. No differences were observed in glutamate or GABA concentrations between persons with multiple sclerosis and healthy controls, or between cognitively preserved, impaired and healthy control groups. Twenty-two persons with multiple sclerosis (12 cognitively preserved and 10 impaired) and 10 healthy controls successfully underwent [11C]flumazenil positron emission tomography. Persons with multiple sclerosis showed a lower influx rate constant in the thalamus, indicating lower perfusion. For the volume of distribution, persons with multiple sclerosis showed higher values than controls in deep grey matter, reflecting increased GABA-receptor density. When comparing cognitively impaired and preserved patients to controls, the preserved group showed a significantly higher volume of distribution in cortical and deep grey matter and hippocampus. Positive correlations were observed between both positron emission tomography measures and information processing speed in the multiple sclerosis group only. Whereas concentrations of glutamate and GABA did not differ between multiple sclerosis and control nor between cognitively impaired, preserved and control groups, increased GABA-receptor density was observed in preserved persons with multiple sclerosis that was not seen in cognitively impaired patients. In addition, GABA-receptor density correlated to cognition, in particular with information processing speed. This could indicate that GABA-receptor density is upregulated in the cognitively preserved phase of multiple sclerosis as a means to regulate neurotransmission and potentially preserve cognitive functioning.

Genetically identical twin-pair difference models support the amyloid cascade hypothesis.

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-ß pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-ß and tau in an independent manner instead of there being a causal relationship between amyloid-ß and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-ß PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-ß)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-ß, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-ß were strongly associated with within-pair differences in tau (ß = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (ß = -0.37, P = 0.03) and memory functioning (ß = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (ß = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (ß = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-ß on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-ß to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-ß, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-ß on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.

Characterizing the Bone Marrow Environment in Advanced-Stage Myelofibrosis during Ruxolitinib Treatment Using PET/CT and MRI: A Pilot Study.

Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([15O]water, [18F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [15O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [18F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [15O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [18F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.

[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant.

PURPOSE: PET with 16α-[18F]-fluoro-17ß-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]-fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER-positive breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant. EXPERIMENTAL DESIGN: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES). Visual, quantitative, and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS). RESULTS: The HS and PFS in the entire group did not correlate (n = 16, Spearman's rho, P = 0.06), but patients with a low HS (< 25.0%, n = 4) had a PFS of > 5 months whereas patients with no [18F]FES uptake (HS 100.0%, n = 3) had a PFS of < 2 months. [18F]FES uptake was not affected by estrogen receptor 1 (ESR1) mutations. On-treatment [18F]FES PET/CT scans showed no [18F]FES uptake in any of the baseline [18F]FES-positive lesions. At progression, [18F]FES uptake remained blocked in patients scanned ≤ 1-2 half-lives of rintodestrant whereas it restored in patients scanned ≥ 5 days after end of treatment. CONCLUSIONS: Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs. See related commentary by Linden and Mankoff, p. 2015.

TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFß1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFß1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFß1 in both cell groups. We present for the first time TGFß1 as a triggering factor of Activin A production in FOP. As TGFß1 can promote the induction of the main driver of FOP, TGFß1 could also be considered a possible therapeutic target in FOP treatment.

NiftyPAD - Novel Python Package for Quantitative Analysis of Dynamic PET Data.

Current PET datasets are becoming larger, thereby increasing the demand for fast and reproducible processing pipelines. This paper presents a freely available, open source, Python-based software package called NiftyPAD, for versatile analyses of static, full or dual-time window dynamic brain PET data. The key novelties of NiftyPAD are the analyses of dual-time window scans with reference input processing, pharmacokinetic modelling with shortened PET acquisitions through the incorporation of arterial spin labelling (ASL)-derived relative perfusion measures, as well as optional PET data-based motion correction. Results obtained with NiftyPAD were compared with the well-established software packages PPET and QModeling for a range of kinetic models. Clinical data from eight subjects scanned with four different amyloid tracers were used to validate the computational performance. NiftyPAD achieved [Formula: see text] correlation with PPET, with absolute difference [Formula: see text] for linearised Logan and MRTM2 methods, and [Formula: see text] correlation with QModeling, with absolute difference [Formula: see text] for basis function based SRTM and SRTM2 models. For the recently published SRTM ASL method, which is unavailable in existing software packages, high correlations with negligible bias were observed with the full scan SRTM in terms of non-displaceable binding potential ([Formula: see text]), indicating reliable model implementation in NiftyPAD. Together, these findings illustrate that NiftyPAD is versatile, flexible, and produces comparable results with established software packages for quantification of dynamic PET data. It is freely available ( https://github.com/AMYPAD/NiftyPAD ), and allows for multi-platform usage. The modular setup makes adding new functionalities easy, and the package is lightweight with minimal dependencies, making it easy to use and integrate into existing processing pipelines.

Distinct disease mechanisms may underlie cognitive decline related to hearing loss in different age groups.

BACKGROUND: Hearing loss in older adults is associated with increased dementia risk. Underlying mechanisms that connect hearing loss with dementia remain largely unclear. METHODS: We studied the association of hearing loss and biomarkers for dementia risk in two age groups with normal cognition: 65 participants from the European Medical Information Framework (EMIF)-Alzheimer's disease (AD) 90+ study (oldest-old; mean age 92.7 years, 56.9% female) and 60 participants from the EMIF-AD PreclinAD study (younger-old; mean age 74.4, 43.3% female). Hearing function was tested by the 'digits-in-noise test' and cognition by repeated neuropsychological evaluation. Regressions and generalised estimating equations were used to test the association of hearing function and PET-derived amyloid burden, and linear mixed models were used to test the association of hearing function and cognitive decline. In the oldest-old group, mediation analyses were performed to study whether cognitive decline is mediated through regional brain atrophy. RESULTS: In oldest-old individuals, hearing function was not associated with amyloid pathology (p=0.7), whereas in the younger-old individuals hearing loss was associated with higher amyloid burden (p=0.0034). In oldest-old individuals, poorer hearing was associated with a steeper decline in memory, global cognition and language, and in the younger-old with steeper decline in language only. The hippocampus and nucleus accumbens mediated the effects of hearing loss on memory and global cognition in the oldest-old individuals. CONCLUSIONS: Hearing loss was associated with amyloid binding in younger-old individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.

The profile of cognitive impairment and hemodynamic compromise in moyamoya: a single-center prospective cohort study.

OBJECTIVE: Patients with moyamoya vasculopathy often experience cognitive impairments. In this prospective single-center study, the authors investigated the profile of neurocognitive impairment and its relation with the severity of ischemic brain lesions and hemodynamic compromise. METHODS: Patients treated in a Dutch tertiary referral center were prospectively included. All patients underwent standardized neuropsychological evaluation, MRI, digital subtraction angiography, and [15O]H2O-PET (to measure cerebrovascular reactivity [CVR]). The authors determined z-scores for 7 cognitive domains and the proportion of patients with cognitive impairment (z-score < -1.5 SD in at least one domain). The authors explored associations between patient characteristics, imaging and CVR findings, and cognitive scores per domain by using multivariable linear regression and Bayesian regression analysis. RESULTS: A total of 40 patients (22 children; 75% females) were included. The median age for children was 9 years (range 1-16 years); for adults it was 39 years (range 19-53 years). Thirty patients (75%) had an infarction, and 31 patients (78%) had impaired CVR (steal phenomenon). Six of 7 cognitive domains scored below the population norm. Twenty-nine patients (73%) had cognitive impairment. Adults performed better than children in the cognitive domain visuospatial functioning (p = 0.033, Bayes factor = 4.0), and children performed better in processing speed (p = 0.041, Bayes factor = 3.5). The authors did not find an association between infarction, white matter disease, or CVR and cognitive domains. CONCLUSIONS: In this Western cohort, cognitive functioning in patients with moyamoya vasculopathy was below the population norm, and 73% had cognitive impairment in at least one domain. The cognitive profile differed between adults and children. The authors could not find an association with imaging findings.

18F-sodium fluoride PET-CT visualizes both axial and peripheral new bone formation in psoriatic arthritis patients.

PURPOSE: As bone formation is associated with psoriatic arthritis (PsA), positron emission tomography (PET) using a 18F-Fluoride tracer may enable sensitive detection of disease activity. Our primary aim was to determine the feasibility of whole-body 18F-sodium fluoride PET-CT in clinically active PsA patients to depict new bone formation (as a reflection of disease activity) at peripheral joints and entheses. Our secondary aim was to describe 18F-sodium fluoride findings in the axial skeleton. METHODS: Sixteen patients (female 10/16, age 50.6 ± 8.9 years) with PsA fulfilling CASPAR criteria or with a clinical diagnosis of PsA according to the treating rheumatologist and with ≥ 1 clinically active enthesitis site were included. Of each patient, a whole-body 18F-sodium fluoride PET-CT scan was performed. All scans were scored for PET-positive lesions at peripheral joints, enthesis sites and the spine. Clinical disease activity was assessed by swollen/tender joint count 44, enthesitis according to MASES and SPARCC scores. RESULTS: Out of 1088 evaluated joints, 109 joints showed PET enhancement, mainly in the interphalangeal and metatarsal joints of the feet (14/109, 12.9%) and the distal interphalangeal joints of the hands (14/109, 12.9%). PET positivity was found at 44/464 enthesis sites, mainly at the patella tendon insertion (11/44, 25%) and quadriceps tendon insertion (10/44, 22.7%). Of the PET-positive joints and enthesis sites, respectively 18.2% and 29.5% were clinically positive; 81.8% and 70.5% of the PET-positive joints and entheses respectively were clinically asymptomatic. In 11 patients, ≥ 1 axial PET-positive lesion was observed, mainly in the cervical spine. CONCLUSIONS: New molecular bone formation was observed on 18F-sodium fluoride PET-CT scans, in all domains in which PsA disease activity can be observed, with a substantial part showing no clinical symptoms. CLINICAL TRIAL REGISTRATION: EudraCT: 2017-004,850-40, registered on 13 December 2017.