Sarah Ceyssens

Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity, inter-observer variability and prognostic value

Purpose18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) PET imaging studies allow the investigation of metabolism and amino acid transport in brain tumours. Their (relative) usefulness and prognostic value in suspected recurrence or progression of primary brain tumours after previous therapy is an issue of debate. The aim of this study was to compare directly both radioligands in this setting.MethodsCerebral uptake of FDG and MET was determined sequentially on the same day in 30 patients (21 males, nine females; age 40.4±15.6 years), on average 4.0 years (range 0.1–18) after therapy for a primary brain tumour (23 grade II–IV astrocytomas, four oligodendrogliomas and three mixed oligo-astrocytomas). Images were acquired on a Siemens HR+ dedicated PET camera. Two observers scored FDG and MET scans independently. Semi-quantitative indices defined by the tumour (maximum)-to-background ratio were calculated based on manual ROI delineation and by using MET ROIs for FDG after automated co-registration. Patient follow-up was conducted until the last contact with inconspicuous clinical findings (average 41 months, range 12–62 months after PET) [(n=10)] or until death (n=20).ResultsOverall median survival was 15.0 months. MET showed pathologically increased uptake in 28/30 scans, and FDG in 17/30. The inter-observer agreement was 100% for MET and 73% for FDG. Using Kaplan-Meier survival analysis, significant differences were found for both FDG (cut-off 0.8, log-rank p=0.007) and MET (cut-off 2.2, log-rank p=0.014). The combination of FDG and MET information resulted in the highest prognostic accuracy (p=0.003), while MET alone was the best prognostic predictor in the subgroup of patients with primary astrocytoma (n=23).Conclusion FDG and MET PET studies provide complementary prognostic information in patients with suspected brain tumour recurrence or progression after primary therapy. MET is considered the single agent of choice in the evaluation of these patients because of its sensitivity and clearer delineation of the suspected recurrence.

Evaluation of anatomy based reconstruction for partial volume correction in brain FDG-PET

UNLABELLED FDG-PET contributes to the diagnosis and management of neurological diseases. In some of these diseases, pathological gray matter (GM) areas may have a reduced FDG uptake. Detection of these regions can be difficult and some remain undiscovered using visual assessment. The main reason for this detection problem is the relatively small thickness of GM compared to the spatial resolution of PET, known as the partial volume effect. We have developed an anatomy-based maximum-a-posteriori reconstruction algorithm (A-MAP) which corrects for this effect during the reconstruction using segmented magnetic resonance (MR) data. Monte-Carlo based 3-D brain software phantom simulations were used to investigate the influence of the strength of anatomy-based smoothing in GM, the influence of misaligned MR data, and the effect of local segmentation errors. A human observer study was designed to assess the detection performance of A-MAP versus post-smoothed maximum-likelihood (ML) reconstruction. We demonstrated the applicability of A-MAP using real patient data. The results for A-MAP showed improved recovery values and robustness for local segmentation errors. Misaligned MR data reduced the recovery values towards those obtained by post-smoothed ML, for small registration errors. In the human observer study, detection accuracy of hypometabolic regions was significantly improved using A-MAP, compared to post-smoothed ML (P < 0.004). The patient study confirmed the applicability of A-MAP in clinical practice. CONCLUSION A-MAP is a promising technique for voxel-based partial volume correction of FDG-PET of the human brain.

The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer

Background Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC). Methods Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions. Results Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8–10.5) and 4.2 months (95% CI: 3.4–4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21–0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36–0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS. Conclusion The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC. Trial Registration ClinicalTrials.gov NCT01290926

Validation of the semi-quantitative static SUVR method for [18F]-AV45 PET by pharmacokinetic modeling with an arterial input function

Increased brain uptake of 18F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (VT) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min 18F-AV45 (291 ± 67 MBq) and 1-min 15O-H2O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18F-AV45 VT was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50–60 min after injection, using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by 15O-H2O SUV. Data are presented as mean ± SEM. Results: There was rapid metabolization of 18F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with VT, differences in cortical Aβ load between aMCI and AD were overestimated by SUVRWM (+4% ± 2%) and underestimated by SUVRCB (−10% ± 2%). VT correlated better with SUVRWM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVRCB (Pearson r: from 0.51 for temporal lobe [P = 0.002] to 0.82 for precuneus [P < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. 15O-H2O data showed that blood flow was decreased in AD compared with aMCI in cortical regions (−5% ± 1%) and in the reference regions (CB, −9% ± 8%; WM, −8% ± 8%). Conclusion: Increased brain uptake of 18F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.

The Cerebrospinal Fluid Aβ1–42/Aβ1–40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer’s Disease in a Clinical Setting

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1–42/Aβ1–40 ratio is used as compared to CSF Aβ1–42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer’s disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1–42, Aβ1–40, T-tau, P-tau181). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1–42/Aβ1–40 was applied compared to Aβ1–42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusions: The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1–42/Aβ1–40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

[18F]PBR111 PET Imaging in Healthy Controls and Schizophrenia: Test – Retest Reproducibility and Quantification of Neuroinflammation

Activated microglia express the translocator protein (TSPO) on the outer mitochondrial membrane. 18F-PBR111 is a second-generation PET ligand that specifically binds the TSPO, allowing in vivo visualization and quantification of neuroinflammation. The aim of this study was to evaluate whether the test–retest variability of 18F-PBR111 in healthy controls is acceptable to detect a psychosis-associated neuroinflammatory signal in schizophrenia. Methods: Dynamic 90-min 18F-PBR111 scans were obtained in 17 healthy male controls (HCs) and 11 male schizophrenia patients (SPs) during a psychotic episode. Prior genotyping for the rs6917 polymorphism distinguished high-affinity binders (HABs) and mixed-affinity binders (MABs). Total volume of distribution (VT) was determined from 2-tissue-compartment modeling with vascular trapping and a metabolite-corrected plasma input function. A subgroup of HCs (n = 12; 4 HABs and 8 MABs) was scanned twice to assess absolute test–retest variability and intraclass correlation coefficients of the regional VT values. Differences in TSPO binding between HC and SP were assessed using mixed model analysis adjusting for age, genotype, and age*cohort. The effect of using different scan durations (VT-60 min versus VT-90 min) was determined based on Pearson r. Data were mean ± SD. Results: Mean absolute variability in VT ranged from 16% ± 14% (19% ± 20% HAB; 15% ± 11% MAB) in the cortical gray matter to 22% ± 15% (23% ± 15% HAB; 22% ± 16% MAB) in the hippocampus. Intraclass correlation coefficients were consistently between 0.64 and 0.82 for all tested regions. TSPO binding in SP compared with HC depended on age (cohort*age: P < 0.05) and was increased by +14% ± 4% over the regions. There was a significant effect of genotype on TSPO binding, and VT of HABs was 31% ± 8% (HC: 17% ± 5%, SP: 61% ± 14%) higher than MABs. Across all clinical groups, VT-60 min and VT-90 min were strongly correlated (r > 0.7, P < 0.0001). Conclusion: 18F-PBR111 can be used for monitoring of TSPO binding, as shown by medium test–retest variability and reliability of VT in HCs. Microglial activation is present in SPs depending on age and needs to be adjusted for genotype.

BLOOD FLOW–INDEPENDENT QUANTIFICATION OF [18F]-AV45 PET USING MODEL-BASED KINETICS WITH A METABOLITE-CORRECTED ARTERIAL INPUT FUNCTION

tex yielded a 0.664 AUC to distinguish between MCI converters and non-converters. Of the available regions from the FreeSurfer atlas, the Right Inferior Temporal was the most sensitive (AUC 1⁄4 0.698). Results for the next best other individual regions are shown in Table 2. The Lasso method selected a composite region made of 15 subregions (see Table 1), showing marginally higher sensitivity (AUC 1⁄4 0.700). Conclusions:While a regional analysis of cortical thickness best predicts conversion to AD, compared towhole cortex analysis, looking for an optimal aggregation did not provide significantly better results. Nevertheless, such approach may be more robust to image quality issues, which is to be further confirmed on other datasets. A similar analysis will be performed on longitudinal data in order to determine which single or composite region would provide the best effect size when measuring change in cortical thickness over time.

How to Perform Translocator Protein PET-CT Scanning for Microglial Activation in Schizophrenia Patients.

Introduction Activated microglia express translocator protein (TSPO) on the outer mitochondrial membrane. PET ligands targeting TSPO allow in vivo non-invasive visualization and quantification of neuroinflammation. Whereas inflammation in schizophrenia was previously studied using 11 C-PK11195, 18 F-PBR111 is a novel second-generation tracer, with high specific TSPO binding and longer half-life. Objective To establish a protocol for 18 F-PBR111 TSPO PET in schizophrenia. Methods A pilot study on a Siemens Biograph mCT PET-scanner in healthy controls and schizophrenia patients (n=9). Results Subjects underwent a 90-minute dynamic brain PET-CT, following i.v. bolus injection of 214±13 MBq 18 F-PBR111. An arterial input function was measured using continuous blood sampling (Twilite, Switzerland) with discrete samples for metabolite analysis. The metabolite corrected plasma input function (IPF) was calculated from the whole blood input function, individual plasma to whole blood and parent fraction data as determined by a SEP-PAK procedure. Dynamic PET data were reconstructed and a post-reconstruction motion correction was applied. Regional tissue time activity curves (TACs) were extracted from the PET images for regions of interest determined from individual MRI images. Total volume of distribution (V T ) was then calculated from fitting a reversible two-tissue compartmental model to the measured TACs using the individual IPF. Prior genotyping for TSPO receptor polymorphism (rs6971) allowed to exclude low-affinity binders (estimated 10% of European population). The procedure was well tolerated. Conclusions We established a protocol for 18 F-PBR111 TSPO PET in healthy subjects and schizophrenia patients, thereby providing useful information for others considering 18 F-PBR111 TSPO PET imaging for evaluation of neuroinflammation.