Repeatability of arterial input functions and kinetic parameters in muscle obtained by dynamic contrast enhanced MR imaging of the head and neck

BACKGROUND: Quantification of pharmacokinetic parameters in dynamic contrast enhanced (DCE) MRI is heavily dependent on the arterial input function (AIF). In the present patient study on advanced stage head and neck squamous cell carcinoma (HNSCC) we have acquired DCE-MR images before and during chemo radiotherapy. We determined the repeatability of image-derived AIFs and of the obtained kinetic parameters in muscle and compared the repeatability of muscle kinetic parameters obtained with image-derived AIF's versus a population-based AIF. MATERIALS AND METHODS: We compared image-derived AIFs obtained from the internal carotid, external carotid and vertebral arteries. Pharmacokinetic parameters (ve, Ktrans, kep) in muscle-located outside the radiation area-were obtained using the Tofts model with the image-derived AIFs and a population averaged AIF. Parameter values and repeatability were compared. Repeatability was calculated with the pre- and post-treatment data with the assumption of no DCE-MRI measurable biological changes between the scans. RESULTS: Several parameters describing magnitude and shape of the image-derived AIFs from the different arteries in the head and neck were significantly different. Use of image-derived AIFs led to higher pharmacokinetic parameters compared to use of a population averaged AIF. Median muscle pharmacokinetic parameters values obtained with AIFs in external carotids, internal carotids, vertebral arteries and with a population averaged AIF were respectively: ve (0.65, 0.74, 0.58, 0.32), Ktrans (0.30, 0.21, 0.13, 0.06), kep (0.41, 0.32, 0.24, 0.18). Repeatability of pharmacokinetic parameters was highest when a population averaged AIF was used; however, this repeatability was not significantly different from image-derived AIFs. CONCLUSION: Image-derived AIFs in the neck region showed significant variations in the AIFs obtained from different arteries, and did not improve repeatability of the resulting pharmacokinetic parameters compared with the use of a population averaged AIF. Therefore, use of a population averaged AIF seems to be preferable for pharmacokinetic analysis using DCE-MRI in the head and neck area

Model selection criteria for dynamic brain PET studies

BACKGROUND: Several criteria exist to identify the optimal model for quantification of tracer kinetics. The purpose of this study was to evaluate the correspondence in kinetic model preference identification for brain PET studies among five model selection criteria: Akaike Information Criterion (AIC), AIC unbiased (AICC), model selection criterion (MSC), Schwartz Criterion (SC), and F-test. MATERIALS AND METHODS: Six tracers were evaluated: [11C]FMZ, [11C]GMOM, [11C]PK11195, [11C]Raclopride, [18F]FDG, and [11C]PHT, including data from five subjects per tracer. Time activity curves (TACs) were analysed using six plasma input models: reversible single-tissue model (1T2k), irreversible two-tissue model (2T3k), and reversible two-tissue model (2T4k), all with and without blood volume fraction parameter (V B). For each tracer and criterion, the percentage of TACs preferring a certain model was calculated. RESULTS: For all radiotracers, strong agreement was seen across the model selection criteria. The F-test was considered as the reference, as it is a frequently used hypothesis test. The F-test confirmed the AIC preferred model in 87% of all cases. The strongest (but minimal) disagreement across regional TACs was found when comparing AIC with AICC. Despite these regional discrepancies, same preferred kinetic model was obtained using all criteria, with an exception of one FMZ subject. CONCLUSION: In conclusion, all five model selection criteria resulted in similar conclusions with only minor differences that did not affect overall model selection

The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer’s disease

Purpose: The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer’s disease (AD) patients and healthy elderly controls. Methods: Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [[superscript 11]C]PIB to assess amyloid-β plaque load and [[superscript 18]F]FDG to assess glucose metabolism. [[superscript 11]C]PIB binding and [[superscript 18]F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. Results: While amyloid-β plaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho=0.56, p<0.05). Conclusion:The present study shows that in a group of AD patients amyloid-β plaque load as measured by [[superscript 11]C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [[superscript 18]F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration.Hersenstichting Nederland (KS2011(1)-24)Athinoula A. Martinos Center for Biomedical ImagingInternationale Stichting Alzheimer Onderzoek (Project Number 11539

[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: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-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+ breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant.PATIENTS AND METHODS: 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 (&lt;25.0%, n=4) had a PFS of &gt;5 months whereas patients with no [18F]FES uptake (HS 100.0%, n =3) had a PFS of &lt;2 months. [18F]FES uptake was not affected by 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.CONCLUSION: 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.</p

Predictive value of quantitative F-18-FDG-PET radiomics analysis in patients with head and neck squamous cell carcinoma

BACKGROUND: Radiomics is aimed at image-based tumor phenotyping, enabling application within clinical-decision-support-systems to improve diagnostic accuracy and allow for personalized treatment. The purpose was to identify predictive 18-fluor-fluoro-2-deoxyglucose (18F-FDG) positron-emission tomography (PET) radiomic features to predict recurrence, distant metastasis, and overall survival in patients with head and neck squamous cell carcinoma treated with chemoradiotherapy. METHODS: Between 2012 and 2018, 103 retrospectively (training cohort) and 71 consecutively included patients (validation cohort) underwent 18F-FDG-PET/CT imaging. The 434 extracted radiomic features were subjected, after redundancy filtering, to a projection resulting in outcome-independent meta-features (factors). Correlations between clinical, first-order 18F-FDG-PET parameters (e.g., SUVmean), and factors were assessed. Factors were combined with 18F-FDG-PET and clinical parameters in a multivariable survival regression and validated. A clinically applicable risk-stratification was constructed for patients' outcome. RESULTS: Based on 124 retained radiomic features from 103 patients, 8 factors were constructed. Recurrence prediction was significantly most accurate by combining HPV-status, SUVmean, SUVpeak, factor 3 (histogram gradient and long-run-low-grey-level-emphasis), factor 4 (volume-difference, coarseness, and grey-level-non-uniformity), and factor 6 (histogram variation coefficient) (CI = 0.645). Distant metastasis prediction was most accurate assessing metabolic-active tumor volume (MATV)(CI = 0.627). Overall survival prediction was most accurate using HPV-status, SUVmean, SUVmax, factor 1 (least-axis-length, non-uniformity, high-dependence-of-high grey-levels), and factor 5 (aspherity, major-axis-length, inversed-compactness and, inversed-flatness) (CI = 0.764). CONCLUSIONS: Combining HPV-status, first-order 18F-FDG-PET parameters, and complementary radiomic factors was most accurate for time-to-event prediction. Predictive phenotype-specific tumor characteristics and interactions might be captured and retained using radiomic factors, which allows for personalized risk stratification and optimizing personalized cancer care. TRIAL REGISTRATION: Trial NL3946 (NTR4111), local ethics commission reference: Prediction 2013.191 and 2016.498. Registered 7 August 2013, https://www.trialregister.nl/trial/3946

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-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β 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-β 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-β)-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-β, 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-β were strongly associated with within-pair differences in tau (β=0.68, p < 0.001), and moderately associated with within-pair differences in hippocampal volume (β=-0.37, p = 0.03) and memory functioning (β=-0.57, p < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β=-0.53, p < 0.001) and strongly associated with within-pair differences in memory functioning (β=-0.68, p < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β 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-β to tau to memory functioning (proportion mediated: 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β 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

Spatial concordance of DNA methylation classification in diffuse glioma.

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists