Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease

Introduction: Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-beta aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods: Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe, PS1 M146V, and PS1 E Delta 9 mutations, 13 sporadic AD, and 14 control cases. Results: H-3-PIB, H-3-florbetaben, H-3-AZD2184, and BTA-1 shared a high-and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The H-3-AZD2184 and H-3-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on H-3-AZD84 binding followed by H-3-florbetaben and minimal on H-3-PIB. Discussion: This study implies amyloid tracers of different structures detect different sites on amyloid-beta fibrils or conformations. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.Peer reviewe

Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing

Ventilation Distribution Studies Comparing Technegas and ""Gallgas"" Using (68)GaCl(3) as the Label

Ventilation distribution can be assessed by SPECT with Technegas. This study was undertaken in piglets with different degrees of ventilation inhomogeneity to compare PET using (68)Ga-labeled pseudogas or ""Gallgas"" with Technegas. Methods: Twelve piglets were studied in 3 groups: control, lobar obstruction, and diffuse airway obstruction. Two more piglets were assessed for lung volume (functional residual capacity). Results: In controls, SPECT and PET images showed an even distribution of radioactivity. With lobar obstruction, the absence of ventilation of the obstructed lobe was visible with both techniques. In diffuse airway obstruction, SPECT images showed an even distribution of radioactivity, and PET images showed more varied radioactivity over the lung. Conclusion: PET provides detailed ventilation distribution images and a better appreciation of ventilation heterogeneity. Gallgas with PET is a promising new diagnostic tool for the assessment of ventilation distribution.Uppsala UniversityCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)-Ministry of Education, BrazilGE Healthcar

Amyloid-beta Positron Emission Tomography Imaging Probes:A Critical Review

<p>The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.</p>