The progression of b-amyloid deposition in the brains of mice overexpressing Swedish mutant b-amyloid precursor protein (APPSwe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel b-amyloid tracer 18 Fflorbetaben. Methods: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of 18 F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BP ND ) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of b-amyloid plaque load. Results: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BP ND based on the entire dynamic emission recordings. 18 F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P , 0.01) in cortical 18 F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P , 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P , 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R 5 0.95, P , 0.001). Conclusion: In the first longitudinal PET study in an AD mouse model using the novel b-amyloid tracer 18 F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.
ObjectivesIn recent years several [18F]-labelled amyloid PET tracers have been developed and have obtained clinical approval. There is accumulating evidence that early (post injection) acquisitions with these tracers are equally informative as conventional blood flow and metabolism studies for diagnosis of Alzheimer's disease, but there have been few side-by-side studies. Therefore, we investigated the performance of early acquisitions of [18F]-florbetaben (FBB) PET compared to [18F]-fluorodeoxyglucose (FDG) PET in a clinical setting.MethodsAll subjects were recruited with clinical suspicion of dementia due to neurodegenerative disease. FDG PET was undertaken by conventional methods, and amyloid PET was performed with FBB, with early recordings for the initial 10 min (early-phase FBB), and late recordings at 90–110 min p.i. (late-phase FBB). Regional SUVR with cerebellar and global mean normalization were calculated for early-phase FBB and FDG PET. Pearson correlation coefficients between FDG and early-phase FBB were calculated for predefined cortical brain regions. Furthermore, a visual interpretation of disease pattern using 3-dimensional stereotactic surface projections (3D-SSP) was performed, with assessment of intra-reader agreement.ResultsAmong a total of 33 patients (mean age 67.5 ± 11.0 years) included in the study, 18 were visually rated amyloid-positive, and 15 amyloid-negative based on late-phase FBB scans. Correlation coefficients for early-phase FBB vs. FDG scans displayed excellent agreement in all target brain regions for global mean normalization. Cerebellar normalization gave strong, but significantly lower correlations. 3D representations of early-phase FBB visually resembled the corresponding FDG PET images, irrespective of the amyloid-status of the late FBB scans.ConclusionsEarly-phase FBB acquisitions correlate on a relative quantitative and visual level with FDG PET scans, irrespective of the amyloid plaque density assessed in late FBB imaging. Thus, early-phase FBB uptake depicts a metabolism-like image, suggesting it as a valid surrogate marker for synaptic dysfunction, which could ultimately circumvent the need for additional FDG PET investigation in diagnosis of dementia.
Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (IRAEs). Characterisation and data on treatment of musculoskeletal IRAEs are scarce. In this cohort study, patients receiving ICI therapy who experienced arthralgia were evaluated for the presence of synovitis. Data on demographics, ICI regime, time of onset, imaging and response to therapy of synovitis were prospectively collected. Arthritis was demonstrated in 14 of 16 patients of whom 7 showed monarthritis, 5 had oligoarthritis and 2 had polyarthritis. Patients with ICI-induced arthritis were predominantly male (57%) and seronegative (69%). Regarding the detection of synovitis in staging imaging, moderate sensitivity for contrast-enhanced CT with PET-CT as reference was observed. Disease burden at baseline was high and was significantly reduced after anti-inflammatory treatment. Nine patients were treated with systemic and eight patients with intra-articular glucocorticoids. Six patients who flared on glucocorticoid treatment on tapering were given methotrexate resulting in long-term remission. Patients with synovitis were more likely to have good tumour response. Patients with ICI-induced arthritis were predominantly male and seronegative showing different patterns of arthritis with high disease burden. Good efficacy and safety was observed for methotrexate, particularly for ICI-induced polyarthritis.
Early TBRmax assessment (5-15 min p.i.) is more accurate for the differentiation between LGG and HGG than the standard static scan (20-40 min p.i.) mainly caused by the characteristic high (18)F-FET uptake of HGG in the initial phase. Therefore, when dynamic (18)F-FET-PET cannot be performed, early TBRmax assessment can be considered as an alternative for tumour grading.
Relative to gold standard ex vivo results, microPET estimates of DMFP BP(ND) were unbiased, whereas FP BP(ND) in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D(2/3)-receptors in striatum of living mice.
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