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Obesity is linked to increased risk for and severity of Alzheimer's disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We recently showed that non-flowing capillaries, caused by adhered neutrophils, contribute to CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensory-motor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd on capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting that capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study is to evaluate the diagnostic performance of simultaneous FDG-PET/MR including diffusion compared to FDG-PET/CT in patients with lymphoma. Methods: Eighteen patients with a confirmed diagnosis of non-Hodgkin's (NHL) or Hodgkin's lymphoma (HL) underwent an IRB-approved, single-injection/dual-imaging protocol consisting of a clinical FDG-PET/CT and subsequent FDG-PET/MR scan. PET images from both modalities were reconstructed iteratively. Attenuation correction was performed using low-dose CT data for PET/CT and Dixon-MR sequences for PET/MR. Diffusion-weighted imaging was performed. SUV was measured and compared between modalities and the apparent diffusion coefficient (ADC) using ROI analysis by an experienced radiologist using OsiriX. Strength of correlation between variables was measured using the Pearson correlation coefficient ( r). Results: Of the 18 patients included in this study, 5 had HL and 13 had NHL. The median age was 51 ± 14.8 years. Sixty-five FDG-avid lesions were identified. All FDG-avid lesions were visible with comparable contrast, and therefore initial and follow-up staging was identical between both examinations. SUV from FDG-PET/MR [(mean ± sem) (21.3 ± 2.07)] vs. FDG-PET/CT (mean 23.2 ± 2.8) demonstrated a strongly positive correlation [ r = 0.95 (0.94, 0.99); p < 0.0001]. There was no correlation found between ADC and SUV from FDG-PET/MR [ r = 0.17(−0.07, 0.66); p = 0.09]. Conclusion: FDG-PET/MR offers an equivalent whole-body staging examination as compared with PET/CT with an improved radiation safety profile in lymphoma patients. Correlation of ADC to SUV was weak, understating their lack of equivalence, but not undermining their potential synergy and differing importance. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine the accuracy of detection of small pulmonary nodules on quiet breathing attenuation correction CT (CTAC) and FDG-PET when performing integrated PET/CT, as compared with a diagnostic inspiratory CT scan acquired in the same imaging session. Methods: PET/CT scans of 107 patients with a history of carcinoma (54 male and 53 female, mean age 57.3 years) were analyzed. All patients received an integrated PET/CT scan including a CTAC acquired during quiet respiration and a contrast-enhanced CT acquired during inspiration in the same session. Breathing CTAC scans were reviewed by two thoracic radiologists for the presence of pulmonary nodules. FDG-PET scans were reviewed to determine accuracy of nodule detection. Diagnostic CT was used as the gold standard to confirm or refute the presence of nodules. Results: On the CTAC scans 200 nodules were detected, of which 183 were true positive (TP) and 17, false positive. There were 109 false negatives (FN). Overall, 51 (48%) patients had a false interpretation, including 19 in whom CT was interpreted as normal for lung nodules. The average size of the nodules missed was 3.8±2 mm (range 2-12 mm). None of the nodules missed on the CTAC scans were detected by PET. In the right lung there were 20 TP, 42 true negative (TN), 11 FP, and 34 FN interpretations with a sensitivity in nodule detection of 37% (CI 24-51%) and a specificity of 79% (CI 66-89%). In the left lungs there were 16 TP, 65 TN, 3 FP, and 23 FN interpretations, with a sensitivity of 41% (CI 26-58%) and a specificity of 96% (CI 88-99%). Conclusion: The detection of small pulmonary nodules by breathing CTAC and FDG-PET is relatively poor. Therefore an additional diagnostic thoracic CT scan obtained during suspended inspiration is recommended for thorough evaluation of those patients in whom detection of pulmonary metastases is necessary for management. [ABSTRACT FROM AUTHOR]

Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a time dependent drug-induced increase in field potential duration in the cardiac compartment in response to terfenadine and that response was modulated using a metabolically competent liver module that converted terfenadine to fexofenadine. Using this data, a mathematical model was developed to predict the effect of terfenadine in preclinical species. Developing confidence that microphysiological models could have a transformative effect on drug discovery, we also tested a previously discovered proprietary AstraZeneca small molecule and correctly determined the cardiotoxic response to its metabolite in the heart:liver system. Overall our findings serve as a guiding principle to future investigations of temporal concentration response relationships in these innovative in vitro models, especially, if validated across multiple time frames, with additional pharmacological mechanisms and molecules representing a broad chemical diversity. [ABSTRACT FROM AUTHOR]