Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower Alzheimer's disease plaque formation and microglial activation in AßPP/PS-1 transgenic mouse brain.

Alzheimer's disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-ß (Aß). Activation of microglia, which closely associate with Aß plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aß fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aß-induced inflammation, we treated transgenic amyloid-ß protein protein/presenilin-1 (AßPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aß plaques was measured ex vivo in intact brains at 60 µm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AßPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aß plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aß plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2- fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aß plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction.

SPION-enhanced magnetic resonance imaging of Alzheimer's disease plaques in AßPP/PS-1 transgenic mouse brain.

In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimer's disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-ß plaques in AD. Here we report studies in AßPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AßPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.1 ± 0.5 to 8.3 ± 0.2 when the plaque contrast to noise ratio was compared in control AD mice with AD mice treated with SPIONs. The number of MRI-visible plaques per brain increased from 347 ± 45 in the control AD mice, to 668 ± 86 in the SPION treated mice. These results indicated that our SPION enhanced amyloid-ß detection method delivers an efficacious, non-invasive MRI detection method in transgenic mice.

Thoracic radiography of pet macaques in Sulawesi, Indonesia.

This report describes the results from a study of thoracic radiographs taken on a sample (n = 20) of pet macaque monkeys (Macaca) on the Indonesian island of Sulawesi. We present findings relating to general thoracic health, as well as describe our field methods and outline some of the challenges of conducting thoracic radiography in remote areas of the developing world. Examination of the radiographic images identified six possible cases of cardiac enlargement, and one case of minor lung consolidation possibly consistent with tuberculosis. The study did not identify major radiographic evidence of significant respiratory illness in the monkeys as might be expected based on the intense exposure to human respiratory diseases. These largely negative findings may be in part a consequence of image quality which seems to be influenced by power output and incomplete inspiration during film exposure.

Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster.

BACKGROUND: Pancreatic cholesterol esterase has three proposed functions in the intestine: 1) to control the bioavailability of cholesterol from dietary cholesterol esters; 2) to contribute to incorporation of cholesterol into mixed micelles; and 3) to aid in transport of free cholesterol to the enterocyte. Inhibitors of cholesterol esterase are anticipated to limit the absorption of dietary cholesterol. RESULTS: The selective and potent cholesterol esterase inhibitor 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone (figure 1, structure 1) was administered to hamsters fed a high cholesterol diet supplemented with radiolabeled cholesterol ester. Hamsters were gavage fed 3H-labeled cholesteryl oleate along with inhibitor 1, 0-200 micromoles. Twenty-four hours later, hepatic and serum radioactive cholesterol levels were determined. The ED50 of inhibitor 1 for prevention of the uptake of labeled cholesterol derived from hydrolysis of labeled cholesteryl oleate was 100 micromoles. The toxicity of inhibitor 1 was investigated in a 30 day feeding trial. Inhibitor 1, 100 micromoles or 200 micromoles per day, was added to chow supplemented with 1% cholesterol and 0.5% cholic acid. Clinical chemistry urinalysis and tissue histopathology were obtained. No toxicity differences were noted between control and inhibitor supplemented groups. CONCLUSIONS: Inhibitors of cholesterol esterase may be useful therapeutics for limiting cholesterol absorption.