[18F]-florbetaben PET/CT Imaging in the Alzheimer's Disease Mouse Model APPswe/PS1dE9.

BACKGROUND: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aß), a pathological hallmark of Alzheimer's disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aß plaques. METHODS: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aß plaque load in cortex, hippocampus and cerebellum were analyzed. RESULTS: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. CONCLUSION: The findings suggest that histopathological characteristics of Aß plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure.

BACKGROUND: Activation of the receptor for advanced glycation endproducts (RAGE) causes sustained activation of multiple inflammatory pathways. Therefore, RAGE has potential as a new therapeutic target in sepsis. The aim of this study was to analyse whether RAGE blockade in vivo prevents microcirculatory dysfunction and subsequent tissue injury in endotoxaemic liver failure. METHODS: The hepatic microcirculation was analysed using intravital fluorescence microscopy in murine livers exposed to galactosamine/lipopolysaccharide (G/L) and treated with an anti-RAGE antibody (abRAGE) either 12 h before or h after exposure to G/L. Blood and liver tissue samples were harvested for analysis of leucocyte tissue infiltration, apoptotic and necrotic damage as well as RAGE downstream pathway signalling. RESULTS: Sinusoidal perfusion failure in livers exposed to G/L was reduced significantly by both pretreatment and post-treatment with abRAGE. Hepatic inflammation induced by exposure to G/L was also attenuated by abRAGE administration, as shown by a 55 per cent reduction in sinusoidal leucocyte stasis, a 65 per cent decrease in venular leucocyte rolling and adhesion, and an 85 per cent reduction in leucocyte tissue infiltration. Treatment with abRAGE markedly reduced hepatocellular apoptosis and necrosis in livers exposed to G/L, and blunted the rise in plasma high-mobility group protein B1 levels. Finally, G/L-induced activation of the mitogen-activated protein kinase cascade was also reduced significantly by blockade of RAGE. CONCLUSION: RAGE plays an important role in mediating endotoxaemic liver damage. RAGE blockade may have potential therapeutic value. SURGICAL RELEVANCE: The innate immune response to endoxaemia is initiated by a group of pattern recognition receptors, including the receptor for advanced glycation endproducts (RAGE). As RAGE is well known for perpetuation of inflammatory processes, blockade of this receptor might be of particular value in reducing or even halting endoxaemia-related organ disorders. Using intravital fluorescence microscopy this study demonstrated in vivo that pretreatment, but also post-treatment, with a RAGE-blocking antibody attenuated hepatic microcirculatory deterioration and leucocyte recruitment, and thus diminished liver injury in a murine model of endotoxaemic organ failure. These data underline the important role of RAGE in the innate immune response and support the potential therapeutic value of blocking this pattern recognition receptor.

Diabetes aggravates acute pancreatitis and inhibits pancreas regeneration in mice.

AIMS/HYPOTHESIS: It is well established that acute pancreatitis often causes diabetes and that a high blood glucose level associated with pancreatitis is a marker of poor prognosis. The aim of this study was to evaluate if diabetes merely reflects the severity of pancreatitis or whether it can also aggravate the progression of this disease in a vicious circle. METHODS: Reversible acute oedematous pancreatitis was induced in untreated and streptozotocin-treated diabetic mice by injection of cerulein. Progression of pancreatitis was studied by immunohistochemistry, ELISA and various other enzyme assays. The production of regenerating islet-derived 3ß (REG3ß) was determined by western blot and immunohistochemistry. RESULTS: While cerulein treatment in non-diabetic mice resulted in acute pancreatitis followed by regeneration of the pancreas within 7 days, diabetes aggravated pancreatitis, inhibited the regeneration of the exocrine tissue and led to strong atrophy of the pancreas. The aggravation of pancreatitis by diabetes was characterised by decreased production of the anti-inflammatory protein REG3ß, increased inflammation, augmented oedema formation and increased cell death during the acute phase of pancreatitis (p < 0.05). During the regenerative phase, diabetes augmented inflammation, increased cell death, reduced acinar cell expansion and increased the expansion of duct as well as interstitial cells, resulting in the formation of tubular complexes (p < 0.05). Administration of insulin reversed the observed phenotype in diabetic mice. CONCLUSIONS/INTERPRETATION: Diabetes aggravates acute pancreatitis and suppresses regeneration of the exocrine tissue. Thus, diabetes is not just a concomitant phenomenon of pancreatitis, but can have a fundamental influence on the progression of acute pancreatitis.