Jean-Baptiste Langlois

MRI Monitoring of Neuroinflammation in Mouse Focal Ischemia

Background and Purpose— A growing body of evidence suggests that inflammatory processes are involved in the pathophysiology of stroke. Phagocyte cells, involving resident microglia and infiltrating macrophages, secrete both protective and toxic molecules and thus represent a potential therapeutic target. The aim of the present study was to monitor phagocytic activity after focal cerebral ischemia in mice. Methods— Ultrasmall superparamagnetic particles of iron oxide (USPIO) were intravenously injected after permanent middle cerebral artery occlusion and monitored by high resolution MRI for 72 hours. Results— We here present the first MRI data showing in vivo phagocyte-labeling obtained in mice with focal cerebral ischemia. USPIO-enhanced MRI kinetic analysis disclosed an inflammatory response surrounding the ischemic lesion and in the contralateral hemisphere via the corpus callosum. The imaging data collected during the first 36 hours postinjury suggested a spread of USPIO-related signal from ipsi- to contralateral hemisphere. Imaging data correlated with histochemical analysis showing inflammation remote from the lesion and ingestion of nanoparticles by microglia/macrophages. Conclusions— The present study shows that MR-tracking of phagocyte cells is feasible in mice, which may have critical therapeutic implications given the potential neurotoxicity of activated microglia/macrophages in central nervous system disorders.

Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma

BackgroundGlioblastoma (GBM) is the most frequent and aggressive type of adult brain tumor. Most GBMs express telomerase; a high level of intra-tumoral telomerase activity (TA) is predictive of poor prognosis. Thus, telomerase inhibitors are promising options to treat GBM. These inhibitors increase the response to radiotherapy (RT), in vitro as well as in vivo. Since typical treatments for GBM include RT, our objective was to evaluate the efficiency of Imetelstat (TA inhibitor) combined with RT.FindingsWe used a murine orthotopic model of human GBM (N = 8 to11 mice per group) and μMRI imaging to evaluate the efficacy of Imetelstat (delivered by intra-peritoneal injection) alone and combined with RT. Using a clinically established protocol, we demonstrated that Imetelstat significantly: (i) inhibited the TA in the very center of the tumor, (ii) reduced tumor volume as a proportion of TA inhibition, and (iii) increased the response to RT, in terms of tumor volume regression and survival increase.ConclusionsImetelstat is currently evaluated in refractory brain tumors in young patients (without RT). Our results support its clinical evaluation combined with RT to treat GBM.

3D region growing integrating adaptive shape prior

We propose an automated region growing integrating adaptive shape prior in order to segment biomedical images. In our work, the segmentation method is improved by taking into account a shape reference model by non-linear way. Thus, the proposed method is driven by statistical data computed from the evolving region and by a priori shape information given by the model. An improvement of the method is proposed by adapting automatically the degree of integration of shape prior for each pixel of the image. The proposed method was applied for segmenting 3D micro-CT image of mouse skull in the framework of small animal imaging. The method gives promising results and appears to be well adapted to the context.

Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given Ad libitum in Old ApoE−/− Mice

Aim: Advanced atherosclerosis increases inflammation and stroke risk in the cerebral vasculature. Exercise is known to improve cardio-metabolic profiles when associated with a caloric restriction, but it remains debated whether it is still beneficial without the dietary control. The aim of this study was to determine both the peripheral and central effects of exercise training combined with a cholesterol-rich diet given ad libitum in old ApoE−/− mice. Methods: Forty-five-weeks old obese ApoE−/− mice fed with a high cholesterol diet ad libitum were divided into Exercise-trained (EX; running wheel free access) and Sedentary (SED) groups. Insulin tolerance and brain imaging were performed before and after the twelve-weeks training. Tissue insulin resistance, oxidative stress, and inflammation markers in plasma, aorta, and brain were then assessed. Results: In EX ApoE−/− mice, no beneficial effect of exercise was observed on weight, abdominal fat, metabolic parameters, oxidative stress, or inflammation compared to SED. Despite the regular exercise training in ApoE−/− EX mice (mean of 12.5 km/week during 12 weeks), brain inflammation imaging score was significantly associated with increased blood brain barrier (BBB) leakage evaluated by imaging follow-up (r2 = 0.87; p = 0.049) with a faster evolution compared to SED ApoE−/−mice. Conclusion: We conclude that in a context of high cardio-metabolic risk, exercise does not provide any protective effect in old ApoE−/− animals under high cholesterol diet given ad libitum. Peripheral (insulin sensitivity and oxidative/inflammatory status) but also central features (BBB preservation and protection against inflammation) did not show any benefits of exercise. Indeed, there was a fast induction of irreversible brain damage that was more pronounced in exercise-trained ApoE−/− mice.

Does acute behavioral testing reflect successful ischemia in rats with transient middle cerebral artery occlusion

Background Models of intraluminal middle cerebral artery occlusion present an intrinsic variability in infarct size. Behavioral evaluation is frequently performed during arterial occlusion to confirm success of surgery. Aims and/or hypothesis We compared the value of behavioral testing and multimodal magnetic resonance imaging performed during arterial occlusion for identifying successfully operated animals. Methods Rats were tested with behavioral assessment (using three scoring scales and the adhesive removal test) and multimodal magnetic resonance imaging (including magnetic resonance angiography, diffusion-weighted and perfusion-weighted imaging), both performed during the two-hours of middle cerebral artery occlusion using the intraluminal suture model. Behavioral assessment was repeated 24 h after reperfusion, followed by sacrifice. Results Acute apparent diffusion coefficient lesion volume was correlated with both 2,3,5-triphenyl tetrazolium chloride infarct size (r = 0.75, P = 0.02) and behavioral status (r = 0.66, P = 0.05) on day one. Conversely, no correlation was found between acute behavioral examination and day one outcomes (2,3,5-triphenyl tetrazolium chloride infarct volume, r = 0.40, P = 0.28; behavioral examination, r = 0.39, P = 0.30). Day zero apparent diffusion coefficient volumes (P = 0.04), but not behavioral assessment (P = 0.60), discriminated animals with day one corticostriatal infarcts from these with subcortical infarcts. Conclusions Acute behavioral testing performed during arterial occlusion fails to identify successfully operated animals. Acute diffusion magnetic resonance imaging may be more appropriate to assess and reduce infarct size variability in this model.

Multimodal imaging for the detection and characterization of liver lesions in a mouse model of neuroendocrine tumor

BACKGROUND The aim of this study was to compare in vivo magnetic resonance imaging (MRI) and ex vivo autoradiography with histopathological results for the detection and characterization of liver lesions in an experimental model of human neuroendocrine tumors. MATERIAL AND METHODS Intestinal STC-1 endocrine tumor cells were injected into 30 nude mice to achieve hepatic dissemination. Seven to 30 days after injection, T2-weighted in vivo images covering the entire liver were acquired with a 7-T system. Autoradiographs were also obtained in 28 mice after injection of fluorodeoxyglucose (18F-FDG). The autoradiographic liver samples were then stained with an antichromogranin antibody before histological analysis. Tumor size and the hepatic tumor fraction were measured using the three imaging modalities. RESULTS Metastatic tumors visualized on the histological liver sections ranged in size from 50 microm (day 7) to 3 mm (day 30). The hepatic tumor fraction increased with time, reaching 30% of the hepatic surface area on day 30. Visual analysis revealed variable tumor distribution and type (solid and/or cystic). On MRI, lesions were identified from day 12 (about 100 icrom in diameter) and the hepatic tumor fraction was up to 48% at day 30. The smallest lesions (350 microm in diameter) were also detected at day 12 on the autoradiographs. There was good correlation between tumor fractions determined from autoradiographic and histological data. CONCLUSION In vivo, MRI appears to be well suited to the follow-up of liver lesions in a mouse model of neuroendocrine tumor. Preliminary results using 18F-FDG in this animal model are promising, showing differences in FDG uptake.