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Microglial Activation in Perinatal Rabbit Brain Induced by Intrauterine Inflammation: Detection with ¹¹C-(R)-PK11195 and Small-Animal PET

¹ Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, Michigan; ² Department of Radiology, Wayne State University School of Medicine, Detroit, Michigan; ³ Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan; ⁴ Perinatology Research Branch, NICHD, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland and Detroit, Michigan; and ⁵ Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan

View larger version (62K): [in this window] [in a new window]   FIGURE 1.  Coregistration of MRI and PET images: a representative newborn rabbit kit (30 µg/kg of endotoxin) on day 1 of life. (A) T1-weighted MR images. (B) Coregistered images. (C) microPET images. Coregistration was done using markers on a custom-made head holder that is visible on PET and MRI. Red arrows indicate water as marker noted on MR image, and green arrows indicate markers evident on PET scan. Overlap of markers (indicated by yellow arrows) is seen on coregistered images. Because of partial-volume effects, 3D ROIs (indicated by orange dashed lines) were drawn for the whole brain and SUV over time was calculated and compared between groups.

View larger version (13K): [in this window] [in a new window]   FIGURE 2.  Slope of SUV for 11C-(R)-PK11195 over time in postnatal day 1 kits. Lines represent slopes for each group estimated by HLM, markers represent mean SUV for all kits in that group for that time point, and error bars indicate SD for mean. Slope was negative for control group (mean slope = –0.003 min–1) and positive for both endotoxin groups (mean slopes = +0.0006 min–1 for 20-µg/kg endotoxin kits [Endo20] and +0.002 min–1 for 30-µg/kg endotoxin kits [Endo30]), indicating retention of tracer in brain due to specific binding of the tracer to peripheral benzodiazepine binding sites in newborn rabbits exposed to endotoxin in utero. Upregulation of binding sites suggests that there is increased microglial activation in brain of kits exposed to endotoxin in utero.

View larger version (5K): [in this window] [in a new window]   FIGURE 3.  SUV slope values for each group. Individual slopes for each kit in control, 20 µg/kg of endotoxin (Endo20), and 30 µg/kg of endotoxin (Endo30) groups are depicted. Mean slope for each group is represented as horizontal line. There is no overlap in slope values between control and endotoxin groups.

View larger version (37K): [in this window] [in a new window]   FIGURE 4.  PET images of 11C-(R)-PK11195 uptake in brain in first 10 min of scan (frame 1) and in last 10 min of scan (frame 6) on day 1 of life. Red circle indicates ROI involving whole brain that was drawn to measure uptake in that region. Red arrows indicate region of interventricular zone at level of hippocampus and dentate gyrus. Activity in brain decreases over time for saline-injected control kits, whereas it increases over time for newborn rabbit kits exposed to endotoxin in utero, indicating specific binding of tracer to activated microglial cells in endotoxin-exposed kits. Image intensity is adjusted for dose injected and weight of animal and the SUV scale provided.

View larger version (50K): [in this window] [in a new window]   FIGURE 5.  Morphology of microglial cells using tomato lectin staining. (A) In control group, cells are highly ramified (arrow). (B and C) In endotoxin-treated group, cells had shorter and thicker processes. In this latter group, cells are bushy (B, arrow), becoming amoeboid and round (C, arrow). Increase in density of microglial cells is observed in endotoxin-treated group compared with that of control group. Scale bar = 100 µm.

View larger version (198K): [in this window] [in a new window]   FIGURE 6.  Localization of microglial cells and morphology using tomato lectin staining in control kits and in kits exposed to 20, 30, and 40 µg/kg of endotoxin. Microglial cells are seen in corpus callosum, along inferior border of lateral ventricle (A), around angle of lateral ventricle (B), in area of internal capsule (C), between 2 fields of hippocampus (D), and in fimbria hippocampus (E). Increase in density of microglial cells is observed in endotoxin-treated groups compared with control group. In all of these regions, microglial cells are ramified in control group and become less ramified/bushy, amoeboid, and round in endotoxin-treated groups. E. = endotoxin; LV = lateral ventricle; CC = corpus callosum; IC = internal capsule; Fi = fimbria hippocampus. Scale bar = 200 µm.