Abstract
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Objectives: Traumatic Brain Injury (TBI) can lead to long term cognitive deficits. These cognitive impairments are often associated with complex metabolic alterations (1). Currently there is no treatment for the cellular and metabolic dysfunction that occurs after injury. The objective of this pilot study was to trace regional metabolic changes due to intranasal insulin / saline treatment in the injured rat brain with novel object recognition test during uptake (2,3).
Methods: Adult male Sprague Dawley rats were imaged at 3 time points [(baseline, prior to injury), day 2 and day 10 (post injury)]. The animals were given intranasal insulin (n=7) or saline (n=5) treatment beginning at 24 hours after injury and continuing daily for 14 days. For PET/CT imaging, [18F] FDG (1.8 ± 0.06 mCi) was injected in the anesthetized animals via lateral tail vein. For the conscious uptake, the animals were kept in a separate cage (without food and water) on a heating pad (37°C). Cognitive testing (novel object recognition) was performed during the uptake period. For PET/CT imaging (Siemens Inveon pre-clinical system, Erlangen, Germany), the animals were anesthetized after 30 minutes of conscious uptake. Total uptake time before PET acquisition was 45 minutes. Static PET scans were acquired for 30 minutes followed by CT scans for anatomical localization and scatter and attenuation correction. The PET data were reconstructed as a single static frame with OSEM3D/MAP algorithm and corrected for scatter and attenuation. The CT images were reconstructed using Feldkamp algorithm, downsample2 with beam hardening and HU corrections applied. The reconstructed PET/CT data were processed and analyzed using Vivoquant Software version 2.5 (inviCRO, Boston MA). The PET data were registered to the 13 regions rat brain atlas by way of CT using an automatic algorithm (Figure 1, 2). The data analysis was performed using a semi quantitative method. Standardized Uptake Value (SUV - activity concentration in a specific region normalized to the total injected activity and body weight) normalized to the whole brain (SUVw) was analyzed in 13 different brain regions. All statistical analyses were conducted using Graph Pad Prism software version 7.01
Results: 1. There were no significant changes in the baseline scans of insulin versus saline treated animals (multiple t-tests using Holm-Sidak method with alpha = 0.05). 2. Significant changes in regional brain glucose metabolism were found in insulin and saline treated groups after injury (from baseline to day 2 and /or day 10, repeated measures two-way ANOVA, Sidak’s multiple comparisons tests). Insulin Group i) Hypermetabolism was seen in hypothalamus, midbrain and olfactory regions on day 2 when compared to baseline scans, returning to baseline scans by day 10. ii) Significant decrease in glucose metabolism was detected in cortex and corpus callosum on day 2 when compared to baseline scans. Saline Group i) A significant decrease in cortical uptake was observed at day 2 and day 10 compared to baseline. ii) Increased uptake was evident in hypothalamus at day 2 and day 10 when compared to baseline scans. iii) Significant increase in uptake was observed in olfactory and hippocampal regions on day 2 compared to baseline and remained elevated at day 10. iv) Increase in glucose uptake in corpus callosum is apparent only at day 10. v) Increased uptake in cerebellum and midbrain were also noticed at day 2 compared to baseline but returns to baseline by day 10.
Conclusion: Our findings demonstrate that metabolic changes due to TBI and treatment can be evaluated using [18F] FDG imaging. Regional brain glucose uptake changes after TBI revert back to normal (baseline) in the insulin treated group by day 10 compared to saline treated animals. This suggests that insulin treatment post-TBI may mediate metabolic changes associated with injury. Research Support: This project is supported by CNRM and HJF.
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