[¹⁸F] FDG PET to study the effect of simulated high altitude on regional brain activity in mice

Objectives: It is well known that prolonged hypoxia at high altitude (HA) can lead to several adaptive changes in systemic physiology and tissue metabolism. During deployments our service members are exposed to extreme environmental conditions including low oxygen, low ambient air pressure and extreme temperatures. Most of the individuals develop a spectrum of high altitude symptoms known as acute or chronic mountain sickness. Therefore, exposure to HA can significantly impact brain functions causing a decline in neurocognitive performance. The aim of this study was to use Positron Emission Tomography (PET) and [¹⁸F]-2-deoxy-2-fluro-D-glucose (FDG) imaging to assess regional brain glucose metabolic changes in high altitude using mice as a model.

Methods: In this study adult male mice were used (BALB/c, n=8). Four mice were exposed to hypobaric conditions (5000 meters) for about 8 months before imaging. Control mice (n=4, sea level, age matched) were also imaged to compare regional brain fluorodeoxyglucose uptake with the high altitude animals. For imaging, a trace amount of [¹⁸F] FDG (0.52 ± 0.03 mCi) was injected intra peritoneal in the animals. For the conscious uptake (30 minutes), the animals were kept in a separate cage (without food and water) on a heating pad (37°C) to avoid brown adipose tissue uptake. Total uptake time before PET imaging was 45 minutes. PET/CT images of the brain were acquired using a Siemens Inveon PET/CT pre-clinical imaging system (Siemens Medical Solutions, Erlangen, Germany). Static PET images were acquired in list mode for 30 minutes. CT scans were acquired immediately following PET scans for anatomical localization and attenuation and scatter corrections. The PET data were reconstructed as a single static frame with OSEM3D/MAP (Ordered Subset Expectation Maximization/maximum a posteriori) 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) for brain atlas based analysis and Siemens Inveon Research Workplace software version 4.2 for Volume-of-Interest (VOI) analysis. The PET data were registered to the 14 regions mouse brain atlas by way of CT using an automatic algorithm that combines a rigid transformation of the data and scaling of the atlas. 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 14 different brain regions. VOI were drawn on the heart to get the uptake concentration. SUV_heart was analyzed for high altitude and control mice. All statistical analyses were conducted using Graph Pad Prism software version 7.01.

Results: 1. An increase in glucose metabolism was detected in cerebellum and medulla of the mice exposed to high altitude compared to controls. 2. Cortical regions displayed significant hypometabolism in higher altitude mice when compared to sea level controls. 3. Lower cardiac uptake was seen in the high altitude mice compared to sea level controls.

Conclusion: The acclimation response of the central nervous system to prolonged exposure to high altitude hypoxia in BALB/c mice seems like a complex phenomena. It includes stabilized glucose metabolism in certain brain regions, hypermetabolism in two (medulla and cerebellum) and hypometabolism in one (cortex) region of the brain. Interestingly, lower myocardial glucose metabolism was measured in the high altitude mice compared to sea level, contrary to the study done on Quechua and Sherpa subjects. Research Support: This work was supported by the Department of Defense through the Center for Neuroscience and Regenerative Medicine and the Henry M. Jackson Foundation for the Military Medical Research.

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