Abstract
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Objectives: Hypobaric hypoxia can cause severe brain damage, including acute mountain sickness, brain swelling, increased intracranial pressure, or even high-altitude cerebral edema. Traumatic brain injury (TBI) on the other hand is a complex neurodegenerative disorder with a broad spectrum of symptoms and disabilities. The objective of this study was to evaluate if the altitude related factors (hypoxia/hypobaria) confound glucose uptake in TBI as measured by FDG uptake.
Methods: Adult male C57BL/6J mice (n=32, 6-8 weeks) were used in this study. FDG PET and CT images were acquired using a Siemens Inveon preclinical scanner (Siemens Medical Solutions, Erlangen, Germany) at three time points - (1) before exposing the animals to hypobaric conditions (5000 meters) [baseline], (2) after 12 weeks of high-altitude exposure or at sea-level [week 12] and (3) 12 days after a repetitive closed head injury or sham injury [post-TBI]. The PET/CT data were processed and analyzed using a volume-of-interest (VOI) method. The CT data were registered to a VivoQuant (inviCRO, Boston, MA) mouse atlas and the PET data was transformed to the atlas space. Average values of uptake concentration in different brain regions were extracted, and the Standardized Uptake Value normalized to the whole brain (SUVw) was computed and analyzed for different brain regions at all time points. Four questions of interest were identified: Q1) What is the effect of 12 weeks of high altitude (HA) exposure on SUVw? Q2a) What is the effect of repetitive TBI at sea level (SL) relative to sham on SUVw? Q2b) What is the effect of repetitive TBI at high altitude relative to sham on SUVw? Q3) What is the effect of repetitive TBI at high altitude relative to repetitive TBI at sea level on SUVw? To answer these questions, a linear mixed-effects model was used, with SUVw as the response variable. Fixed-effects factors were altitude (SL, HA), injury (sham, injured), time (baseline, week 12, post-TBI), and their three-way interactions, and subject was a random-effects factor. Multiple comparisons were corrected using the Benjamini Hochberg method.
Results: 1. Compared to sea level, high altitude animals showed significant increase in FDG uptake in cerebellum (p<0.0001), medulla (p<0.0001) and pons (p<0.0001) and decreased uptake in corpus callosum (p=0.002), cortex (p=0.004), midbrain (p<0.0001) and thalamus (p=0.0001) (baseline vs week 12, Q1), Figure 1. 2. Repetitive TBI affects glucose metabolism in both the sea level and high altitude animals, with decreased cortical uptake in the repetitive TBI animals compared to sham (Q2a,b); [repeat TBI SL, p=0.003; repeat TBI HA, p=0.005]. As expected, the effect was larger on the left side, which was the ipsilateral side of the injury, Figure 2. 3. Moreover, high altitude animals exposed to repetitive TBI show increased uptake in cerebellum (p=0.007) and decreased uptake in the midbrain (p=0.002) and thalamus (p<0.0001) relative to the repetitive TBI animals at sea level (Q3), Figure 3.
Conclusions: Adaptation of the central nervous system to prolonged hypobaric-hypoxia in C57BL/6 mice varies by brain region (Cramer et al. 2018) and appears to allow the HA-exposed brain more susceptible to repeated concussion relative to sea level mice. Research Support: This work is supported by the Department of Defense through the Center for Neuroscience and Regenerative Medicine and a Uniformed Services University Program Project Grant 308430. Reference: Neuronal and vascular deficits following chronic adaptation to high altitude. Cramer et al. Exp Neurol. 2019 Jan;311:293-304. doi: 10.1016/j.expneurol.2018.10.007. Epub 2018 Oct 13
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