Herman, Nicole

Many individuals travel to high altitude each year. Acclimatization to altitude occurs over the course of several days as the body adequately adapts to function in an environment with reduced partial pressure of oxygen. However, with a faster accent to attitude, comes an increased potential for maladaptations to occur, leading to the development of acute mountain sickness (AMS). Each year scientists and support workers are transported by plane from McMurdo Station in Antarctica (sea level) to the Amundsen‐Scott South Pole Station (2835m). This uniform and rapid deployment to altitude provides a unique opportunity to study the effects of hypobaric hypoxia on gene expression, which may help to illustrate the body’s ability to acclimatize to these environmental conditions. Purpose To detect pathway specific gene expression changes associated with the development of AMS and help identify potential targets that may aid in the prediction of risk in the development of AMS symptoms due to rapid exposure to high altitude. Methods Venous blood samples were collected from 53 (height 176.65±8.91cm, weight: 80.49±14.36kg) healthy subjects (38 (27 males; 11 females) that did not develop AMS and 15 (10 males; 5 females) that did develop AMS, as defined by the Lake Louis symptom questionnaire, collected at 2 different time points, with the first being at sea level and the second being after 48hr of altitude exposure). Microarray analysis was performed on the peripheral blood mononuclear cells (PBMCs) from the collected samples, and a logistic regression was performed to determine probe set association with AMS. Results There was a total of 178 significant (p<0.05) probe sets, with 156 of the probe sets being associated with AMS and 22 of the probe sets being associated with no AMS. The probe sets were entered into the Reactome Pathway Database (reactome.org). Pathways identified in association with AMS involved immune system pathways (interleukin signaling) and cellular responses to stimuli pathways (oxidative stress induced senescence signaling), and gene transcription pathways (mitochondrial biogenesis signaling, differentiation of hematopoietic stem cells). Interestingly, pathways identified in association with no development of AMS involved cell cycling pathways (mitotic signaling), chromatin organization pathways (chromatin modifying enzymes), metabolism pathways (utilization of ketone bodies) and the circadian clock pathway (circadian gene expression signaling). Conclusion These findings indicate potential maladaptive responses within the immune system and mitochondrial function, may play a key role in why some individuals develop AMS symptoms. An individual’s ability to sufficiently utilize different metabolic fuel sources and adapt their circadian rhythm may also prevent the development of AMS symptoms.

Objective To identify novel genes and pathways associated with acute mountain sickness (AMS). Background The uniform, rapid transfer of adults from McMurdo Station (sea level, SL) in Antarctica to the South Pole (SP, 2835m) provides a unique opportunity to study changes in gene expression related to the body's adaptation to hypobaric hypoxia. Methods Venous blood was drawn at SL and after 2 d at SP in 98 subjects (age 37±9 y, 70% male). Peripheral blood mononuclear cells (PBMCs) were isolated and microarray analysis of the mRNA isolated from these cells was performed (Affymetrix HG U133 Plus 2 microarray chip). Analysis and the computation of expression fold changes and phenotypic regression were performed using the Bioconductor package in R. Pathway analysis was performed using MetaCore™. Results ~3200 probe sets with sig. p‐values (p<0.05) and fold changes for each subject were used in a binary logistic regression with the presence or absence of AMS during the 2 d at altitude. Corresponding p‐values and z‐values were entered into MetaCore™ for pathways analysis. Identified pathways included smooth muscle contraction, calcium signaling, and acetylcholine regulation of nerve impulses. Conclusions Probe sets associated with the presence of AMS had a significant representation in pathways involving aspects of the autonomic nervous system including smooth muscle contraction and nerve signaling. NSF B‐179‐M.

Background It is documented that cognitive performance can diminish with altitude, but the sensitivity of specific tests have not been investigated. Our objective was to assess and compare cognitive performance from several tests and relate this to quality of sleep and acute mountain sickness (AMS). Methods During an Everest expedition, 3 cognitive tests (Stroop, Trail Making, and a proprietary motor accuracy test) were used along with a questionnaire to assess sleep and AMS. Six athlete climbers and 9 core team members were assessed pre and post‐expedition and at several time points during the expedition (up to 17,500 ft). Results To normalize for individual differences, scores were assessed as % change from baseline. There was no difference in the variation between repeated attempts in a single testing session (0.19<p<0.87), demonstrating that each test was reproducible. There was no decrement in test scores with altitude, nor was there an association with reported sleep quality. The Stroop performance was associated with AMS (p<0.05) and trending with headache (p< 0.15). The in‐house motor test trended towards an association with AMS and headache (p<0.15). However, the trail making test was not associated with AMS/headache. Conclusion With appropriate acclimatization, cognitive performance is maintained at altitude but is linked to presence of headache and AMS. Mayo Clinic and TNF.

Objective To identify novel genes that change expression in healthy adults exposed to hypobaric hypoxia. Background The uniform and rapid transfer of adults from McMurdo Station (sea level, SL) in Antarctica to the South Pole (2835m, SP) provides a unique opportunity to study the changes in gene expression related to the body's adaptation to high altitude. We hypothesized that a large number of genes would change expression and that many of these genes would be associated with inflammatory processes. Methods Peripheral venous blood was drawn at SL and after 2 d at SP in 98 subjects (age 37±9 y, 70% male). Peripheral blood mononuclear cells (PBMCs) were isolated and microarray analysis of the mRNA isolated from these cells was performed (Affymetrix HG U133 Plus 2 microarray chip). Analysis and the computation of expression fold changes was performed using the Bioconductor package in R. Pathway analysis was performed using MetaCore™. Results 1118 probe sets with significant p‐values (p<0.05) and fold changes were identified and entered into MetaCore™. Several pathways including oxidative phosphorylation, cytoskeletal remodeling, and platelet aggregation were identified as having significant representation in the restricted data set. Conclusion Several pathways indicating significantly increased activity in PBMCs were identified. This is indicative of an increased inflammatory response. NSF B‐179‐M.

Objective It is well documented that cognitive performance may be altered with ascent to altitude, but the association of various cognitive performance tests with symptoms of acute mountain sickness (AMS) is not well understood. Our objective was to assess and compare cognitive performance during a high-altitude expedition using several tests and to report the association of each test with AMS, headache, and quality of sleep. Methods During an expedition to Mount Everest, 3 cognitive tests (Stroop, Trail Making, and the real-time cognitive assessment tool, an in-house developed motor accuracy test) were used along with a questionnaire to assess health and AMS. Eight team members were assessed pre-expedition, postexpedition, and at several time points during the expedition. Results There were no significant differences ( P >.05) found among scores taken at 3 time points at base camp and the postexpedition scores for all 3 tests. Changes in the Stroop test scores were significantly associated with the odds of AMS ( P <.05). The logistic regression results show that the percent change from baseline for Stroop score (β = −5.637; P = .032) and Stroop attempts (β = −5.269; P = .049) are significantly associated with the odds of meeting the criteria for AMS. Conclusions No significant changes were found in overall cognitive performance at altitude, but a significant relationship was found between symptoms of AMS and performance in certain cognitive tests. This research shows the need for more investigation of objective physiologic assessments to associate with self-perceived metrics of AMS to gauge effect on cognitive performance.