High erythropoietin levels are associated with low neurofilament light levels in simulated high altitudea further hint for neuroprotection by erythropoietin

Klaus Berek¹Anna Berek¹Angelika Bauer¹Dagmar Rudzki¹Franziska Di Pauli¹Gabriel Bsteh²Markus Ponleitner²Benedikt Treml¹Axel T Kleinsasser¹Thomas Berger²Maria Wille³Martin Burtscher³Markus Reindl¹Florian Deisenhammer¹Harald Hegen^1*

• ¹Innsbruck Medical University, Innsbruck, Austria
• ²Medical University of Vienna, Vienna, Vienna, Austria
• ³University of Innsbruck, Innsbruck, Tyrol, Austria

Background: Erythropoietin (EPO) plays a crucial role in the early adaption to high altitude and is possibly involved in neuroprotection. Neurofilament light chain (NfL) is an established marker of neuroaxonal damage. Objective: To investigate whether EPO dynamics in simulated high altitude is linked to neuroaxonal damage as measured by NfL. Methods: Sixty-three healthy subjects were exposed to simulated altitude of 4,500m for 12 hours in a normobaric hypoxic chamber at the University of Innsbruck. Clinical data (heart rate, arterial oxygen saturation) were assessed before and 3 hours after high altitude exposure; plasma samples were drawn before (measurement (M) 1) and after 12 hours (M2). The levels of EPO and hypoxia-inducible factor (HIF)-1α were quantified using commercially available ELISA kits. NfL concentrations were measured using the Simoa SR-X Analyzer, and NfL Z scores calculated using age- and body mass index (BMI)-adjusted reference values. Results: EPO significantly increased after 12 hours (M2: 10.12 [7.86-14.06] mU/ml versus M1: 4.17 [2.99-5.67] mU/ml, p<0.001), while HIF-1α did not significantly change (p=0.409). Subjects with high EPO levels at M2 showed significantly lower NfL concentrations (5.85 [4.15-6.85] pg/ml versus 6.73 [4.70-8.64] pg/ml, p=0.030) as well as lower NfL Z scores (0.64 [-0.88-1.17] versus 0.95 [0.25-1.48], p=0.040) than those with low EPO levels. The extent of heart rate increase showed a positive correlation with EPO levels at M2 (rs=0.322, p=0.011). Conclusions: Higher EPO concentrations were associated with lower NfL levels. This might further substantiate the hypothesis of a neuroprotective role of EPO.