Serum hypoxia-inducible factors, heat shock proteins, and mitochondrial biomarkers in relation to neurocognitive performance in obstructive sleep apnea: a cross-sectional study.
STUDY OBJECTIVES Obstructive sleep apnea(OSA) is linked to impaired cognitive functions through a variety of underlying mechanisms. We investigated possible hypoxic, inflammatory and mitochondrial mediators of cognitive dysfunction in OSA. METHODS We prospectively enrolled 146 adult patients with OSA and 103 healthy controls. We analyzed demographic and clinical data, neurocognitive assessments by a set of cognitive batteries(Montreal Cognitive Assessment[MoCA], Digit Span Test[backward/forward], and Stroop test), and full night polysomnography(PSG) recordings. We also analyzed biochemical parameters including hypoxia-induced factors(HIF-1α,HIF-2α), interleukin-6, tumor necrosis factor-alpha(TNF-α), alpha-enolase(Eno1), and members of heat shock proteins-70 family(HspA1A,HspA8) by the ELISA method. mtDNA copy number was measured and mRNA expressions of peroxisome proliferator-activated receptor gamma coactivator-1-alpha(PGC-1α) and mitochondrial transcription factor-A(TFAM) were determined. RESULTS Mean age was similar between groups, while male-to-female ratio and body mass index(BMI) were significantly higher in patients with OSA, for which all statistical analyses were corrected. We observed positive correlations between HIF-1α and average time/number of errors in Stroop test; Eno1 and number of errors in Stroop test; HSPA1A and average time in Stroop test; mtDNA copy number and numbers in DST-backward. Negative correlations were observed between HIF-2α and MoCA; TNF-α and number of errors in Stroop test; Eno1 and numbers in DST-backward; HSPA1A and MoCA. Of PSG parameters, WASO negatively correlated with mtDNA copy number; duration of REM-sleep positively correlated with PPARGC1A-mRNA expressions; apnea-hypopnea index negatively correlated with HIF-1α. CONCLUSIONS Our results demonstrated complex and important correlations between neurocognitive assessments and mediators of hypoxia, inflammation, protein misfolding, and mitochondrial trafficking, which may serve as biochemical biomarkers of cognitive impairment in OSA.