Increased serum levels of cyclophilin a and matrix metalloproteinase-9 are associated with cognitive impairment in patients with obstructive sleep apnea

Objectives: To investigate the relationship between serum cyclophilin A (CyPA) and matrix metalloproteinase-9 (MMP-9) levels and mild cognitive impairment (MCI) in patients with obstructive sleep apnea (OSA). Methods: Study subjects underwent whole-night in-laboratory polysomnography (PSG), and all partici-pants were scored using a neuropsychological scale and peripheral blood samples were collected the next morning. The presence and severity of OSA were assessed with the apnea hypopnea index (AHI), and OSA was defined as AHI >5 events/hour. MCI was defined as the MoCA <25, and met the revised Mayo Clinic criteria. Serum CyPA and MMP-9 levels were measured with enzyme-linked immunosorbent assays (ELI-SAs). A univariate analysis and a logistic model were used to assess risk factors for MCI in patients with OSA. A correlation analysis was performed to estimate whether a linear relationship existed between serum CyPA and MMP-9 levels and the severity of cerebral small vessel disease (CSVD) and white matter hyperintensities (WMHs). A linear regression analysis was used to clarify the relationship between serum CyPA and MMP-9 levels and the degree of cognitive impairment in patients with OSA.Results: The 186 patients who met the criteria for inclusion and exclusion comprised 71 patients with OSA presenting with MCI (OSA + MCI), 73 patients with OSA without MCI (OSA-MCI), and 42 controls. Patients with OSA + MCI presented higher serum CyPA and MMP-9 levels than patients in the OSA-MCI (11.56 +/- 4.52 ng/ml vs 9.95 +/- 3.63 ng/ml, p = 0.020; 597.71 +/- 204.41 ng/ml vs 523.05 +/- 205.47 ng/ml, p = 0.030) and control groups (11.56 +/- 4.52 ng/ml vs 8.80 +/- 3.71 ng/m, p = 0.001; 597.71 +/- 204.41 ng/ml vs 490.39 +/- 155.07 ng/ml, p = 0.002). The logistic regression analysis revealed that both CyPA (OR: 1.111, 95% CIs: 1.012-1.219, p = 0.027) and MMP-9 levels (OR: 1.003, 95% CIs: 1.000-1.004, p = 0.011) contributed significantly to MCI in patients with OSA. In the OSA + MCI group, positive correlations were observed between serum CyPA and MMP-9 levels with Scheltens scores (r = 0.437, p = 0.000; r = 0.613, p = 0.000, respectively) and total CSVD burden scores (r = 0.318, p = 0.003; r = 0.487, p = 0.000, respectively). Serum CyPA and MMP-9 levels were linearly negatively correlated with mean oxygen saturation during sleep (mean SaO2) (r =-0.595, p = 0.000; r =-0.570, p = 0.000). There was linear correlation between mean SaO2 and MoCA scores by Pearson's correlation coefficient (r = 0.403, p = 0.000). The linear regression analysis revealed negative correlations between serum CyPA and MMP-9 levels and the Montreal Cognitive Assessment (MoCA) scores (r =-0.528, p = 0.000; r =-0.459, p = 0.000, respectively), and serum CyPA levels were negatively correlated with score of cognitive subdomainss, including visuo-executive function, attention and delayed recall. However, serum MMP-9 levels were negatively correlated with score of cognitive subdomains, including visuo-executive function and delayed recall.Conclusions: Increased serum levels of CyPA and MMP-9 are associated with MCI in OSA patients and directly related to the severity of CSVD and WMHs. The results suggest that damage to the blood-brain barrier (BBB) may be involved in the early stages of cognitive impairment in patients with OSA.(c) 2021 Elsevier B.V. All rights reserved.