Reply to Fan <i>et al.</i> : Assessment of the Neuroprotective Effect of Continuous Positive Airway Pressure in Obstructive Sleep Apnea: Can Static Metrics Map Dynamic Pathology?

From the Authors: We thank Fan and colleagues for their discerning comments on our recent randomized controlled trial (1). Obstructive sleep apnea (OSA) is associated with neurocognitive dysfunction, including memory impairment (2). Our study showed that continuous positive airway pressure (CPAP) could improve neuroimaging biomarkers and emphasizes the importance of early intervention (1). We agree with Fan and colleagues that future prospective studies with larger sample sizes should be performed to validate the neuroprotective mechanisms of CPAP. With regard to some other issues that Fan and colleagues raised, we provide a response here. First, the intranetwork functional connectivity (FC) of default mode network (DMN) assessed by functional magnetic resonance imaging is one of the key secondary outcomes in our study. We found that there were significant differences in the FC of DMN between the CPAP group and the best supportive care group at 6 months after treatment. We acknowledged that positron emission tomography imaging is also an important tool in assessing brain function and activity. Combined assessment with positron emission tomography and functional magnetic resonance imaging might give more important information; this should be considered in future studies. Heterogeneity in response to CPAP treatment might exist among different phenotypic subtypes of OSA (3). In our study, we excluded subjects with obesity hypoventilation syndrome (see online supplement for (1); therefore, the factor (OSA with or without obesity hypoventilation syndrome) could not be analyzed. Second, we only got time of usage and residual apnea–hypopnea index from the CPAP machine, whereas the nocturnal oxygen saturation fluctuations or sleep efficiency could not be obtained. Future studies may benefit from using pulse oximeters to dynamically record oxygen saturation during CPAP treatment. We agree that the potential interference of comorbidities and pharmacological interventions should not be ignored; therefore, we performed additional subgroup analyses by comorbidities (hypertension, coronary artery disease, diabetes mellitus, and hyperlipidemia). There were no statistically significant differences in the key secondary outcomes (FC of DMN and cortical thickness) between the CPAP + BSC group and the BSC group, and no significant interactions between the comorbidities and the interventions were observed (for interactions, all P > 0.05) (Figures 1 and 2). Effects of CPAP treatment on functional connectivity (FC) of default mode network (DMN) by comorbidity subgroups at 6 months. We used linear mixed models for repeated measures of the DMN to assess between-groups difference at 6 months after enrollment. Outcome analyses are reported as least-squares means and 95% CIs, including the mean differences between groups. BSC = best supportive care; CIs = confidence intervals; CPAP = continuous positive airway pressure. Effects of CPAP treatment on cortical thickness by comorbidity subgroups at 6 months. We used linear mixed models for repeated measures of the cortical thickness to assess between-groups difference at 6 months after enrollment. Outcome analyses are reported as least-squares means and 95% CIs, including the mean differences between groups. BSC = best supportive care; CIs = confidence intervals; CPAP = continuous positive airway pressure. Finally, we agree with Fan and colleagues that the Montreal Cognitive Assessment is not sensitive for detecting subclinical impairment, and we have stated this in our study (1). We completely agree that computerized cognitive tests and neuroinflammatory markers are important for future randomized controlled trials, which will enable us to elucidate potential neuroprotective mechanisms of CPAP treatment. Author Contributions: All authors contributed to the writing and review of the manuscript and approved the final copy of the manuscript. Artificial Intelligence Disclaimer: No artificial intelligence tools were used in writing this manuscript. Originally Published in Press as DOI: 10.1164/rccm.202505-1243LE on July 30, 2025 Author disclosures are available with the text of this letter.

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