The Role of Inflammation in Cognitive Impairment of Obstructive Sleep Apnea Syndrome

Abstract

Obstructive sleep apnea syndrome (OSAS) has become a major worldwide public health concern, given its global prevalence. It has clear links with multiple comorbidities and mortality. Cognitive impairment is one related comorbidity causing great pressure on individuals and society. The clinical manifestations of cognitive impairment in OSAS include decline in attention/vigilance, verbal-visual memory loss, visuospatial/structural ability impairment, and executive dysfunction. It has been proven that chronic intermittent hypoxia (CIH) may be a main cause of cognitive impairment in OSAS. Inflammation plays important roles in CIH-induced cognitive dysfunction. Furthermore, the nuclear factor kappa B and hypoxia-inducible factor 1 alpha pathways play significant roles in this inflammatory mechanism. Continuous positive airway pressure is an effective therapy for OSAS; however, its effect on cognitive impairment is suboptimal. Therefore, in this review, we address the role inflammation plays in the development of neuro-impairment in OSAS and the association between OSAS and cognitive impairment to provide an overview of its pathophysiology. We believe that furthering the understanding of the inflammatory mechanisms involved in OSAS-associated cognitive impairment could lead to the development of appropriate and effective therapy.

Keywords: chronic intermittent hypoxia; cognitive impairment; inflammation; obstructive sleep apnea syndrome.

Figure 1

Inflammation and cognitive impairment in OSAS. CIH, the characteristic of OSAS, causes peripheral inflammation and access the CNS through BBB to induce the production of NF-κB and HIF-1α, which both promote the expression of inflammatory cytokines in the CNS. Further, HIF-1α and NF-κB can interact with each other. The high level of inflammation in CNS further causes neuronal necrosis, apoptosis, synaptic damage, and losses, which finally leads to neurocognitive deficits, including attention/vigilance decline, verbal–visual memory decrease, and executive dysfunction.

Figure 2

The canonical pathway of NF-κB. In this process, IKKβ activated by CIH leads to the phosphorylation of IκB to form the RelA/p50 complex. The complex translocates to the nucleus to promote the transcription of target genes and IκB is subsequently degraded by the proteasome.

Figure 3

The activation of hypoxia-inducible factor (HIF)-1α. CIH can evoke oxidative stress and reactive oxygen species (ROS), while ROS can activate the Ca²⁺-dependent calpain proteases (CAMK) that can directly phosphorylate p300, and activate the mammalian target of rapamycin (mTOR) that promotes the expression of HIF-1α protein. The HIF-1α/HIF-1β/p300 complex in the nucleus can promote the transcription of HIF-1 genes. However, oxygen can induce the degradation of HIF-1α through prolyl hydroxylases (PHDs).