**5. Mechanisms associated to cognitive impairment in OSA**

OSA causes oxygen desaturation producing arousals and nocturnal intermittent hypoxemia. The intermittent hypoxia is linked to cerebral microvascular and neurovascular changes. Several models have been proposed to explain the pathophysiology of neurocognitive impairment in patients with OSA. Some of these models include: prefrontal model sleep disruption, neuroinflammatory process, hypoperfusion and endothelial dysfunction. Neuroinflammatory process is one of the mechanisms proposed to explain the association between OSA and cognitive impairment. Healthy microglia of central nervous system (CNS) show a surveillance phenotype that synthesizes neuroprotective growth factors. In OSA ischemic condition actives several genes including vascular endothelial growth factor (VEGF), erythropoietin, atrial natriuretic peptide (ANP), hypoxia inducible factor-1 (HIF-1), and brain-derived neurotrophic factor (BDNF) [68]. Altered resting cerebral blood flow pattern and hypoperfusion in several CNS regions have been demonstrated in patients with OSA during sleep and awake states [69]. Repetitive hypoxia and reoxygenation promote oxidative stress producing blood-brain barrier hyperpermeability and neuroinflammation. These alterations result in plasma proteins leaking into the arteriolar walls and perivascular spaces (Virchow-Robin spaces) and subsequent accumulation of macrophages and fibrosis in the arteriolar walls leading to the development or progression of C-SVD. Severe and prolonged hypoxia can activate microglia toward a toxic, pro-inflammatory phenotype causing white matter damage and lacunar infarction and accumulation of plasma proteins in the small arterial walls. Additionally, inflammation at the blood-brain barrier alters the transport of molecules across the barrier, resulting in progressive synaptic plasticity and neuronal dysfunction. This maladaptive neuroinflammatory process, observed in patients with OSA, increases hippocampal apoptosis, impaired synaptic plasticity, and cognitive impairment [70–74].

In hypoperfusion model, the cognitive impairment is explained in this way: in normal conditions the cerebral autoregulation mechanism protects the brain through maintaining cerebral perfusion during blood pressure changes. In OSA this system is impaired because of changes in nocturnal intracranial hemodynamics and oxygen saturation, resulting in cerebral hypoperfusion in the regions with poor collateral circulation. Chronic hypoperfusion in small arteries and arterioles leads to ischemic changes in white and gray matter. Although cerebral blood flow is increased to compensate for oxygen desaturation in patients with OSA, this mechanism is not enough and the chronic hypoxemia promotes the progression of C-SVD resulting in lacunar infarcts, white matter abnormalities and gray matter

**149**

*Cognitive Impairment and Obstructive Sleep Apnea DOI: http://dx.doi.org/10.5772/intechopen.82756*

treatment [75–79].

neuronal damage [80–83].

**6. Conclusions**

**Acknowledgements**

of CPAP in patients with OSA and other comorbidities.

modifiable risk factor for dementia.

impairment in patients with OSA.

tools for OSA and cognitive impairment.

loss. Damage to prefrontal and frontal lobes, basal ganglia and hippocampus are associated with abnormal myelin and axonal integrity. Prolonged hypoxic–ischemic damage to the frontal and prefrontal cortex is associated with executive dysfunction in patients with moderate to severe OSA, but this damage could improve with CPAP

In endothelial dysfunction model, neurocognitive impairment is produced for several mechanisms. The apneic episodes cause repetitive intracranial blood flow impairing the endothelial cells of small arteries and arterioles and decreasing endothelial vasodilator production. Nitric oxide regulates cerebral blood flow in response to hypercapnia, but in OSA nitric oxide is decreased, and the vasodilatory capacity of cerebral vasomotor reactivity in response to hypercapnia is compromised. Altered cerebral vasomotor reactivity associated with poor microvascular blood flow produce white matter lesions. Additionally, disruption of nitric oxide pathways causes a cascade of neuronal metabolic deficiencies, resulting in destabilizing neurons, synapses, and neurotransmission, and generating synaptic loss and

Investigations about the impact of patients with OSA treated with CPAP in the cognitive function have showed that daytime sleepiness decrease and cognitive function improves. The amount of improvement depends of biologic variability present in each patient [55, 84, 85]. Previous studies had been demonstrated that sleep disruption impaired cognitive function and the mechanisms of cognitive harm in OSA and chronic obstructive pulmonary disease (COPD) are similar. However, the pathophysiology of neurocognitive impairment in OSA and insomnia seems to be different, and the cognitive deficit in individuals with OSA is greater [46, 85, 86]. Therefore, other mechanisms such as changes in the brain could explain the cognitive impairment associated with OSA. Additionally, in some patients with OSA cognitive deficit persist, even after prolonged treatment with CPAP. For this reason, it is necessary to design future studies to identify appropriate treatment that can be administered before irreversible atrophic and metabolic changes occur [41, 87, 88]. Further studies should be performed to elucidate mechanisms of neurocognitive impairment and to identify genetics profiles for prediction of neurocognitive effects

• Obstructive sleep apnea is associated with cognitive impairment and is a

• Sleep fragmentation, hypoxia, maladaptive pathways, neuroinflammation, hypoperfusion and endothelial dysfunction contribute with neurocognitive

• Future studies should be conducted to identify novel diagnosis and therapeutic

• The exact pathophysiology of cognitive impairment in OSA patients remain

elusive as the role of therapy for OSA on cognitive impairment.

Supported by Colciencias Grant 850-2017, project 57720.

*Cognitive Impairment and Obstructive Sleep Apnea DOI: http://dx.doi.org/10.5772/intechopen.82756*

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

**5. Mechanisms associated to cognitive impairment in OSA**

plasticity, and cognitive impairment [70–74].

OSA causes oxygen desaturation producing arousals and nocturnal intermittent hypoxemia. The intermittent hypoxia is linked to cerebral microvascular and neurovascular changes. Several models have been proposed to explain the pathophysiology of neurocognitive impairment in patients with OSA. Some of these models include: prefrontal model sleep disruption, neuroinflammatory process, hypoperfusion and endothelial dysfunction. Neuroinflammatory process is one of the mechanisms proposed to explain the association between OSA and cognitive impairment. Healthy microglia of central nervous system (CNS) show a surveillance phenotype that synthesizes neuroprotective growth factors. In OSA ischemic condition actives several genes including vascular endothelial growth factor (VEGF), erythropoietin, atrial natriuretic peptide (ANP), hypoxia inducible factor-1 (HIF-1), and brain-derived neurotrophic factor (BDNF) [68]. Altered resting cerebral blood flow pattern and hypoperfusion in several CNS regions have been demonstrated in patients with OSA during sleep and awake states [69]. Repetitive hypoxia and reoxygenation promote oxidative stress producing blood-brain barrier hyperpermeability and neuroinflammation. These alterations result in plasma proteins leaking into the arteriolar walls and perivascular spaces (Virchow-Robin spaces) and subsequent accumulation of macrophages and fibrosis in the arteriolar walls leading to the development or progression of C-SVD. Severe and prolonged hypoxia can activate microglia toward a toxic, pro-inflammatory phenotype causing white matter damage and lacunar infarction and accumulation of plasma proteins in the small arterial walls. Additionally, inflammation at the blood-brain barrier alters the transport of molecules across the barrier, resulting in progressive synaptic plasticity and neuronal dysfunction. This maladaptive neuroinflammatory process, observed in patients with OSA, increases hippocampal apoptosis, impaired synaptic

*Magnetic resonance imaging in patient with cognitive impairment and OSA and in healthy individual.*

In hypoperfusion model, the cognitive impairment is explained in this way: in normal conditions the cerebral autoregulation mechanism protects the brain through maintaining cerebral perfusion during blood pressure changes. In OSA this system is impaired because of changes in nocturnal intracranial hemodynamics and oxygen saturation, resulting in cerebral hypoperfusion in the regions with poor collateral circulation. Chronic hypoperfusion in small arteries and arterioles leads to ischemic changes in white and gray matter. Although cerebral blood flow is increased to compensate for oxygen desaturation in patients with OSA, this mechanism is not enough and the chronic hypoxemia promotes the progression of C-SVD resulting in lacunar infarcts, white matter abnormalities and gray matter

**148**

**Figure 1.**

loss. Damage to prefrontal and frontal lobes, basal ganglia and hippocampus are associated with abnormal myelin and axonal integrity. Prolonged hypoxic–ischemic damage to the frontal and prefrontal cortex is associated with executive dysfunction in patients with moderate to severe OSA, but this damage could improve with CPAP treatment [75–79].

In endothelial dysfunction model, neurocognitive impairment is produced for several mechanisms. The apneic episodes cause repetitive intracranial blood flow impairing the endothelial cells of small arteries and arterioles and decreasing endothelial vasodilator production. Nitric oxide regulates cerebral blood flow in response to hypercapnia, but in OSA nitric oxide is decreased, and the vasodilatory capacity of cerebral vasomotor reactivity in response to hypercapnia is compromised. Altered cerebral vasomotor reactivity associated with poor microvascular blood flow produce white matter lesions. Additionally, disruption of nitric oxide pathways causes a cascade of neuronal metabolic deficiencies, resulting in destabilizing neurons, synapses, and neurotransmission, and generating synaptic loss and neuronal damage [80–83].

Investigations about the impact of patients with OSA treated with CPAP in the cognitive function have showed that daytime sleepiness decrease and cognitive function improves. The amount of improvement depends of biologic variability present in each patient [55, 84, 85]. Previous studies had been demonstrated that sleep disruption impaired cognitive function and the mechanisms of cognitive harm in OSA and chronic obstructive pulmonary disease (COPD) are similar. However, the pathophysiology of neurocognitive impairment in OSA and insomnia seems to be different, and the cognitive deficit in individuals with OSA is greater [46, 85, 86]. Therefore, other mechanisms such as changes in the brain could explain the cognitive impairment associated with OSA. Additionally, in some patients with OSA cognitive deficit persist, even after prolonged treatment with CPAP. For this reason, it is necessary to design future studies to identify appropriate treatment that can be administered before irreversible atrophic and metabolic changes occur [41, 87, 88]. Further studies should be performed to elucidate mechanisms of neurocognitive impairment and to identify genetics profiles for prediction of neurocognitive effects of CPAP in patients with OSA and other comorbidities.
