**3. Physiopathology of cognitive impairment in obstructive sleep apnea**

Neurocognitive impairment has over the years been associated with OSA but the prevalence of neurocognitive impairment in patients with OSA is not known [12]. One in four patients with OSA has neurophysiological impairment [33]. OSA patients are 7.5 to 20 times more likely to have difficulties with concentration, learning new tasks and execution monotonous tasks [34]. While current test for cognition not specifically assess impairments in OSA [35], some studies suggest that in the association between OSA and cognitive dysfunction, multitude of susceptibility and protective factors have been including, but others important factors should be considered. Susceptibility factors associated with neurocognitive impairment include: increased nocturnal awakenings, latency to REM sleep, [36, 37] changes in cerebral blood flow, neurovascular and neurotransmitter changes, intermittent hypoxemia, neuroinflammation, oxidative stress, ischemic precondition, hypercapnia [38, 39] and neural regulation in OSA [40]. Nevertheless, it is necessary to investigate the role of other factors such as genetic susceptibility, duration of OSA, hypertension, metabolic dysfunction, systemic inflammation, cerebral blood flow and blood-brain barrier [41].

Excessive daytime somnolence exhibit in patients with OSA increase the risk of cognitive decline and dementia. Sleep deprivation impair neuronal excitability, decrease myelination, produce cellular oxidative stress, misfolding of cellular

proteins, and alter molecular signaling pathways that regulate synaptic strength, plasticity-related gene expression and protein translation. These alterations create microinfarcts and brain atrophy that are associated with lower nocturnal oxygenation and reduction in NREM SWS sleep [42–44]. In OSA the proportion of stage N2 NREM sleep is increased and proportions of stages N1, N3 and REM sleep are decreased. During the NREM SWS abstraction of rules and integration of knowledge take place while in REM sleep creativity is beneficiated. In patients with OSA both sleep stages are reduced and fragmented, suggesting that some of the cognitive impairment is due to this dysregulation [45–47]. Frequently, obstructive events during NREM sleep have been associated with cognitive deficits and REM sleep events have been associated with greater sympathetic activity, hypertension and cardiovascular instability in patients with OSA. However, some studies reported that OSA reduction of REM sleep produce dissociation of REM traits to other sleep stages, affecting memory formation and consolidation [48, 49]. Gray matter atrophy in the prefrontal cortex observed in OSA and aging can mediate the degree of SWS disruption and consequent impaired overnight episodic hippocampal memory. Although several models have been proposed to explain the pathophysiology of cognitive impairment in OSA patients, the exact mechanisms of this association remain elusive [40, 50].

It has been suggested in meta-analysis and systematic review that cognitive deficit in patients with OSA is the result of poor night-time sleep and changes in the brain. Hypoxemia produces alteration of the prefrontal cortex and other CNS regions [51]. Then, global cognitive function is associated with hypoxemia and attention and vigilance dysfunction with sleep fragmentation. Sleep fragmentation is produced by the frequent sleep arousals that associated with apneic episodes contribute to abnormal sleep architecture, less restorative sleep and increased daytime sleepiness [14]. Therefore, treatment with continuous positive airway pressure (CPAP), should improve cognition and sleepiness. Evidence from clinical trials demonstrate that CPAP improves attention, vigilance memory executive functions and sleepiness, but deficits in learning memory and psychomotor function persist [52]. These findings suggest that improvements in sleepiness is not always associated with improvements in cognition, and it has been suggested that the improvement of cognition could be related with duration and severity of OSA [53].

Large-scale, multicenter, randomized, double-blind cohort study, the Apnea Positive Pressure Long-term Efficacy Study (APPLES), investigated the effects of CPAP on cognitive function in patients with OSA [53]. In this study, patients with severe OSA improved more than those with mild OSA. Although attention/psychomotor and learning/memory functions did not improve at either the 2-month or 6-month follow-up, improvement in the verbal delayed recall test was observed in patients on CPAP for 6 hours a day. Therefore, it was suggested that long-term memory deficits might be reversible with optimized CPAP treatment. Other studies following 3 and 12 months of treatment with CPAP show changes in gray frontal and hippocampal regions) and white matter correlated with improvements in memory, attention and executive functions [54, 55].

While several studies show that CPAP improves some cognitive domains, other studies reported less responsive for psychomotor activities. Additionally, the relationship between cognitive impairment and OSA severity is complex and the findings are inconsistent [9]. This complexity is represented by individual differences, genetic profiles and difficulties to measure OSA severity and cognitive impairment. Sleepiness questionnaire scores are not objectives and AHI (apnea/hypopnea index,

**147**

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

related with sleep cycles are needed [41].

**4. Brain changes associated with OSA**

sleepiness [58].

insular cortex) [62, 63].

number of apnea and hypopnea events per hour of sleep) cannot measure the individual differences in the length of each event. Furthermore, oxygen desaturation index cannot identify the sleep cycle when hypoxia and arousal occur. Therefore, novel measures that separate sleep fragmentation and oxygen desaturation and measures to identify these events in each sleep cycle because cognitive functions are

Several factors contribute to individual differences in the relationship between

There is evidence of structural and functional brain changes in critical areas

Several studies reported that OSA is a risk factor for cerebral small vessel disease (C-SVD). C-SVD is a group of pathologic processes that affect small arteries and veins, arterioles, and capillaries. Restricted blood flow in diseased small vessels, produce low perfusion pressure and hypoperfusion of the affected brain areas. Subsequently, chronic hypoperfusion develop ischemic C-SVD [64, 65]. Changes in white matter associated with OSA has also been reported. Degradation of multiple areas of subcortical tracts of the superior and inferior parietal lobe, deep frontal white matter and arcuate fasciculus. The white matter fiber integrity was recuperated after 12 months of CPAP treatment and this recuperation was associated with improvement in memory, attention, and executive functions [55]. The gray matter is also affected in patients with OSA. Some studies report that extent of gray matter volume loss increases correlated positively with OSA severity. Decreased gray matter has been observed in the frontal and parietal cortex, temporal lobe, anterior

cingulate, hippocampus, and cerebellum [66, 67] (**Figure 1**).

for cognition in patients with OSA. Numerous investigations have reported changes in the electroencephalogram of OSA patients compared with healthy individuals. These changes show abnormal cortical excitability associated with neurocognitive deficits [59, 60]. In the prefrontal model sleep disruption, intermittent hypoxemia, and hypercapnia observed in OSA produce cellular and biochemical stresses that alter neuronal and glial viability within prefrontal regions of the brain cortex, affecting the efficacy of restorative process occurring during sleep. This model explains the relationship between sleep fragmentation and nocturnal hypoxemia with predominantly frontal deficits. However, the neuroanatomic regions that have most commonly been reported in OSA are thalamus and frontoparietal cortex [61]. Degenerative areas in brain include: hippocampus (memory and new learning), the thalamus (sensory and motor signaling and in regulating sleep and alertness) and the amygdala (regulation of emotion) [16]. The findings in fMRI suggested a dysfunctional connectivity of the posterior default mode neuronal network and changes in network in the anterior insula, posterior-medial frontal cortex and thalamus (right amygdala-hippocampus complex and the

OSA and cognition. Aging is associated with changes in morphology, size and reflex sensitivity of upper airway, resulting in a reduction in upper airway dilator muscle function at sleep in older people [56, 57]. Also, it has been suggested that co-morbidities such as hypertension, hyperlipidemia, diabetes, metabolic syndrome, and Alzheimer disease are the primary causes of the neurological damage. Other individual differences are related with genetic predisposition, mood, changes in macro and microcirculation in the brain, gender and experience of

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

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

remain elusive [40, 50].

severity of OSA [53].

proteins, and alter molecular signaling pathways that regulate synaptic strength, plasticity-related gene expression and protein translation. These alterations create microinfarcts and brain atrophy that are associated with lower nocturnal oxygenation and reduction in NREM SWS sleep [42–44]. In OSA the proportion of stage N2 NREM sleep is increased and proportions of stages N1, N3 and REM sleep are decreased. During the NREM SWS abstraction of rules and integration of knowledge take place while in REM sleep creativity is beneficiated. In patients with OSA both sleep stages are reduced and fragmented, suggesting that some of the cognitive impairment is due to this dysregulation [45–47]. Frequently, obstructive events during NREM sleep have been associated with cognitive deficits and REM sleep events have been associated with greater sympathetic activity, hypertension and cardiovascular instability in patients with OSA. However, some studies reported that OSA reduction of REM sleep produce dissociation of REM traits to other sleep stages, affecting memory formation and consolidation [48, 49]. Gray matter atrophy in the prefrontal cortex observed in OSA and aging can mediate the degree of SWS disruption and consequent impaired overnight episodic hippocampal memory. Although several models have been proposed to explain the pathophysiology of cognitive impairment in OSA patients, the exact mechanisms of this association

It has been suggested in meta-analysis and systematic review that cognitive deficit in patients with OSA is the result of poor night-time sleep and changes in the brain. Hypoxemia produces alteration of the prefrontal cortex and other CNS regions [51]. Then, global cognitive function is associated with hypoxemia and attention and vigilance dysfunction with sleep fragmentation. Sleep fragmentation is produced by the frequent sleep arousals that associated with apneic episodes contribute to abnormal sleep architecture, less restorative sleep and increased daytime sleepiness [14]. Therefore, treatment with continuous positive airway pressure (CPAP), should improve cognition and sleepiness. Evidence from clinical trials demonstrate that CPAP improves attention, vigilance memory executive functions and sleepiness, but deficits in learning memory and psychomotor function persist [52]. These findings suggest that improvements in sleepiness is not always associated with improvements in cognition, and it has been suggested that the improvement of cognition could be related with duration and

Large-scale, multicenter, randomized, double-blind cohort study, the Apnea Positive Pressure Long-term Efficacy Study (APPLES), investigated the effects of CPAP on cognitive function in patients with OSA [53]. In this study, patients with severe OSA improved more than those with mild OSA. Although attention/psychomotor and learning/memory functions did not improve at either the 2-month or 6-month follow-up, improvement in the verbal delayed recall test was observed in patients on CPAP for 6 hours a day. Therefore, it was suggested that long-term memory deficits might be reversible with optimized CPAP treatment. Other studies following 3 and 12 months of treatment with CPAP show changes in gray frontal and hippocampal regions) and white matter correlated with improvements in

While several studies show that CPAP improves some cognitive domains, other studies reported less responsive for psychomotor activities. Additionally, the relationship between cognitive impairment and OSA severity is complex and the findings are inconsistent [9]. This complexity is represented by individual differences, genetic profiles and difficulties to measure OSA severity and cognitive impairment. Sleepiness questionnaire scores are not objectives and AHI (apnea/hypopnea index,

memory, attention and executive functions [54, 55].

**146**

number of apnea and hypopnea events per hour of sleep) cannot measure the individual differences in the length of each event. Furthermore, oxygen desaturation index cannot identify the sleep cycle when hypoxia and arousal occur. Therefore, novel measures that separate sleep fragmentation and oxygen desaturation and measures to identify these events in each sleep cycle because cognitive functions are related with sleep cycles are needed [41].

Several factors contribute to individual differences in the relationship between OSA and cognition. Aging is associated with changes in morphology, size and reflex sensitivity of upper airway, resulting in a reduction in upper airway dilator muscle function at sleep in older people [56, 57]. Also, it has been suggested that co-morbidities such as hypertension, hyperlipidemia, diabetes, metabolic syndrome, and Alzheimer disease are the primary causes of the neurological damage. Other individual differences are related with genetic predisposition, mood, changes in macro and microcirculation in the brain, gender and experience of sleepiness [58].
