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Chapter

Cognitive Impairment and

Obstructive Sleep Apnea
Liliana Otero, María del Carmen Figueredo,
Alain Riveros-Rivera and Patricia Hidalgo

Abstract

Obstructive sleep apnea (OSA) is a frequent sleep disorder characterized by

repetitive interruption of ventilation caused by partial or complete collapse of the
upper airway during sleep. OSA is highly prevalent in the world and it has been
associated with cardiovascular disease and cognitive impairment in children and
adults. The cognitive impairment in individuals with OSA includes deficiencies in
attention and constructional abilities, delayed long-term visual and verbal memory,
and executive functions. Although, the pathogenesis of cognitive impairment
in patients with OSA is complex and remains incompletely understood, several
mechanisms, such as hypoxia, inflammation and sleep fragmentation have been
proposed. The aim of this chapter is to describe some findings reported in the
literature to explain the association between OSA and cognitive impairment.

Keywords: obstructive sleep apnea, cognitive impairment, hypoxia, sleep

fragmentation

1. Introduction

Obstructive sleep apnea (OSA) is a breathing disorder of sleep produced by

partial or complete obstruction of the upper airways. This sleep disorder is char-
acterized by breathing cessation and reduction of airflow resulting in temporary
decrease, in cerebral oxygenation and sleep disruption [1]. The prevalence of OSA
is approximately 10% in men and 3% in women between the ages of 30–49%, but
rising to 17% in men older than 50 years and 9% in women post-menopause. It has
been reported that prevalence of OSA has increased since 1990 in the United States
and other countries. However, 80% of individuals with OSA remain undiagnosed
and untreated [2].
The pathophysiology of OSA includes oxygen desaturation, alteration in sleep
architecture and abnormal ventilation [3]. Hypoxemia and sleep fragmentation
(arousals) cause excessive daytime sleepiness increasing the risk of road and work
accidents [4] and reduced quality of life [5]. Additionally, OSA increase the risk
of cardiovascular, cerebrovascular and metabolic diseases [6], neurocognitive
impairment [7] and death [8]. One at time, cardiovascular diseases and metabolic
consequences of OSA increase the risk of cognitive impairment. Cognitive deficits
in individuals with OSA include attention and vigilance, episodic memory, delayed
long-term visual and verbal memory, visuospatial/constructional abilities and
executive functions [9–11]. Some studies reported that psychomotor function and

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Updates in Sleep Neurology and Obstructive Sleep Apnea

language do not seem compromised, [12] whereas others demonstrated to psycho-

motor function is affected by OSA and this domain does not improve with CPAP
therapy [13]. Although the cognitive impairment in individuals with OSA is largely
recognized as mild cognitive impairment, [14] OSA has also recognized as modifi-
able risk for dementia, neuropsychiatric disorders and stroke [15, 16]. However, the
pathophysiology of cognitive impairment in adults with OSA is complex and the
whole mechanisms involved in cognitive deficit have not been clarified yet.

2. Sleep’s role in memory

Since, Hervey de Saint Denys published Les Rêves et les Moyens de les Diriger in
1867, was established that sleep benefits the retention of memory [17]. Rosa Heine
was the first person, in 1914, who demonstrated that learning before a period of
sleep results in a lower rate of forgetfulness in the following 24 hours than learning
before a period of wakefulness. These results demonstrated the importance of sleep
for memory. Likewise, Ellenbogen et al. showed that sleep after learning benefits
the consolidation of memories and strengthens the traces of memory against future
interference. Current research findings show an active sleep role in the consolida-
tion of memory, learning and brain plasticity [18].
Sleep is defined as “a natural and reversible state of reduced response to external
stimuli and relative inactivity, accompanied by decreased consciousness” [19].
Sleep has four basic states, rapid eye movement (REM), no REM sleep 1 (N1),
NREM sleep 2 (N2) and NREM sleep 3 (N3). Slow wave sleep (SWS) is observed
in N3. In humans, SWS predominates in the early stages of the sleep and REM
in the final period, alternating in a cyclic manner. In terms of memory, forming
and recovering memories is a fundamental ability to achieve adaptation. Memory
functions involved different process such as encoding, consolidation and retrieval.
During encoding, the stimulus results in the formation of a new memory fragment
that is stabilized in consolidation process avoiding forgetting and incorporating the
memory into preexisting knowledge complexes. Consolidation occurs during SWS
and REM sleep stabilizes transformed memories [20, 21]. Also, it has been sug-
gested the possibility that cholinergic tone during delayed REM sleep is necessary
for the successful consolidation of memory [22, 23].
Theories that propose a differential role of the sleep stages in memory are based
on the “dual process hypothesis.” In this dual hypothesis, SWS has a benefit in the
declarative memories of events, such as learning word lists, word pairs or spatial
locations, and processing dependent on the hippocampus [24], while REM sleep,
benefits the consolidation of non-declarative memories (related to procedural
memory, including mirror tracing, priming, implicit memory, and the emotional
modulation of memories). A complex learning task can often involve both proce-
dural and declarative learning components (complex motor movements, language
learning). Emotive and sensitive events are better evoked than neutral ones, due
to stimuli of the amygdala in the process of coding in the hippocampus. Changes
registered in REM sleep for patients with mood disorders and lived dreams, clarify
the link between REM sleep and the increase in amygdala activity. This activity has
been related with the emotive and sensitive recycling during this stage of sleep.
REM sleep seems also to be related with strength and weakened of emotional
memory [25]. Findings from electroencephalogram (EEG) and functional magnetic
resonance imaging (fMRI) show activity in brain regions (hippocampal) correlated
with REM and SWS sleep, following both declarative and procedural learning.
Although other theories hypothesized that memory consolidation occurs during
different sleep states [26], neural processes of memory consolidation have been

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Cognitive Impairment and Obstructive Sleep Apnea
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observed during sleep and wakefulness [27]. Additional findings show that sleep
enhances memory performance in brain-damaged individuals, except in patients
with Parkinson [23].
The effect of sleep on memory is lasting and adaptive. Coding and initial
recovery depends on the integrity of the hippocampus. The beneficial effect of sleep
is linked to the interaction between slow oscillatory activity during SWS, thalamo-
cortical sleep spindles and spontaneous reactivations of hippocampal memory [28].
In humans, slow wave sleep is correlated with hippocampus-dependent memory
and REM sleep is associated with emotional memory. Currently, it is considered
that an active consolidation of memory is established specifically during sleep and
originates from the reactivation of newly coded memory representations that are
integrated into the long-term knowledge networks. Findings from fMRI suggest
that the process of consolidation in declarative memory is gradual. Then, the early
activity after learning is observed in hippocampal locations, and after reinforced
during sleep, long-lasting changes of memories are observed in medial prefrontal
cortical activity. REM and NREM sleep are important for preservation, integration,
and recollection of episodic memory [29]. In summary, sleep enhances learning of
skills, semantic, episodic and emotional memories and stimulates creativity.
Some factors such as age, psychiatric and neurodegenerative conditions, sleep
disruption and sleep apnea impair episodic memory [30, 31]. In patients with OSA
cognitive processing, memory, vigilance, divided attention and executive function-
ing are affected. These deficits are observed identifying decreased ability to digest
information, decreased ability to register, store, retain, and retrieve information,
inability to maintain attention over the time, inability to respond to more than
one task or stimuli, disorganization, emotional liability, impulsivity and difficulty
maintaining motivation [32]. Beyond physiologic functions, the role of sleep in
brain plasticity and memory consolidation processes is relevant, but the mecha-
nisms involved in these processes remain to be fully understood. Therefore, it is
necessary to perform future investigations to elucidate the pathophysiology of sleep
disorders in neurocognitive impairment.

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, learn-
ing new tasks and execution monotonous tasks [34]. While current test for cogni-
tion 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, hyper-
capnia [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

3
Updates in Sleep Neurology and Obstructive Sleep Apnea

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 oxygen-
ation 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 knowl-
edge 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 atro-
phy 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 frag-
mentation 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 posi-
tive 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 psycho-
motor function persist [52]. These findings suggest that improvements in sleepi-
ness 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/psy-
chomotor 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 rela-
tionship between cognitive impairment and OSA severity is complex and the find-
ings 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,

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

number of apnea and hypopnea events per hour of sleep) cannot measure the indi-
vidual 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 dila-
tor 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 dam-
age. Other individual differences are related with genetic predisposition, mood,
changes in macro and microcirculation in the brain, gender and experience of
sleepiness [58].

4. Brain changes associated with OSA

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

for cognition in patients with OSA. Numerous investigations have reported
changes in the electroencephalogram of OSA patients compared with healthy indi-
viduals. These changes show abnormal cortical excitability associated with neuro-
cognitive 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 fronto-
parietal 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
insular cortex) [62, 63].
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 recuper-
ated 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).

5
Updates in Sleep Neurology and Obstructive Sleep Apnea

Figure 1.
Magnetic resonance imaging in patient with cognitive impairment and OSA and in healthy individual.

5. Mechanisms associated to cognitive impairment in OSA

OSA causes oxygen desaturation producing arousals and nocturnal intermit-

tent 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 surveil-
lance 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 fac-
tor-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 bar-
rier 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 hemodynam-
ics 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

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

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 compro-
mised. 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 destabi-
lizing 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.

6. Conclusions

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

modifiable risk factor for dementia.

• Sleep fragmentation, hypoxia, maladaptive pathways, neuroinflammation,

hypoperfusion and endothelial dysfunction contribute with neurocognitive
impairment in patients with OSA.

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

tools for OSA and cognitive impairment.

• The exact pathophysiology of cognitive impairment in OSA patients remain

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

Acknowledgements

Supported by Colciencias Grant 850-2017, project 57720.

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Updates in Sleep Neurology and Obstructive Sleep Apnea

Author details

Liliana Otero1*, María del Carmen Figueredo2, Alain Riveros-Rivera3

and Patricia Hidalgo4

1 Dentistry and Sciences Faculties, Pontificia Universidad Javeriana, Bogotá,

Colombia

2 Medicine Faculty, Pontificia Universidad Javeriana, Bogotá, Colombia

3 Department of Physiological Sciences, Pontificia Universidad Javeriana,

Bogotá, Colombia

4 Pontificia Universidad Javeriana, Hospital Universitario San Ignacio,

Bogotá, Colombia

*Address all correspondence to: [email protected]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

8
Cognitive Impairment and Obstructive Sleep Apnea
DOI: http://dx.doi.org/10.5772/intechopen.82756

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