Key words
obstructive sleep apnea - cardiovascular risk - cognition
1. Introduction
Obstructive sleep apnea (OSA) is by far the most common form of sleep-related
breathing disorder. It is characterized by inspiratory flow limitations (hypopneas,
apneas), snoring, and paradoxical respiratory movements of thorax and abdomen.
Obstructive sleep apnea syndrome (OSAS) is the term used to describe OSA with the
typical symptoms of daytime sleepiness and snoring. Often, both terms are used
redundantly. The severity of OSA is classified according to the number of hypopneas
and apneas occurring per hour (apnea-hypopnea index=AHI) into three severity
levels: low-grade (syn. mild): AHI of 5–15/h, moderate: AHI of
15–30/h, and severe: AHI of>30/h.
The following discussion refers to obstructive sleep apnea and its effects on the
cardiovascular disease risk and cognitive performance in adults. Other rarer types
of sleep-related breathing disorders (central sleep apnea, mixed forms) must be
considered on a case-by-case basis depending on the cause and metabolic, neurologic,
as well as cardiovascular comorbidities.
2. Obstructive sleep apnea and cardiovascular diseases
2. Obstructive sleep apnea and cardiovascular diseases
2.1. Pathophysiology
Obstructive sleep apnea is an independent risk factor for the development of
various cardiovascular diseases. OSA leads to structural myocardial alterations
and changes of the vascular microenvironment. The pathogenesis is multifactorial
([Fig. 1]). The imbalance between
airway opening (requiring muscle activity) and occlusion forces (due to anatomic
constriction, airway resistance) results in pharyngeal obstruction, which leads
to hypoxemia, hypercapnia, negative intrathoracic pressure, and an activation of
the sympathetic nervous system with effects on hemodynamics and autonomic
regulation. One of the most important factors for the development and prognosis
of cardiovascular diseases in OSA is intermittent hypoxia. It is characterized
by repeated short cycles of desaturation followed by rapid reoxygenation.
Intermittent hypoxia triggers an increased oxidative stress as important factor
for the development of vascular-endothelial dysfunctions (inflammation,
decreased vascular tone) and arteriosclerosis [1]
[2]
[3]
[4]
[5].
Fig. 1 Pathophysiological correlation between obstructive sleep
apnea (OSA) and cardiovascular diseases.
These complex activations of neural, humoral, metabolic, and inflammatory
mechanisms triggered by OSA lead to an increased risk of cardiovascular diseases
such as arterial hypertension, cardiac arrhythmias, coronary heart disease and
myocardial infarction, heart failure, and stroke.
Most trials on OSA and cardiovascular diseases are based on clinical observations
and reveal a close correlation. The evidence and the proven therapy effects vary
and are described for each condition.
There is a small number of studies on in vitro and animal models [6]. In vitro models mainly investigate the
impact of intermittent hypoxia on oxidative stress and resulting cellular
changes [7]
[8]. Animal models are based on triggering
intermittent obstructions (via tracheostoma, intratracheal balloons, nasal
masks) or exposure to oxygen-reduced gas mixtures. This allows basic research on
the OSA effects of hypoxia, hypercapnia, and sympathetic activation [9]
[10]
[11]
[12]
[13]
[14].
2.2. Arterial hypertension
Experimental and clinical data show that OSA acutely increases nocturnal blood
pressure and can lead to a lack of nocturnal blood pressure drop.
Physiologically, a decrease in blood pressure of at least 10% occurs
during healthy sleep. This blood pressure reduction (syn. dipping) is due to a
resetting of the control point of the baroreceptor reflex. OSA-related
sympathetic activation with increased catecholamine release and stimulation of
baroreceptors by intrathoracic pressure change may result in the development of
chronic hypertension.
OSA is an independent risk factor for the development of arterial
hypertension.
Approximately 50% of all patients with OSA suffer from arterial
hypertension. About 30% of all patients with arterial hypertension have
OSA. The risk of developing hypertension increases with the severity of OSA. In
younger and middle-aged patients with moderate to severe OSA and daytime
sleepiness, the relative risk of developing arterial hypertension increases to
almost threefold. In refractory arterial hypertension and especially in
nocturnal hypertension with failure to lower blood pressure (syn. non-dipping),
OSA is present in up to 70% of the patients. Nocturnal hypertension and
non-dipping are associated with high cardiovascular risk.
According to current recommendations [15]
[16], polygraphic workup is
recommended in cases of clinical suspicion of OSA, pathologic 24-h blood
pressure profile, or refractory arterial hypertension.
The antihypertensive effect of OSA therapy depends on several factors. For
positive airway pressure (PAP) therapy, the most important parameter is adequate
duration of use (>4 h per night). Usually, a combination of drug
therapy and PAP therapy must be applied. Synergistic effects between PAP and
drug therapy are observed with regard to blood pressure reduction, so that blood
pressure medication should be adjusted regularly if patients adhere well to PAP
therapy. PAP therapy lowers systolic and diastolic blood pressure more at night
than during the day. The highest treatment effects are achieved in patients with
refractory blood pressure, non-dipping, age <60 years, and severe OSA
with severe hypoxemia. The highest reduction (-10 mm Hg) was achieved in
patients with severe OSA, arterial hypertension, and daytime sleepiness [17]
[18]. Therapy with mandibular advancement splints also demonstrated a
moderate reduction in mean arterial pressure [18].
2.3. Coronary artery disease and myocardial infarction
Pathophysiologically, OSA-related release of vasoactive substances, increased
oxidative stress, and vascular inflammation result in arteriosclerotic damage to
the coronary arteries with subsequent acute myocardial ischemia [15]. The incidence for coronary artery
disease is two to three times higher in OSA patients [17]
[19]
[20]. In epidemiological
studies and systematic reviews, moderate and severe untreated OSA showed a
significantly higher incidence of fatal and nonfatal cardiovascular events [20]
[21]
[22]
[23]
[24]
[25]. Myocardial infarction
occurs more frequently during nighttime in OSA patients with coronary heart
disease [26].
The results of two larger randomized trials (SAVE, ISAAC) as well as
meta-analyses of all randomized trials on incidence of cardiovascular events in
OSA led to a controversial discussion, since these studies could no longer
clearly reveal the correlation between OSA and cardiovascular diseases [27]
[28]
[29]
[30]
[31]. In the current ISAAC trial (multicenter, randomized), patients
with acute coronary syndrome were randomized 1:1 to a group with PAP therapy and
to a group without PAP therapy, and followed-up for at least one year. A group
with acute coronary syndrome but without OSA served as control group. There were
no significant differences between the incidences of cardiovascular events in
all three groups [30]. Interpretation of
the results was critical because of the exclusion of symptomatic patients and
the overall low utilization times of PAP therapy. Moreover, the main problem of
all studies was the heterogeneity of the included patients with coronary artery
disease [25]
[32]
[33]
[34]. A post-hoc analysis of
the ISAAC trial in 1701 patients yielded in the division into two phenotypes:
patients without prior heart disease/previous acute coronary syndrome
(81%) versus patients with prior heart disease/previous acute
coronary syndrome (19%). For the phenotype without prior cardiovascular
disease, the OSA group showed a significantly increased risk of cardiovascular
events. In contrast, for the other phenotype, there was even a protective effect
of OSA for cardiovascular events. These results support other findings and the
hypothesis that the presence of obstructive sleep apnea may have a protective
effect in persisting coronary stenosis by forming coronary collaterals through
ischemic and hypoxemic conditioning [35]
[36]
[37]. Supporting this hypothesis, the
protective effects in phenotype with previous cardiovascular disease were
independent of age, sex, BMI, and location of the lesion, and notably occurred
only in OSA and not in central sleep apnea.
In summary, there is an increased risk of cardiovascular events (myocardial
infarction, acute coronary syndrome) in male patients with untreated moderate to
high-grade OSA. According to current studies, the treatment effect of OSA is not
as clearly demonstrable as for arterial hypertension.
2.4. Cardiac arrhythmias
OSA-related cardiac arrhythmias can occur as bradycardic and as tachycardic
arrhythmias. The prognosis is critically dependent on the presence of other
cardiac diseases and the type of arrhythmia [4]. Causes include intermittent hypoxemia/hypercapnia,
increased sympathetic tone, and intrathoracic pressure fluctuations.
Bradycardias can occur as higher-grade AV blocks to transient asystole and are a
predictive marker for higher-grade OSA [4]
[38]. In most cases, the
cause is repetitive stimulation of the autonomic nervous system. Treatment of
OSA often leads to a reduction in nocturnal bradycardic arrhythmias [4]
[39].
Up to 70% of all patients with atrial fibrillation have relevant
sleep-disordered breathing. The prevalence of AF is increased five to six times
in OSA and increases with age [4]. PAP
therapy can lead to a significant reduction (up to 60%) in the
recurrence or progression of AF. The effectiveness of cardioversion or drug
therapy is significantly lower in patients with untreated OSA [4]. Therefore, guidelines recommend sleep
apnea screening and therapy for OSA in atrial fibrillation. To date, only
observational studies with proven mechanisms and homogeneous data are available
[40]
[41]
[42], and the results of
randomized trials (SLEEP-AF, study of the PAP effect on atrial fibrillation
burden) are currently pending. Drug therapy approaches are also currently under
discussion for asymptomatic OSA and AF. In basic studies, changes in enzyme
activity (calcium-calmodulin-dependent protein kinase II) as well as a
disturbance in the synthesis of structural proteins (connexin 43) were found in
the myocardial tissue of OSA patients. Drugs for both signaling pathways are in
the state of pre-clinical development [2].
2.5. Heart failure
About 50% of patients with stable heart failure suffer from moderate to
severe OSA. The incidence is significantly higher in patients with acute
decompensated heart failure [43]. As the
severity of the heart failure increases, and especially in the presence of an
impaired ejection fraction, the proportion of central apneas associated to
impaired respiratory regulation (Cheyne-Stokes respiration) increases, so that
the most common cause of central sleep apnea is more severe heart failure. In
contrast, OSA is mostly observed in patients with heart failure with preserved
ejection fraction [44].
In male patients, OSA is an independent risk factor for the development of heart
failure [23]. Pathophysiologically, there
is persistent and progressive subclinical myocardial damage due to OSA-related
increase in left ventricular afterload, sympathetic activation, and increased
oxygen consumption with concomitant hypoxemia [4]
[45].
The effects of PAP therapy are more easily detectable in heart failure patients
than in healthy subjects [46]. There is no
randomized controlled trial showing a clear survival (cardiovascular mortality)
benefit with PAP therapy in heart failure. Single monocentric studies have shown
a reduction in left ventricular afterload and an increase in left ventricular
ejection fraction [47]. PAP therapy in
heart failure patients is recommended in symptomatic OSA. In this case, there is
an improvement in quality of life. In heart failure patients without daytime
sleepiness, the indication for PAP therapy must be individualized [43]
[48].
2.6. Stroke
Based on several mechanisms, OSA can be a trigger for an apoplectic insult.
Oxidative stress leads to cerebral arteriosclerosis, which is the main cause of
ischemic strokes. Acutely, increases in blood pressure or thromboembolic events
as result of a cardiac arrhythmia can lead to a hemorrhagic insult. After
stroke, secondary sleep-related breathing disorders occur in up to 70%
of the patients, which may lead to an increase in stroke damage and acute stroke
mortality [49]. OSA is associated with
stroke incidence independently of other risk factors [50]
[51]. In cases of severe OSA, the incidence for stroke is increased
2–3-fold, independently of sex and age [50]
[52].
The effect of PAP therapy on stroke incidence could not be revealed in a
meta-analysis of 7 randomized trials [27].
Smaller randomized trials show that PAP therapy after stroke improves
neurological recovery as well as sleepiness and depressive symptoms [50]. Therefore, PAP therapy is recommended
as a therapeutic component in the context of multimodal management after
stroke.
2.7. Determination of the individual cardiovascular risk
2.7.1. Arousal burden
The arousal burden is defined by the cumulative length of all waking
reactions related to the sleep duration. The measurement is automated by
analysis algorithms. The parameter describes sleep fragmentation
significantly better than the apnea-hypopnea index (AHI) does, and is a
potential predictor of long-term cardiovascular risk. In a systematic
analysis of data from 8001 participants in three cohort studies, a high
arousal burden was associated with increased cardiovascular mortality,
especially in women [53].
2.7.2. Hypoxemia load
The hypoxemia load is calculated from the area under the desaturation curve
during a respiratory event relative to the baseline saturation. This
captures the hypoxemias that are specific to sleep apnea. Data analysis of
two cohort studies (7534 participants) showed a significantly higher
incidence of heart failure in men with a high hypoxemia load [54].
2.7.3. Biomarkers
In accordance with the pathophysiological basis, the search for biomarkers of
cardiovascular risk was performed by analyzing markers of oxidative stress
and inflammation, adhesion molecules, and endothelial proteins [55]. A systematic review identified
over 20 different biomarkers. Mostly studies with small numbers of
participants and retrospective design are available. The cardiovascular
conditions included are not redundant and range from studies of hypertension
alone to inclusion of all cardiovascular events. Elevated levels of some
biomarkers were associated with cardiovascular events in OSA: YKL-40
(glycoprotein)/low-density lipoprotein with coronary artery disease,
high-sensitivity
CRP/interleukin-1Ra/interleukin-8/TNF-α with
acute cardiovascular events, intercellular adhesion molecule (ICAM 1) with
acute coronary syndrome and cerebrovascular ischemia, and
endoglin/fms-like tyrosine kinase 1 with arterial hypertension.
Biomarkers for oxidative stress and catecholamine were not significantly
increased in patients with OSA and cardiovascular disease in the few studies
available on this topic [56].
2.7.4. Phenotyping
In recent years, attempts to identify OSA phenotypes have been made to
incorporate new knowledge in OSA pathogenesis and its importance for a
targeted, individualized treatment strategy [57]. Four pathophysiological phenomena are considered, which in
individual cases have a different weighting on the development, the
severity, and thus the treatment indication of OSA. Thus, in addition to the
narrow/collapsed airway, ineffective upper airway dilator function
during sleep, unstable respiratory control (high loop gain) and a low
threshold for arousal responses are considered [58]. Depending on the expression of the
four components and the resulting severity of OSA, first recommendations for
a targeted therapy were developed, which – in addition to PAP
therapy that is certainly the most frequently indicated one –
include other therapy options such as weight reduction, positional therapy,
mandibular advancement splint, surgical measures, and drug therapy also as
first-line therapy or combination therapy.
A review on the cardiovascular risk summarized all studies with cluster
analyses [59]. From the available
data, four OSA subtypes (A-D) were clustered based on age, body mass index
(BMI), sex, symptoms, and comorbidities as well as two OSA subtypes (E, F)
based on polysomnography data and PAP adherence as major subtypes. Subtype A
corresponds to the classic OSA patient (male, middle-aged, increased BMI,
daytime sleepiness, few comorbidities). In this group, the parameter of
excessive daytime sleepiness was most strongly associated with increased
cardiovascular risk. Subtype B includes elderly, overweight patients,
predominantly male, with mild to moderate symptoms, increased comorbidities,
and severe OSA with a high hypoxemia burden. In this group, the prevalence
of hypertension, diabetes, and cardiovascular disease is increased, but the
risk of new onset myocardial infarction and stroke is not clearly higher.
The above-mentioned preventive effect of OSA for cardiovascular events is
discussed as the cause. Subtype C comprises predominantly middle-aged women
with moderate obesity and insomnia symptoms (difficulty with initiating and
maintaining sleep, non-restorative sleep) as well as moderate to severe OSA.
The prevalence for cardiovascular diseases in this subtype is between
subtype A and B. The risk for stroke is lower than in the other OSA
subtypes. Subtype D includes younger male patients with upper airway
resistance syndrome (snoring, sudden awakening with dyspnea) without
significant daytime sleepiness and comorbidities. These patients have poor
PAP adherence, and cardiovascular risk is unknown. The two subtypes of E and
F differ with regard to hypoxemia. Subtype E groups patients with
particularly severe OSA (AHI of 66–84/h) and marked
hypoxemia parameters. This subtype has an increased risk of nonfatal or
fatal cardiovascular event. Subtype F comprises patients with severe OSA
(AHI of 34–68/h) and few hypoxemic events with lower PAP
adherence and lower cardiovascular risk.
2.8. Summary
In summary, obstructive sleep apnea is a clear risk factor for cardiovascular
disease. OSA is highly prevalent in cardiovascular disease patients with
difficult-to-control arterial hypertension, coronary artery disease,
arrhythmias, or heart failure and is associated with a poor prognosis. Therapy
for OSA may usefully complement the treatment of cardiovascular disease because
of its effects on arterial blood pressure and quality of life in selected
patients. Therefore, integrative cardiology and sleep medical care for these
patients is very important. The German Society of Cardiology has highlighted the
significance of the comorbidity of sleep-related breathing disorders in
cardiovascular disease in its position paper on sleep medicine in cardiology and
with the initiation of a curriculum in sleep medicine to obtain the additional
qualification of cardiovascular sleep medicine.
The objective of current and future scientific development is the creation of
individualized therapy concepts. The prerequisites for estimating the individual
cardiovascular risk are constantly being approved through the use of artificial
intelligence in the evaluation of large biological and measurement data volumes
and their correlation. Thus, studies on effects of different therapies on
cardiovascular risk in different patient groups with respect to age, sex, and
comorbidities can be performed with greater evidence.
3 Obstructive sleep apnea syndrome and cognition
3 Obstructive sleep apnea syndrome and cognition
The term “cognition” (from the Latin word cognitio) is a collective
term for processes and structures that relate to the reception, processing, and
storage of information. The most important cognitive functions are attention,
memory, and the executive functions ([Table
1]) [60]
[61]
[62]
[63].
Table 1 Overview of cognitive functions.
The term of cognitive disorders summarizes impairments of information processing in
the brain. Cognitive impairment affects daily activities, occupational performance,
and quality of life.
The association between OSA and cognitive impairments has been demonstrated in many
studies with clear evidence [64]
[65]
[66].
The cognitive impairments are mainly manifest in areas of attention, executive
functions, and memory compared with control groups. Cohort studies and meta-analyses
also revealed an increased risk in OSA patients for the development of mild
cognitive impairment, dementia, or Alzheimer’s disease [64]
[67]
[68]
[69]. 40% of dementias are due to
modifiable risk factors, one of which is untreated OSA [70]
[71]
[72].
3.1. Pathophysiology
Decisive factors for cognitive and behavioral changes in obstructive sleep apnea
are the apnea-and hypopnea-induced intermittent hypoxemias and sleep
fragmentation ([Fig. 2]). Mainly due to
the intermittent hypoxemias, reversible and irreversible inflammatory changes of
brain vessels, brain structures, and neurotransmitter systems occur [73]
[74]
[75]. Studies of brain
metabolism and structures showed alterations in the integrity and structure of
the white matter [76]
[77]
[78]
[79], hippocampus [80]
[81], and a decrease in cortical thickness [82]
[83]
[84] in OSA patients. Most
of the studies were performed using imaging techniques [85]
[86]
[87]
[88]. They show two partially opposite
effects. Gray matter atrophy, higher white matter hyperintensity, lower
fractional white matter anisotropy, and higher water diffusivities indicate
cellular damage, some of which is irreversible. In contrast, gray matter
hypertrophy and limited white matter diffusivity are more likely to reflect
reversible consequences such as intracellular edema, reactive gliosis, or
compensatory structural changes [89]
[90].
Fig. 2 Pathophysiological correlations between obstructive sleep
apnea (OSA) and cognitive dysfunctions.
Evidence of the morphologic disturbances primarily in the prefrontal cortex
correlates with the executive function disorders most commonly seen in OSA
patients [63].
Memory is subject to a broader range of influencing factors with activation of
different brain regions so that the correlations cannot be clearly verified.
Correlations are shown in sleep-related memory performance such as spatial
memory and consolidation of memory content [64]. Language and psychomotor skills are unchanged in OSA patients
compared to control groups [66]
[91]. Sleep fragmentation has an additional
reinforcing effect on hypoxemia-induced cognitive changes. The exact mechanisms
are still unknown. A higher vulnerability to hypoxemic events due to changes in
neurotransmitter homeostasis is discussed [60]
[74]
[92].
A correlation to OSA severity has been identified in attention and vigilance, but
no correlation was found in executive functions, language, memory, and
psychomotor functions [60]
[65]
[91]
[93]
[94]. Fine motor skills appear to be more
sensitive to hypoxemic injury [73].
Executive function deficits correlate poorly with self-assessed or measured
daytime sleepiness [94].
In meta-analyses and systematic reviews, correlations between OSA and single
cognitive deficits could be better demonstrated in smaller sleep
medicine-managed cohorts and controlled case studies than in large epidemiologic
studies [71]
[95]
[96]. Large epidemiologic trials often capture only the history of OSA
without assessing the severity or utilization efficiency of therapy. Smaller
sleep medicine supervised studies show better diagnostic representation of OSA
severity and controlled evidence of therapy utilization. Protective or
vulnerable factors, which are less frequently assessed in epidemiological
studies, also have a significant influence on the development of cognitive
impairment.
Various influencing factors are discussed with regard to vulnerability and
protection of the development of cognitive disorders. Important risk factors are
age, sex, and menopause as well as concomitant diseases such as obesity,
hypertension, and depression. Significant protective factors are cognitive
reserve and physical activity.
3.2. Risk factors for cognitive deficits in cases of OSA
3.2.1. Age
OSA and advanced age (>65 y) independently impair cognitive
function. The combination of untreated OSA and advanced age has an additive
effect with respect to cognitive impairment [97]
[98]. In elderly
patients with untreated OSA, conditions such as mild cognitive impairment
and dementia are more likely to occur, and symptomatology is exacerbated in
manifest cognitive disease [70]
[99]
[100]. Crucial factors are the number and extent of intermittent
hypoxemia [101]. While low and
moderate severity show less correlations, significant deteriorations in
executive functions, memory, and attention are found in elderly patients and
high severity OSA [68]
[102]
[103]. A systematic review of 68 studies showed that attention,
executive functions, and memory were impaired in young and middle-aged
patients (30–60 y), whereas this was not as evident in older
patients (>60 y) [68].
The cause is discussed to be the increasing influence of concomitant
diseases such as cardiovascular disease, hypertension, and neurodegenerative
diseases, which reduce the differences in cognitive impairment between
patients with and without OSA in higher ages.
3.2.2. Sex
The prevalence of dementia is up to 29% higher in women than in men,
up to 2/3 of Alzheimer patients are female. Discussed influencing
factors are the longer life expectancy and hormonal differences
(e. g. pharyngeal fat distribution, body trunk) in females.
Differences are evident in symptomatology and in the development of
sequelae. Men complain of OSA-typical symptoms such as snoring, breathing
interruptions, or daytime sleepiness. In women, symptoms are more unspecific
like headache, tiredness, depression, anxiety, and sleep disturbances [101]. Few studies show differences
between OSA and cognition as a function of sex, as most studies on OSA are
dominated by the male sex. Women with OSA were more likely to develop
dementia than men [104]. Differences
between men and women in symptomatology and effect on cognitive performance
increasingly equalize after menopause and in higher ages [71]
[99]
[105].
3.3. Protective factors for cognitive deficits in cases of OSA
3.3.1. Cognitive reserve
Cognitive reserve defines the ability to optimize or maximize performance
through differential recruitment of brain networks and the use of
alternative cognitive strategies [106]. Morphologically, there are more synapses, a higher number of
redundant neural networks, and more efficient processes with the same number
of synapses. Educational level, intelligence level, and occupational
activity are markers of cognitive reserve [107].
Studies revealed that highly intelligent OSA patients
(IQ≤90th percentile) show fewer attentional deficits
than normally intelligent OSA patients, regardless of OSA severity and
daytime sleepiness [64]
[108]. The cause is thought to be the
cognitive reserve of the highly intelligent patients who thus have a higher
tolerance to neurodegenerative brain changes.
3.3.2. Physical activity
Physical activity is one of the clearest preventive factors for the
development of Alzheimer’s disease. Training programs lead to
improved cognitive functions in inactive elderly patients by influencing
neuroplasticity and reducing blood pressure, weight, and inflammatory
parameters. In OSA patients, the negative effects add up through a cycle of
daytime sleepiness, fatigue, and reduction in physical activity and weight
gain [109].
The risk factors and protective factors need to be better investigated in
future studies and taken into account in the interpretation especially of
meta-analyses and epidemiological studies.
3.4. Therapy effects on cognitive disorders
Most studies are available on PAP therapy. Some few trials reveal therapy effects
with mandibular advancement splints and surgical measures.
3.4.1. PAP therapy
Study results on the effect of PAP therapy are inconsistent due to the
inhomogeneity of data, use of different test instruments, and frequent lack
of recording of PAP use [110]
[111].
A meta-analysis of 13 randomized trials (554 patients) revealed effects on
attention [112]. In elderly patients,
a meta-analysis (5 randomized trials, 680 patients) showed a slight
improvement in cognitive function [113]. In both analyses, there was a significant improvement in
daytime sleepiness with PAP therapy. One of the few studies of long-term
effects investigated the PAP effect after 10 years (126 patients) in severe
OSA and revealed improvements in memory function, attention, and executive
functions [113]. Treatment effects are
also seen in low-grade and moderate OSA, although they are less pronounced
and more often result in lower treatment adherence or treatment
discontinuation [114]. Crucial for the
therapy effect is the duration of use and adherence [115]
[116]. Therapy effects have been demonstrated after a minimum
usage time of 3 months or more, and no positive effects were shown with a
shorter usage time [64]
[92]
[117]. Some cognitive functions such as visual-constructive
skills, executive functions, and memory respond poorly to PAP therapy
compared to attention and vigilance [73]
[102]
[118]
[119]
[120].
The morphologically detectable changes are partially reversible by successful
PAP therapy [66]
[121]
[122]
[123]. The irreversible
morphologic brain changes are associated with residual daytime sleepiness
despite adequate therapy [64]
[78]
[124].
PAP therapy has a preventive effect on the occurrence and symptomatology of
mild cognitive impairment, dementia, and Alzheimer’s disease [65]
[120]
[125]
[126]
[127]. Meta-analyses of PAP therapy and depression revealed an
overall improvement in depressive symptoms, but considerable heterogeneity
was identified in study design and outcome [116]
[128]
[129]
[130]. The greatest improvements were achieved when the initial
burden of depression was significant at the time of study onset [129]
[131].
3.4.2. Non-PAP therapy
There are few studies on cognition and other OSA therapies.
Therapy with mandibular advancement splints for six months improved
attention, but showed no effect on working memory [132]. An improvement in depressive
symptoms was achieved during therapy with mandibular advancement splints
[129].
A study with 32 participants showed a positive effect of
uvulopalatopharyngoplasty on attention three to six months postoperatively
[133].
3.5. OSA and neurocognitive diseases
3.5.1. Mild cognitive impairment (MCI)
Mild cognitive impairment is defined as a level of thinking performance that
is significantly below the one that can be expected according to the age and
education of the person affected. In contrast to dementia, however, only
minimal everyday impairments occur. MCI is considered as precursor to
various forms of dementia. OSA is associated with mild cognitive impairment
in up to a quarter of cases [64]
[101]
[120]. The manifestation of mild cognitive impairment occurred 10
years (72.6 versus 83.6) earlier in patients with untreated OSA than in
patients with treated OSA in a long-term study [134].
3.5.2. Alzheimer’s diseaes
Alzheimer’s disease is the most common form of dementia, accounting
for up to 80%. Studies on Alzheimer’s disease suggest a
reciprocal relationship between OSA and Alzheimer’s disease [67]. Both diseases are common in the
elderly population and frequently co-occur [97]. A meta-analysis found that OSA was five times more common in
Alzheimer patients compared to age-matched controls [135]. The immediate adverse effects of
OSA on cognition, particularly executive function and attention, may
contribute to worsening the clinical picture and more rapid progression of
Alzheimer’s disease. Based on a combination of mechanisms
(disordered sleep architecture, intermittent hypoxia and hemodynamic
changes, effects of concomitant vascular disease), OSA represents a
cumulative predisposing factor for the development of Alzheimer’s
disease. Unlike other predisposing factors such as genetic predisposition,
age, and cerebral trauma, OSA can be diagnosed and treated. Treatment of OSA
has a preventive effect on preclinical Alzheimer’s disease as well
as on slowing cognitive decline in clinical Alzheimer’s disease
[68]
[70]
[125]
[127].
3.5.3. Depression
OSA patients have twice the prevalence to acquire depression [136]
[137]. Sleep fragmentation, in particular, leads to alteration in
brain regions where emotional modulation occurs [93]. Depressive and OSA symptoms such
as fatigue and loss of concentration overlap. Untreated OSA can lead to a
worsening of depression, and depressive symptoms negatively affect treatment
adherence and compliance in OSA [138]
[139]. In general
population and in study populations without OSA, prevalence of depression is
lower in men than in women [140].
However, if OSA is present, this difference is no longer as clear [93]. In men with OSA, the severity of
depressive symptoms correlated significantly with the severity of OSA. Women
were at higher risk for clinically significant depressive symptoms only when
the AHI was in the moderate range [141]. Treatment of OSA primarily improves overlapping symptoms
such as fatigue and lack of motivation [129].
3.6. Determination of the individual cognitive risk
3.6.1. Humoral biomarkers
Biomarkers of neurodegenerative diseases have been discussed as predictors of
morphologic changes due to OSA and investigated in a few studies. These
include phosphorylated tau protein (p-tau), β-amyloid, and
neurofilament light chain (NFL). First trials show an association between
OSA severity and p-tau [86]
[142] and β-amyloid elevation in
CSF [68]
[86]
[143] and plasma [144].
3.6.2. Electrophysiological biomarkers
The event-related potential P300 in the EEG is a known predictor of cognitive
processes. Changes in amplitude and latency of P300 are associated with
memory and attentional changes. A study of 55 patients with severe OSA with
a high hypoxemia load demonstrated a correlation with the amplitude of P300
potentials compared with normal subjects [145].
3.6.3. Genetic predictors
Detection of the apolipoprotein E4 allele (syn. ApoE-4 allele) on chromosome
19 is a genetic risk factor for Alzheimer’s disease. This genetic
variant is found in 20–25% of all Alzheimer’s
patients and in up to 50% of Alzheimer’s patients with a
late disease onset. Animal studies in mice with ApoE-4 allele indicate
increased vulnerability to cognitive deficits from intermittent hypoxemia
and sleep interruptions [146]. The
genetic variant of the ApoE-4 allele is discussed as a
“vulnerability factor” for the development of cognitive
deficits and sleep-related breathing disorders in elderly patients [98].
3.7. Summary
In summary, obstructive sleep apnea is a risk factor for cognitive deficits and
associated diseases. OSA is common in patients with mild cognitive impairment,
Alzheimer’s disease, and depression and is associated with a worse
prognosis. Therapy for OSA can reduce cognitive impairment. In neurocognitive
disorders, OSA therapy is an additive treatment option to improve symptomatology
and quality of life in selected patients.
To improve the evidence regarding the cognitive effects of OSA and development of
individualized therapy recommendations, long-term studies are particularly
needed taking into account age, sex, educational level, physical activity,
duration of untreated OSA combined with standardized examination methods of
cognitive functions and OSA as well as accurate recording of adherence to OSA
therapy measures.
