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C. M. Van De Heyning et al.
9.5.2 Pathophysiology
Apart from the association of OSA with specic cardiovascular conditions that
carry an increased risk of SCD, following potential pathophysiologic mechanisms
might play a role in ventricular arrhythmogenesis and SCD in OSA [79].
• Intermittent nocturnal hypoxia, resulting in intracellular acidosis, a decrease of
enzyme activity and ATP synthesis, elongation of the QT-interval with myocardial electrical instability, and increased concentrations of reactive oxygen species, resulting in myocardial degeneration and inammation.
• Autonomic dysregulation with increased sympathetic drive and release of cate-
cholamines (see also pathophysiologic mechanisms of AHT).
• Increase in intrathoracic pressure with changes in heart geometry and electrical
feedback.
9.5.3 Treatment
In a randomized trial that followed over 2500 patients with OSA over 3years, no
mortality benet was shown for CPAP with usual care compared to standard care
alone [39]. As mentioned before, this study was potentially hampered by a low
adherence to CPAP and the exclusion of patients with daytime sleepiness.
Interestingly, in an extensive real-life observational study, the termination of CPAP
within the rst year was associated with a signicantly higher all-cause mortality
rate [80]. However, further prospective data from large randomized trials are needed
to draw denite conclusions regarding the effect of CPAP on SCD.
Take-Home Message
• Obstructive sleep apnea (OSA) is associated with a variety of cardiovascular
diseases and is an established cardiovascular risk factor.
• Arterial hypertension is encountered in 50-60% of patients with OSA, and OSA
is a signicant cause of resistant arterial hypertension.
• Around half of heart failure patients have sleep apnea, associated with higher
cardiovascular events and mortality rates.
• OSA is associated with atrial brillation, ventricular arrhythmia, and sudden car-
diac death.
• These cardiovascular implications of OSA share common pathophysiological
pathways, including autonomic dysfunction with increased sympathetic nerve
activity, inammation, metabolic dysregulation, hypoxia, oxidative stress, endothelial dysfunction, and intrathoracic pressure swings.
9 OSA and Cardio vascular Disease
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165
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Obstructive Sleep Apnea:
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ANeurological Approach
KaremJosefinaParejo
10.1 Introduction
About 9% of women and 24% of men between 30 and 60years of age have an
AHI>5in polysomnography (PSG), and between 2% and 4% are associated with
excessive daytime sleepiness (EDS), an incidence that increases with age [1, 2].
In the case of Alzheimer’s disease, it has been seen that treating OSA can improve
cognitive function and sleep quality and that patients with dementia can tolerate
CPAP in the same way as other types of patients [3–5].
In patients with Parkinson’s disease, altered upper airway muscle tone can facilitate OSA, and the severity of the disease is directly related to the severity of sleep
disorders. Furthermore, Parkinson’s disease (PD) is associated with autonomic dysfunction, which could alter respiratory control, and this mechanism may be associated with the incidence of respiratory disorders during sleep [6].
OSA is common in patients with cerebrovascular disease and is associated with
poor functional and cognitive outcomes, and depression. Likewise, OSA can lead to
cognitive deterioration due to increase in microvascular disease due to chronic systemic hypoxia and oxidative stress, and treatment with continuous positive airway
pressure (CPAP) could prevent cognitive decline in these circumstances [7].
Neurologists need to consider the diagnosis and treatment of primary sleep disorders such as OSA and for the somnologist to appreciate the impact on cognitive
function of the sleep disorder. This chapter reviews various aspects of these neurological conditions related to OSA.
10
K. J. Parejo (*)
Fundación Clinica Shaio, Bogotá, Colombia
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
P. M. Baptista et al. (eds.), Obstructive Sleep Apnea,
https://doi.org/10.1007/978-3-031-35225-6_10
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K. J. Parejo
10.2 Alzheimer’s Disease
Alzheimer’s disease (AD) is by far the most frequent form of dementia, accounting
for 60%–70% of all cases of dementia and is usually preceded by a predementia
state called mild cognitive impairment (MCI). Forty percent of dementia cases are
due to potentially modiable factors such as obesity, diabetes, high blood pressure,
physical inactivity, depression, smoking, hearing loss, low educational level, poor
social contact, and environmental pollution. Sleep disorders have gained special
importance, with OSA being a modiable factor of great interest [8].
OSA has been frequently related to cognitive dysfunction and Alzheimer’s disease in middle-aged and older adults [9]. Multiple comorbidities are frequently
found in this type of patient with a lack of response to treatment to the cognitive
dysfunction of some patients. Therefore, it is a priority to nd the main factor contributing to cognitive deterioration and determine the impact of therapeutic interventions to improve this condition.
With increasing age, there are important differences in the prevalence of OSA,
associated comorbidities, and phenotypic presentation, suggesting differences in
cognitive performance between middle-aged and older adults. For example, in older
adults, OSA is characterized by intermittent hypoxia, sleep fragmentation, increased
sympathetic activity, and changes in intrathoracic pressure [8].
According to a systematic review of the literature, the prevalence in adults is
between 9% and 38% for mild OSA, 6% and 17% for moderate to severe, and in
older adults up to 84% for mild OSA and 16% for moderate to severe [8]. An even
more worrying study shows up to 56% of adults over 65years of age were at high
risk of OSA, and only 8% had been studied. Therefore, many older adults remain
undiagnosed and untreated. Of the patients diagnosed, only about 41% continue
with CPAP after 1year of treatment. This lack of adherence to CPAP is concerning,
considering that this treatment could delay of cognitive function deterioration [4].
10.2.1 Mechanisms That Could Explain Cognitive Dysfunction
inOlder Adults withOSA
As it is well known, OSA causes intermittent hypoxia and sleep fragmentation;
these frequent microalerts alter both the macro- (time spent in N3 and REM) and the
microstructure of sleep (characteristics of slow waves and sleep spindles).
Considering the role of sleep continuity, slow-wave sleep, REM sleep, and sleep
spindles in neurogenesis, brain plasticity, alertness, and memory formation and consolidation, chronic sleep changes caused by OSA negatively affect cognitive function. REM sleep-dependent OSA is particularly damaging to the brain as respiratory
events during this period are associated with reduced regional cerebral circulation,
even in mild OSA.
In addition, REM atonia can increase hypoxic levels during obstructive events,
and REM-dependent OSA is associated with more signicant excessive daytime
sleepiness than NREM-dependent OSA, which is more related to cognitive
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impairment. Intermittent hypoxia and sleep fragmentation also alter brain function
and structure. In addition, a biphasic pattern has been seen in imaging ndings, with
acute and transient or compensatory response pattern (in which gray matter hypertrophy and restriction of white matter diffusion) followed by evidence of brain damage (gray matter atrophy, white matter lesions, with increased hyperintensities and
axonal injury [10, 11].
There is increasing evidence that OSA is associated with an increase in
AD-related markers, specically amyloid beta and Tau, measured in cerebrospinal
uid (CSF), positron emission tomography (PET), and serum. In several studies in
which PSG diagnosed OSA, reduced CSF amyloid beta levels were demonstrated in
age-matched controls without OSA [12]. When groups were stratied by ApoE
allele status, the OSA severity was positively correlated with amyloidB42, phosphorylated tau (Ptau), and total tau (Ttau) in ApoE3 carriers and negatively correlated with amyloid B42 levels in those with ApoE2 [13]. In addition, PET amyloid
tracer uptake levels are a predictor of amyloid burden, as well as the future development of AD; greater amyloid deposition has been found in the right posterior cingulate gyrus and right temporal cortex in OSA patients compared to controls [14–18].
Also, there is even a study that shows AD biomarkers in children with obesity and
OSA, both risk factors for developing AD.Increased serum levels of presenilina1
and amyloid beta42 protein were found, these ndings decreased after treatment
(adenotonsillectomy) [19].
Several mechanisms could explain these pathological and neuroimaging ndings
such as inammation [20], oxidative stress, metabolic alterations, cerebral edema,
and endothelial dysfunction [21, 22].
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10.2.2 Research Studies Linking OSA withCognitive Decline
Most large cross-sectional cohort studies investigating the cognitive decline in
middle- aged or older patients with OSA use objective measures such as PSG,
polygraphy, and OSA screening questionnaires. While assessing impairment, some
use a full battery of neuropsychological evaluations and others specic tests to
determine the cognitive function or global functioning. The studies that show this
association found alterations in long-term verbal memory, working memory, and
global cognition. Markers of OSA severity or cognition-related symptoms were
highly heterogeneous (snoring, apneas, hypoxemia, apnea–hypopnea index—AHI)
and other studies found no signicant relationship between OSA severity and cognition [23].
Despite heterogeneous results the greatest ndings are found in the domains of
attention, memory, information processing speed. At the same time there is less
evidence in working memory, executive functions, visual and language skills in
middle-aged or older adults. In contrast, in young people with OSA, the most compromised domains were attention, episodic memory, working memory, and executive functions.
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These ndings indicate that there are altered domains in OSA independent of
age (memory and attention), while others are less impacted by age (working
memory and executive functions [8, 24]. Longitudinal cohort studies have the
advantage of quantifying cognitive decline over time. They use tools such as selfdiagnostic questionnaires, PSG, or portable equipment to identify cases of
OSA.Most use global cognitive measures such as minimental or screening tests.
Only the complete neuropsychological battery was used in one study [25].
Among the main longitudinal cohort studies, the Study of Osteoporotic Fractures
included 298 82-year-old women and found that 45% of women with OSA developed MCI or dementia at 5-year follow-up, compared to 31% of women without
OSA [9, 26].
This suggests that longitudinal studies are more likely to identify long-term
OSA-related cognitive impairment than MCI in specic domains. However, concerning meta-analyses and systematic reviews of the literature, most conclude that
there is a signicant association between OSA and cognitive impairment and that
OSA increases the risk of AD [27, 28].
Notably, small cohorts of cases and controls from sleep clinics show an association between OSA and cognitive impairment, while large population studies do not
detect it or present variable ndings. Probably due to the type of studies, limitations
of study design, etc., or perhaps because only the most severe cases show impairment [25, 28].
K. J. Parejo
10.2.3 Risk Factors
Not all adults with OSA are at risk of developing MCI or dementia; there are individual characteristics that may add or interact with the severity of OSA to explain
the increase in cognitive impairment such as age, gender, menopause, obesity, diabetes, high blood pressure, cardiovascular disease, smoking, excessive alcohol consumption, depression, environmental pollution or being a carrier of the ApoE4 allele
[25]. This must be considered to assertively impact the treatment of cognitive
impairment in a patient with OSA.
10.2.4 Regarding theTreatment
Treatment options for OSA include positive airway pressure devices, oral appliances, behavior/lifestyle modication, surgery, and/or a combination of these. A
decision on the most effective treatment for a person diagnosed with OSA depends
on the severity of the disease, the symptoms they are experiencing, and contributing causes.
CPAP is the most prescribed treatment. Analysis of the Alzheimer’s Disease
Neuroimaging Initiative (ADNI) cohort found that the presence of OSA was associated with an earlier age of cognitive decline and suggested that CPAP treatment may
slow the progression of cognitive decline. A systematic review has found studies
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whose participants were healthy older adults with OSA in which it was shown that
their cognitive difculties improved after treatment with CPAP [29].
Even in diagnostic imaging, it is observed that cortical thinning is attenuated,
and connectivity in the neural network increases. In general, all randomized/controlled studies conducted in older adults with AD show that CPAP improves sleep
parameters (N3, EDS), and cognitive function. These ndings prove evidence that
patients with mild AD to moderate may benet from CPAP treatment.
Subsequent analyses have shown improvements in episodic verbal learning and
memory and executive functioning (cognitive exibility and processing speed) in a
double-blind, placebo-controlled study examining the effects of donepezil, a central
acetylcholinesterase inhibitor, on OSA [30]. Compared to baseline and placebo,
patients with AD found that 3-month donepezil treatment signicantly improved
AHI and oxygen saturation [31].
In addition, REM sleep duration was signicantly higher, and Alzheimer’s
Disease Assessment Cognitive Scale (ADAS-cog) scores improved dramatically.
Regarding the improvement of biomarkers, it is known that a higher load of amyloid
or tau in the brain, a higher load of tau in the cerebrospinal uid (CSF) and a lower
load of amyloid in the CSF are of worse prognosis. A study in middle-aged adults
with OSA and with intervention showed that 1–4months of CPAP use increased
slow-wave sleep (SWS), and levels of amyloid beta in CSF were normalized.
In conclusion, there is sufcient evidence to recommend CPAP treatment as a
treatment for OSA and AD or mild cognitive impairment. The fth Canadian
Consensus Conference highlights the importance of detecting dementia in patients
with OSA and recommends that these patients be treated with CPAP. as it can
improve cognition and lowers the risk of dementia. It emphasizes the importance of
starting CPAP treatment early and improving follow-up to monitor compliance with
this device.
Therefore, CPAP may be a promising treatment for slowing cognitive decline in
older adults with comorbid MCI or AD and OSA.However, other pharmacological
and nonpharmacological approaches need to be evaluated and tested [12, 25].
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10.3 Parkinson’s Disease
Parkinson’s disease (PD) is the second most common neurodegenerative disease,
and its prevalence increases as the population ages. A recent multicenter study
showed that sleep disorders are very common in patients with PD, with around 66%
of these patients reporting sleep difculties [32]. In addition, nonmotor symptoms
of the disease, such as sleep disturbances, signicantly affect the quality of life of
patients with PD.
PSG studies show decreased total sleep time, and reduced percentage of SWS
(N3). It is estimated that 60% of these patients have OSA, causing hypoxemia and
fragmentation of sleep, which have been associated with cardiac arrhythmias, nocturnal arterial hypertension, nocturnal confusion, and neuropsychological alterations [33].
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