SLEEP PROBLEMS IN SPECIAL POPULATION
Sleep Patterns in Dementia
AD is the most frequent cause of dementia in the elderly population. It has been estimated that in 2013, AD affected 4.7 million individuals aged 65 years or older in the United States, a number that is projected to increase to approximately 14 million by 2050 . The classic hallmarks are progressive deterioration of memory, language, and intellect. Sleep and circadian rhythm disorders are very frequent in AD, and it has been reported that up to 45% of the patients may have sleep problems [69-71]. The most frequent disturbances are excessive awakenings (23%), early morning awakening
(11%), EDS (10%), and napping for more than 1 hour during the day (14%) . Such disturbances can appear early in the course of the disease, although they tend to be correlated with the severity of the cognitive decline . Sleep-related breathing disorders (SRBDs) are also very frequent in AD patients and in this group are clearly more prevalent than in the general population [73,74].
Issues that highlight the relevance of the treatment of sleep disorders in patients with AD include the following:
- 1. Sleep disturbances are associated with increased memory and cognitive impairment .
- 2. Sleep and nighttime behavioral disturbances such as wandering, day/night confusion, getting up repeatedly during the night, and nightmares or hallucinations cause signihcant caregiver burden and are a primary cause of patient institutionalization [72,76].
- 3. There is increasing evidence of the role of sleep disturbances in the pathophysiology of AD, and a bidirectional relationship has been proposed [77-79].
- 4. Normal aging is accompanied by sleep architecture changes, such as increased sleep latency, difficulty in sleep maintenance, decrease in SWS, early morning awakenings, and increased daytime somnolence .
- 5. The sleep disturbances present in patients with AD are similar, but more severe than would be expected by the patient’s age . Sometimes, sleep disturbances in AD are so prominent that should be classihed as a primary comorbid sleep disorder, such as chronic insomnia. The change that seems most specihc to AD is a quantitative decrease in the REM stage [82,83]. In particular, electroencephalogram (EEG) slowing during REM sleep has been proposed as a biological marker of AD .
- 6. The architectural changes present in AD patients are probably related to cognition impairment [84,85]. The cognitive impairment could be different depending on the sleep stage that is altered. For example, Rauchs et al. [86,87] found that the mean intensity of fast spindles was positively correlated, in AD patients, with immediate recall performance, while the amount of SWS was positively correlated with the ability to retrieve recent autobiographical memories.
Abnormalities in sleep-wake patterns and circadian-related disorders are also common in AD patients.  In extreme cases, a complete day/night sleep pattern reversal can be observed . Some authors have proposed that the sundowning phenomenon could also be due to a disorder of the circadian rhythm [90-92]. This phenomenon corresponds to an exacerbation of behavioral symptoms of dementia in the late afternoon . The abnormalities in the circadian timing system in AD patients are also manifested in other circadian systems such as body temperature and hormone concentrations [91,94-96]. Stranahan  found that disturbances in the circadian timing system also affect the activity of the hippocampus, worsening learning capacities.
SRBDs are also more frequent in patients with AD than in the general population and are present in 40%-70% of these patients [73,74]. In a longitudinal cohort study of sleep disorders using PSG, it was found that the probability of moderate-to-severe SDB was signihcantly higher in healthy participants with the APOE E4 allele, independent of age, sex, BMI, or race . It has been suggested that SRBD could cause AD . Recently, it has been reported that the presence of SRBD was associated with cognitive decline at an earlier age . Once the dementia is established, the severity of the sleep disturbances seems to be correlated with the severity of the dementia . Apneas alter sleep architecture and lead to a decreased amount of REM sleep and SWS, which causes more frequent awakenings than in patients without apneas . However, Yaffe et al.  found that the oxygen desaturation index and the percentage of time in apnea or hypopnea were associated with cognitive decline, but not with sleep fragmentation or sleep duration. These disturbances and the daytime sleepiness could be responsible for additional cognitive symptoms in patients that would be reversible [104-108].
A bidirectional relationship between sleep disturbances and AD has been proposed (Figure 14.3) [109,110]. The physiopathological mechanism is not completely understood, but an association
FIGURE 14.3 Bidirectional relationship between sleep and AD pathology. (Adapted from Urrestarazu E, Iriarte J. Nature and Science of Sleep. 2016;8:21-33.)
between sleep disturbances and amyloid-P accumulation has been demonstrated in mice [77,78] and humans [111,112]. On the other hand, AD also influences sleep, especially the sleep-wake cycle . Patients with AD suffer some disturbances in the secretion of neurotransmitters related to sleep-wake systems, mainly hypocretins (orexins) and melatonin secretion 130. Hypocretin-1 and Hypocretin-2 are produced by a small cluster of neurons in the posterior hypothalamus [114,115]. The hypocretin system acts as a stabilizing factor in the sleep-wake flip-flop, keeping it in the waking state [116,117]. The disturbances in the secretion of neurotransmitters not only influence the quality of sleep, but they also play a role in the pathogenesis of the AD itself through changes in amyloid-P, originating a complex circle. In fact, it has been reported in mice that physiologic circadian fluctuations of CSF amyloid-P levels are related to the hypocretin system. Melatonin plays a key role not only in sleep disturbances but also in the pathogenesis of AD. Melatonin is a tryptophan metabolite that is synthesized in the pineal gland and has several physiological functions including the regulation of circadian rhythms, clearance of free radicals, improvement of immunity, and inhibition of the oxidation of biomolecules . CSF melatonin levels are already decreased in the preclinical stages of AD [62,63] and continue decreasing further as AD progresses.
The aim of the treatment is to improve the QoL of patients and caregivers. Because of the impact of sleep disorders on cognition, it seems logical to think that the treatment would also improve some cognitive domains. During daytime, AD patients should be encouraged to exercise regularly for at least 30 minutes and walk outdoors. Intake of stimulants such as caffeine or tea should be limited, and naps longer than half an hour or after 1 p.m. should be avoided. Time in bed should be reduced. The schedule for going to sleep and getting up must be regular, and the bedroom should be reserved only for sleeping. Nighttime noise and light exposure and sleep disruptions should be reduced. BLT is a chronotherapeutic intervention used to treat circadian disturbances in AD patients. The most commonly used drugs are melatonin, z-hypnotics such as zolpidem, sedating antidepressants, and antipsychotics. Usually, benzodiazepines are avoided because they may worsen cognitive function. Cholinesterase inhibitors, the first-line treatment for AD, can also improve sleep quality. However, there are few studies assessing the efficacy of these drugs.
Hypnotics are classified into benzodiazepines and nonbenzodiazepines. The side effects of benzodiazepines include daytime sedation, anterograde amnesia, daytime sleepiness, confusion, and risk of falls. Given these risks, they are not recommended for AD patients. They also have a deleterious effect on cognition [118-124].
Sedating antidepressants are used when there is concomitant depression. However, tricyclic antidepressants have anticholinergic activity and may exacerbate the cholinergic disturbances inherent in AD, and should be avoided. They also have other side effects such as somnolence, sedation, and dizziness, which are of great concern in the demented population. Serotonin-reuptake inhibitors with a sedating prohle, especially mirtazapine, are also used to treat insomnia. Trazodone is a triazolopyridine antidepressant that offers a dual action on serotonergic receptors by blocking the 2A receptor and inhibiting serotonin reuptake. It improves sleep in patients with depression, but there is insufficient evidence for its use in patients with insomnia without depression. Antipsychotics are frequently administered to control behavioral and neuropsychiatric manifestations of AD. Sometimes, when the hrst-line treatments have failed, they are also used to treat insomnia. However, they are associated with sedation, increased risk of falls, and might also have serious cardiac side effects. Furthermore, they can aggravate sleep-wake cycle disturbances. Antihistaminic drugs do not seem appropriate to be used in AD patients. They have a wide range of side effects including sedation, cognitive impairment, increased daytime somnolence, and anticholinergic responses.
Acetylcholinesterase inhibitors are a common treatment for AD. Acetylcholine not only plays a key role in memory functions, but it also is related to vigilance states. Levels increase during wakefulness, decrease in non-REM sleep, and rise again in REM sleep. Polysomnographic studies in patients taking acetylcholinesterase inhibitors have shown an increase in the percentage of REM sleep, reduced REM latency, and a decrease in REM sleep slow band power. Galantamine has the best prohle regarding sleep and may be the hrst choice of cholinesterase inhibitor in mild-to- moderate dementia patients in terms of improving sleep quality.