Psychiatric Annals

CME Article 

Sleep Disorders and Dementia: From Basic Mechanisms to Clinical Decisions

Elissaios Karageorgiou, MD, PhD; Christine M. Walsh, PhD; Kristine Yaffe, MD; Thomas C. Neylan, MD; Bruce L. Miller, MD

Abstract

A growing body of evidence shows the bidirectional relationship between sleep disorders and dementia. Sleep disorders often precede cognitive impairment by many years, in keeping with evidence that certain degenerative diseases originate from the brainstem and hypothalamus. Such selective vulnerability is associated with sleep fragmentation, daytime napping, sleep phase disorders, insufficient or excessive sleep duration, and sleep-disordered breathing. However, recent research indicates that sleep disorders accentuate neuropathology, such as decreased slow-wave sleep (SWS) promoting amyloid aggregation. This bidirectional relationship makes for a self-promoting feedback loop that accelerates both processes, highlighting the need for early interventions in elderly patients without dementia. Behavioral interventions, such as sleep hygiene, daytime exercise, and avoidance of alcohol and coffee after a certain time of day, are important first steps. Equally important are interventions that promote sleep consolidation, enhance SWS, or correct sleep-disordered breathing. Finally, optimizing medication timing, such as daytime-only use of cholinesterase inhibitors, can improve sleep and memory consolidation. [Psychiatr Ann. 2017;47(5):227–238.]

Abstract

A growing body of evidence shows the bidirectional relationship between sleep disorders and dementia. Sleep disorders often precede cognitive impairment by many years, in keeping with evidence that certain degenerative diseases originate from the brainstem and hypothalamus. Such selective vulnerability is associated with sleep fragmentation, daytime napping, sleep phase disorders, insufficient or excessive sleep duration, and sleep-disordered breathing. However, recent research indicates that sleep disorders accentuate neuropathology, such as decreased slow-wave sleep (SWS) promoting amyloid aggregation. This bidirectional relationship makes for a self-promoting feedback loop that accelerates both processes, highlighting the need for early interventions in elderly patients without dementia. Behavioral interventions, such as sleep hygiene, daytime exercise, and avoidance of alcohol and coffee after a certain time of day, are important first steps. Equally important are interventions that promote sleep consolidation, enhance SWS, or correct sleep-disordered breathing. Finally, optimizing medication timing, such as daytime-only use of cholinesterase inhibitors, can improve sleep and memory consolidation. [Psychiatr Ann. 2017;47(5):227–238.]

Emerging research highlights the bidirectional causal associations between sleep disorders and neurodegenerative dementias. Traditional conceptual approaches focus on degeneration of critical nuclei leading to sleep disorders, but recent animal studies reveal mechanisms by which sleep disruptions have a causal role in neurodegeneration, with some supportive evidence existing in humans as well. Clarifying this bidirectional relationship allows for better understanding of disease mechanisms and, more importantly, can improve patient treatment with readily available interventions.

The mechanisms that associate neurodegeneration and sleep disorders can be modeled under four general pathways (Figure 1). Conceptually, these reflect, on one hand, early targeted neurodegeneration of brainstem and hypothalamic nuclei leading to specific sleep disruptions and, on the other, sleep changes leading to subsequent degeneration. Various levels of evidence exist to support each of these mechanisms, although dissociation of cause and effect is often untested or unethical to test in people.


            Bidirectional pathways between neurodegeneration and sleep disorders. Starting from neurodegeneration, one pathway reflects attenuated range of brain activity across the sleep-wake cycle, translating as insomnia, sleep fragmentation, and daytime somnolence. A second pathway leads to sleep phase disorder and contributes to sleep fragmentation and “sundowning.” Obversely, sleep disorders can lead to neurodegeneration through prolonged neuronal activation, as promoted by sleep deprivation and decreased slow wave sleep. Finally, pathways intersect when it comes to sleep-disordered breathing, with bidirectional causal relationships between disrupted sleep and neurodegeneration.

Figure 1.

Bidirectional pathways between neurodegeneration and sleep disorders. Starting from neurodegeneration, one pathway reflects attenuated range of brain activity across the sleep-wake cycle, translating as insomnia, sleep fragmentation, and daytime somnolence. A second pathway leads to sleep phase disorder and contributes to sleep fragmentation and “sundowning.” Obversely, sleep disorders can lead to neurodegeneration through prolonged neuronal activation, as promoted by sleep deprivation and decreased slow wave sleep. Finally, pathways intersect when it comes to sleep-disordered breathing, with bidirectional causal relationships between disrupted sleep and neurodegeneration.

This article highlights new advances in our understanding of the relationship between sleep disorders and degenerative dementias, with emphasis on findings that allow improvement of dementia care. Most research to date elucidates mechanisms involved in Alzheimer's disease (AD) and synucleinopathies (Parkinson's disease dementia [PDD], multiple system atrophy [MSA], and dementia with Lewy bodies [DLB]), but there is also emerging literature on primary tauopathies, such as progressive supranuclear palsy (PSP). To better understand the associations between sleep and neurodegeneration, the basic elements of sleep function and dementia progression are initially discussed. In the same vein, sleep changes observed with aging are presented in tandem with evidence demonstrating emergence of sleep disturbances as early signs and symptoms of neurodegeneration. Subsequently, sleep disorders stemming from dementia and, conversely, evidence of pathological changes stemming from sleep disorders are outlined, forming the basis of this bidirectional relationship. In closing, practical clinical approaches are presented.

Basic Concepts in Sleep and Degenerative Dementias

The benefits of sleep on health and brain function fall under three main categories: (1) dynamic brain development and reorganization via synaptic preservation and plasticity allowing memory consolidation, (2) homeostasis via tissue restoration, energy conservation, and immune modulation, and (3) ecological survival advantage and niche (Figure 2).1,2 Sleep-wake modulation is dependent on the mutual competition of isodendritic core and hypothalamic nuclei via a homeostatic process and the cyclic entrainment of the circadian rhythm (Figure 3).3 During wakefulness, arousal network brainstem and hypothalamic nuclei predominate. This in turn leads to increased body-wide metabolic activity and breakdown of adenosine triphosphate (ATP) into adenosine. As brainstem-hypothalamic adenosine receptors saturate, sleep-promoting nuclear activity then predominates until adenosine receptors become available again. Between-state transition is abrupt, as the two systems are under mutual antagonism through “flip-flop” switches. Sleep-wake modulation also abides to a circadian (ie, approximately daily) process, following the activity of the brain's master clock, the suprachiasmatic nucleus (SCN). Cycling is timed by retinal exposure to sunlight and, as activity drops, melatonin is secreted through a polysynaptic pathway. Melatonin levels are anticorrelated to core body temperature, as both are indirectly modulated by the SCN.


            Benefits of sleep on health and brain function.

Figure 2.

Benefits of sleep on health and brain function.


            Sleep-wake cycle regulation: homeostatic and circadian processes. Brain rhythms and, by extension, sleep-wake modulation, are coordinated through brainstem and hypothalamic nuclear activity. This regulation can be conceptualized in two processes: a homeostatic (top) and a circadian (bottom). Color coding for most significant neurotransmitters and hormones produced by noted areas: red, GABA; light green, orexin; dark green, histamine; purple, melatonin; light yellow, vasoactive intestinal polypeptide and arginine vasopressin; dark yellow, acetylcholine; light orange, melanin concentrating hormone; dark orange, glutamate; light blue, dopamine; blue, serotonin; dark blue, noradrenaline. BF, basal forebrain; GABA, gamma-aminobutyric acid; LC, locus coeruleus; LDT, laterodorsal tegmental; LH, lateral hypothalamus; PPT, pedunculopontine tegmental; SLD/PB/PC, sublaterodorsal/medial parabrachial/precoeruleus region; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; vlPAG/LPT, ventrolateral periaqueductal gray/lateral pontine tegmental; VLPO, ventrolateral preoptic.

Figure 3.

Sleep-wake cycle regulation: homeostatic and circadian processes. Brain rhythms and, by extension, sleep-wake modulation, are coordinated through brainstem and hypothalamic nuclear activity. This regulation can be conceptualized in two processes: a homeostatic (top) and a circadian (bottom). Color coding for most significant neurotransmitters and hormones produced by noted areas: red, GABA; light green, orexin; dark green, histamine; purple, melatonin; light yellow, vasoactive intestinal polypeptide and arginine vasopressin; dark yellow, acetylcholine; light orange, melanin concentrating hormone; dark orange, glutamate; light blue, dopamine; blue, serotonin; dark blue, noradrenaline. BF, basal forebrain; GABA, gamma-aminobutyric acid; LC, locus coeruleus; LDT, laterodorsal tegmental; LH, lateral hypothalamus; PPT, pedunculopontine tegmental; SLD/PB/PC, sublaterodorsal/medial parabrachial/precoeruleus region; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; vlPAG/LPT, ventrolateral periaqueductal gray/lateral pontine tegmental; VLPO, ventrolateral preoptic.

Such an interplay between nuclei and their respective neurotransmitters is also present during sleep, contributing to sleep architecture and sleep-mediated memory consolidation (Figure 4). Sleep periods are divided into stages according to the dominant electroencephalogram (EEG) rhythms, presence of spindles and K-complexes, eye movements, and muscle activity, giving rise to rapid eye movement (REM) and non-REM (N1-3) sleep stages. This activity is coordinated by mutually inhibitory brainstem-hypothalamic nuclear networks, giving rise to different brain rhythms and metabolic patterns of activity that facilitate specific types of sleep-mediated memory consolidation. Stages follow recursive sequences in an almost predictable manner overnight (Figure 3, top). During each such cycle (Figure 3, bottom) brain rhythms become slower from N1 to N3 sleep as the cortex becomes less active and then enters a REM period of fast activity with increased cortical activity. A similar interplay seems to happen in wakefulness, although with much attenuated rhythm fluctuations. Sleep architecture, characterized by the recursive cycling between sleep stages, allows for a fronto-hippocampal interplay that facilitates memory consolidation.


            Sleep architecture: encephalographic, neurotransmitter, metabolic, nuclear activity, and relationship to memory consolidation. Color coding for most significant neurotransmitters and hormones produced by noted areas: red, GABA; light green, orexin; dark green, histamine; purple, melatonin; light yellow, vasoactive intestinal polypeptide and arginine vasopressin; dark yellow, acetylcholine; light orange, melanin concentrating hormone; dark orange, glutamate; light blue, dopamine; blue, serotonin; dark blue, noradrenaline. BF, basal forebrain; EEG, electroencephalogram; EMG, electromyogram; GABA, gamma-aminobutyric acid; LC, locus coeruleus; LDT, laterodorsal tegmental; LH, lateral hypothalamus; PPT, pedunculopontine tegmental; REM, rapid eye movement; SLD/PB/PC, sublaterodorsal/medial parabrachial/precoeruleus region; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; vlPAG/LPT, ventrolateral periaqueductal gray/lateral pontine tegmental; VLPO, ventrolateral preoptic.

Figure 4.

Sleep architecture: encephalographic, neurotransmitter, metabolic, nuclear activity, and relationship to memory consolidation. Color coding for most significant neurotransmitters and hormones produced by noted areas: red, GABA; light green, orexin; dark green, histamine; purple, melatonin; light yellow, vasoactive intestinal polypeptide and arginine vasopressin; dark yellow, acetylcholine; light orange, melanin concentrating hormone; dark orange, glutamate; light blue, dopamine; blue, serotonin; dark blue, noradrenaline. BF, basal forebrain; EEG, electroencephalogram; EMG, electromyogram; GABA, gamma-aminobutyric acid; LC, locus coeruleus; LDT, laterodorsal tegmental; LH, lateral hypothalamus; PPT, pedunculopontine tegmental; REM, rapid eye movement; SLD/PB/PC, sublaterodorsal/medial parabrachial/precoeruleus region; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray; vlPAG/LPT, ventrolateral periaqueductal gray/lateral pontine tegmental; VLPO, ventrolateral preoptic.

During this process, NREM sleep displays hippocampal-predominant activity and primarily contributes to episodic memory consolidation, whereas REM sleep reveals medial prefrontal cortex (mPFC)-predominant activity and mainly contributes to implicit procedural and emotional memory consolidation,4–6 although sequential and recursive involvement of both periods is likely required for most memories.4,7,8 A similar pattern of recursive activity with modulation of brain rhythms exists during wakefulness, although in an attenuated manner, giving rise to ultradian rhythms across the sleep-wake cycle.9–13 It is through such a recursive interplay between cortical areas that the brain achieves its main function of information processing, as represented through synaptic strengthening and pruning, and coordinated through bottom-up brainstem and hypothalamic nuclei.2 Approaching brain function through brain rhythms (sleep-wake and ultradian) further highlights that “sleep” is a broad and complex term that facilitates our conceptualization of brain rhythm fluctuations and their effect on information processing and cognitive function.14

The relevance of sleep to the early stages of degenerative diseases is notable when one considers that the earliest, if not the first, areas of degeneration in pathologies such as AD, synucleinopathies, and PSP localize to the brainstem and hypothalamic nuclei.15–18 Evidence suggests that degeneration spreads from these areas across a selectively vulnerable brain network in a prion-like manner, conferring unique clinical characteristics at each stage of the disease that allow for clinicopathological associations.19–21 Thus, early identification of symptoms stemming from brainstem and hypothalamic involvement, such as sleep disorders, can help the clinician intervene earlier in the degenerative process and, as etiologic treatments become available, prevent progression of cognitive decline.

Sleep Changes During Aging and Morbidity Risk

In later adulthood, several changes occur in circadian rhythms and sleep architecture. Changes in circadian mechanisms predominantly relate to melatonin regulation by the suprachiasmatic nucleus. With aging, melatonin secretion is shifted to earlier hours, whereas the total amount secreted remains the same even in people with cognitive complaints, partly explaining the limited efficacy of melatonin supplementation in elderly patients with advanced sleep-phase disorder.22 In turn, people with advanced sleep-phase disorder can become sleep deprived by engaging in normal evening social activities that keep them awake rather than allowing sleep. Through this process of misaligned circadian rhythm to sleep periods, advanced sleep phase-disorder can further lead to earlier morning awakenings, correlating to a morning surge in cortisol and decreasing melatonin levels,23,24 as well as to sleep-onset REM periods and daytime somnolence, both of which are reflective of sleep deprivation.25 Daytime somnolence also leads to increased daytime napping in approximately one-quarter of adults older than age 65 years.26 The clinician, however, should distinguish healthy daytime napping of episodic sleep demand from circadian dysregulation. In any case, more than 1 hour of regular daytime napping is predictive of a 32% increase in all-cause mortality,27 whereas earlier dim-light melatonin onset, reflecting advanced sleep phase, is associated with cognitive decline.22 Besides advanced sleep-phase disorder, aging is associated with worsened sleep fragmentation. In a 5-year prospective study of 1,287 women older than age 80 years, weaker circadian rhythm amplitude, mesor, and robustness were predictive of worsening executive function.28 A 6-year prospective study in 737 people without dementia showed sleep fragmentation was associated with a 20% to 50% increased risk of AD and a 22% risk of accelerated cognitive decline.29 Another well-established predictive risk factor of cognitive decline with aging is extremes in sleep duration (ie, <6 hours or >9 hours). A World Health Organization study in approximately 30,000 people older than age 50 years revealed worse cognitive performance for people with sleep durations of less than 6 hours nightly, but even worse for those with more than 9 hours, suggesting that physicians should further query “great” sleepers.30 Finally, studies have shown conflicting evidence on insomnia in aging and cognitive decline, possibly reflective of poor cohort selection and presence of confounding factors.31,32

Beyond circadian changes, sleep architecture is also affected by aging. Most notably, both slow-wave NREM sleep (SWS) and REM sleep are diminished, possibly contributing to decreased episodic and procedural-emotional memory consolidation, respectively.4,33,34 Additionally, there are more episodes of nighttime awakenings.34 In contrast, stage N2 sleep is proportionally increased, but its sleep spindles, which correlate to hippocampal sharp-wave ripples and thus replay of memories,2 lose their characteristic morphology, including decrease in amplitude, density, and number, with fast frontal-predominant spindles being preferentially affected.35

A factor that merits special reference is sleep-disordered breathing (SDB). Two large prospective studies of cognitively normal men and women concluded that presence of SDB almost doubled the risk for future decline, defined as progression to mild cognitive impairment, dementia, or worse global cognitive performance.36,37 Of clinical significance, this risk was linked to hypoxia and not to the amount of sleep fragmentation. This was recently verified in a postmortem study where people with SDB predominantly had vascular pathology associated with hypoxia and not AD or synucleinopathy.38 This is important to the practitioner because 40% to 70% of patients with dementia have SDB compared with 5% to 19% of cognitively nonimpaired, age-matched people,39 which is consistent with findings showing that vascular lesions are frequently present in dementia, either alone or as a copathology.40

Given the predictive risk of cognitive decline in sleep disorders of aging, a reasonable question is whether sleep disorders and aging are inevitably bound together or whether sleep disorders are precognitive indicators of neurodegeneration. Most research favors the latter. The Sleep in America Survey in people age 55 to 85 years revealed that 10% of those without any comorbidity had sleep problems, which increased to 41% with increasing number of comorbidities.41 Conversely, one-half of the patients with insomnia older than age 65 years studied prospectively for 3 years did not complain of insomnia at the end of the study.42 When considering possible changes in the number of hypothalamic intermediate nucleus cells (the main homeostatic promoters of sleep), they are not significantly fewer with normal aging but do decrease in number in patients with coexistent AD.16 This is of further significance because amyloid pathology increases from 20% to 50% in people age 70 to 85 years without dementia.43 Combined, the above indicate that aging alone does not cause sleep problems, but the factors that accompany aging (eg, disease, medications, circadian behaviors) do.

Sleep Disorders in Dementia

In keeping with the above, most sleep changes in dementia are accentuations of sleep disorders observed in patients without dementia prior to developing cognitive impairment. Additionally, certain dementias are accompanied by unique symptoms, such as REM behavior disorder (RBD) in patients with synucleinopathies and stridor in patients with MSA (Table 1). Certain common symptoms merit further description. First, with dementia progression, melatonin is not only secreted earlier in the day but also shows fluctuations across the day, leading to erratic sleep patterns of alternating sleep and wakefulness that disrupt both the patient and the caregivers.22,44,45 Additionally, the earlier secretion of melatonin while patients are still awake is one proposed mechanism of “sundowning,” via intrusion of sleep cognitive states into wakefulness.46 The opposite also occurs, where more wakefulness-like behaviors (eg, sleep talking) are noted during lighter sleep of patients with dementia.47 This concept of overlapping dissociated states of sleep and wakefulness also helps explain uniquely emerging symptoms, such as RBD, and can prove useful when trying to understand and treat them.46 Furthermore, EEG sleep patterns in dementia show progressive decay, with poorer separation between stages, whereas sleep spindles and K-complexes are fewer and have degraded morphology.48 Deep and REM sleep are further shortened, awakenings increase, and the sleep spectrogram power, especially in AD, is shifted to the right, toward higher frequencies, closer to that of wakefulness.33,34 This latter finding complements spectral patterns of wakefulness in AD and synucleinopathies, where power is shifted to the left, toward lower frequencies, reflective of slower cortical activity and associated with worse cognition.49,50


            Sleep Disturbance Prevalence in Dementia Disorders

Table 1.

Sleep Disturbance Prevalence in Dementia Disorders

In combination, the aforementioned sleep and wakefulness behaviors and EEG patterns reveal that AD patients in particular enter a “twilight zone,” an attenuated range of brain rhythm activity in which they are never deeply asleep and never fully alert, possibly resulting from degeneration of sleep-wake rhythm attractor networks or their ability to mutually inhibit each other.14 This in-between state in patients with AD correlates with comparatively increased cortical activity during sleep and decreased activity during wakefulness, translating to lighter sleep and daytime somnolence, respectively (Figure 1). Compared to AD, patients with DLB have decreased cortical activity during wakefulness but their sleep spectrogram in early disease stages is less affected than that of patients with AD, thus showing a relative attraction toward slow wave states rather than intermediate states across sleep and wakefulness.51 It is also worth considering that a large component of later stage sleep changes in DLB may relate to AD copathology, which is present in approximately one-third to one-half of DLB patients.52,53 In contrast, patients with PSP display increased cortical activity across the sleep-wake cycle with consistently higher power in high frequencies, reflective of a hyperaroused cortex, which further translates to behavioral patterns of difficult-to-manage insomnia.54 Summarily, the above are in line with evidence of early selective vulnerability in the brainstem and hypothalamus in AD, DLB, and PSP, further explaining differential patterns of sleep deficits between dementia syndromes.20,40,55,56

Sleep Disorders as Causal Factors to Proteinopathies

Recent research discussed in detail below also reveals an inverse relationship of what has been discussed above—that sleep disorders lead to pathological protein accumulation. Findings are mostly supported in AD models, and the basic concepts stem from the observation that increased neuronal activity leads to amyloid accumulation. An alternative pathway involves decreased waste-protein clearance during sleep. A reasonable extrapolation is that sleep deprivation and decreased amounts of deep sleep could explain amyloid aggregation.

Neuronal hyperexcitability in amyloid precursor protein (APP) transgenic mice during pre-amyloid deposition stages led to increased interstitial beta-amyloid accumulation.57 This was observed under chemical or somatosensory stimulation of specific pathways. Inversely, decreased neuronal activation was associated with decreased amyloid accumulation. In humans, task-related increased neuronal activity has been observed with aging, as reflected in encephalographic spectral power,58 whereas a prospective 36-month evaluation of patients with mild cognitive impairment using functional magnetic resonance imaging indicated increased hippocampal activity in those with amyloid deposition, as revealed through amyloid positron emission tomography (PET), and faster cognitive decline.59 Such results raised the possibility that sleep disorders, including sleep deprivation and decreased SWS, increase amyloid accumulation through longer periods of network hyperexcitability.

Evaluation of sleep deprivation and sleep promotion on amyloid accumulation was evaluated through a well-designed study on double-transgenic APP/presenilin1 and orexin-knockout mice.60 Orexin deficiency increased sleep and was associated with decreased amyloid deposition. This observation was independent of orexin effects, as verified by controlling for targeted orexin expression in the hippocampus, and thus supportive of a sleep effect. The inverse hypothesis, of sleep deprivation leading to amyloid accumulation, was also supported by saving orexin neurons in these mice through a viral vector, thus increasing wakefulness periods and leading to increased amyloid accumulation. In humans, studies on orexin and amyloid have yielded conflicting results, in which orexin levels in AD may relate to cerebrospinal phospho-tau levels but not amyloid-beta42,61 or may even show a relationship to amyloid-beta42 but without differences in circadian rhythms between patients with AD and control participants.62 The implications of such studies are important because orexin antagonists have become available therapeutically. A more recent association study in humans tried to clarify if poor sleep causes proteinopathies, and although a causal effect cannot be established because of the cross-sectional nature of the study, it hints to such a possibility.63 Specifically, in 26 cognitively normal participants, decreased amount of SWS was associated to higher medial prefrontal cortex (mPFC) amyloid levels on PET imaging. Additionally, overnight episodic memory consolidation was worse in participants with less SWS and higher mPFC amyloid levels. This is of further significance when considering that the default mode network, whose spatial distribution correlates to amyloid deposition in AD,64 shows decreased activation during deeper sleep,65 especially the mPFC, which in turn yields the highest amyloid PET signal in AD.66

A notable limitation of the above studies is the lack of concomitant neuronal activity quantification to verify that the observed sleep effects are mediated through neuronal hyperexcitability rather than poor amyloid clearance during sleep. Indeed, beta-amyloid in humans and animals is cleared as sleep settles in, especially deeper sleep.67–69 Clearance is estimated at 60% through the blood-brain barrier and 40% via the glymphatic system (interstitial flow [cerebrospinal fluid and perivascular]),70 whereas the role of the recently identified meningeal lymphatic system remains unclear.71 Of significance, as amyloid plaques develop in mouse models, the diurnal fluctuation of interstitial beta-amyloid attenuates and clearance is further decreased.67 This observation further supports the concept that patients with AD gradually enter an attenuated range of physiological activities that extend from clearance of pathological proteins to emerging dissociated states in between wakefulness and sleep. These attenuated responses reflect a decay of the subcortical control of alertness in AD, in which sleep-wake attractors show less mutual inhibition and, thus, less bi-stability across the circadian cycle.14

The above evidence points to a possible direct link between neurofibrillary and amyloid pathology in AD. Specifically, the earliest pathological findings of neurofibrillary, but not amyloid, pathology involve the isodendritic core, including sleep-wake homeostatic and circadian centers.15,17,18 Dysfunction of these centers results in overlapping sleep-wake states and a constantly active cortex, with an activity pattern comparable to the default mode network. This persistent activity, combined with the inability to maintain deep sleep, leads to amyloid deposition in the cortical areas that are more active.

Clinical Considerations

The previously described mechanisms would be of little significance if they could not be incorporated into the general framework of preventing and managing dementia in a clinical setting. The overarching goal is to apply the available information in addressing factors that promote degeneration, such as consolidating wakefulness and sleep as separate states, normalizing sleep breathing, and optimizing duration of sleep, especially deep sleep. To achieve these, certain aspects are considered when treating patients with dementia, namely patient lifestyle, medications, and family/social education (Table 2).


            Practical Considerations When Treating Patients with Dementia

Table 2.

Practical Considerations When Treating Patients with Dementia

A first step involves accurate diagnosis of the underlying problem. As such, structured questionnaires have been developed for patients and families to fill out, especially for identifying daytime somnolence and SDB, with different specificities and sensitivities. For example, the Berlin Sleep Questionnaire has higher sensitivity with lower specificity in identifying SDB, whereas the Epworth Sleepiness Scale (ESS) has increased specificity with lower sensitivity.72 The Sleep Apnea Clinical Score has a larger area-under-the-curve on accurately predicting SDB polysomnographic results compared to both the ESS and the Berlin Sleep Questionnaire.73 The Pittsburgh Sleep Quality Index is often preferred for addressing several features of sleep quality. Unfortunately, these instruments are less helpful in low-risk populations.74 The choice of questionnaire ultimately depends on the patient's presentation, including their age and severity of cognitive decline.

Regarding sleep duration, the clinician should focus on both nighttime sleep and the duration of daytime naps. Often, a patient will say their sleep is “great;” however, more than 9 hours of sleep is more concerning than less than 6 hours.30 Daytime napping can indicate sleep deprivation from poor nighttime sleep due to sleep apnea or inadequate deep sleep, but also sleep fragmentation due to disrupted circadian rhythms, melatonin secretion, and limited light exposure. Advanced sleep-phase is also related to melatonin secretion, which could be normal in some people or a result of varied light exposure; however, given the aforementioned observations, it could also reflect early suprachiasmatic nucleus degeneration.22,44,45 A common overdiagnosis is RBD, as clinicians query for it more frequently due to its association to synucleinopathies.75 A related pitfall is interpreting sleep-talking or periodic limb movements of sleep as RBD. Patients who are “living the dream” in RBD usually have violent dreams lasting more than a few seconds, with limb activity predominating, and they occasionally fall out of bed and sustain injuries. Rarer are dreams about sport or musical activities. Overall, though, motor behavior during sleep has a differential diagnosis that includes other entities besides RBD, such as movements during partial arousals in patients with sleep apnea.

With regard to treatment, evaluation of SDB should be pursued for all patients in clinic, but even more for those with cognitive decline, as almost half of patients with dementia have some amount of SDB.39 In addition to snoring, breathing arrests, daytime somnolence, increased napping, dozing off, and poor sleep restfulness, the clinician is urged to quantify the amount of nocturia as a marker of SDB. SDB can lead to decreased antidiuretic hormone levels during sleep, with resultant nocturia.76,77 Similarly, nocturia should not lead to a reflex diagnosis of prostate hypertrophy in men, especially because many men have persistent nocturia after prostate removal and while on appropriate medications. Treating SDB in such cases decreased nocturia and led to a 4-fold decrease of the apnea-hypopnea index (AHI).76,77 A meta-analysis of randomized trials of continuous positive airway pressure treatment in SDB failed to show marked cognitive improvements with use of assisted ventilation, and with only mild improvement in vigilance.78 A targeted trial with 52 patients with AD, however, revealed improvements in AHI (from 29 to 5), number of arousals, deeper sleep duration, and hypoxia, but also a marginal benefit on composite cognitive scores.79 All intervention trials suffer from short follow-up periods, making assessment of changes in cognitive trajectory difficult, whereas larger studies also suffer from variability in studied populations.

Considering pharmacological interventions, one should take into account both effective agents and timing of administration, as well as offending agents. As mentioned, insomnia is associated with dementia, even though its predictive value for cognitive impairment progression is uncertain. Three agents have been studied through randomized controlled trials for treating insomnia in AD: melatonin, ramelteon, mirtazapine, and trazodone.80,81 Melatonin failed to produce a definite benefit in 209 patients with moderate to severe AD; a possible explanation being that melatonin secretion is significantly disrupted only later in the disease course. A further implication of melatonin use is the increase of atonia, a favorable effect in patients with RBD but a complicating factor in patients with untreated SDB.82 Ramelteon failed to improve insomnia in 74 patients with mild to moderate AD.80 Mirtazapine also failed to have a benefit on sleep duration in 24 patients with AD and sleep problems.81 In contrast, trazodone at a dose of 50 mg at night in 30 patients with moderate to severe AD with insomnia increased sleep efficiency and duration by 43 minutes, and there were no cognitive deficits the next day.83 In clinical practice, doses up to 150 mg nightly are sometimes used. A possible additional benefit of trazodone is that it increases SWS,84 possibly improving episodic memory consolidation, but studies are lacking. In contrast, cholinesterase inhibitors decrease deep sleep and are one of of the most frequently prescribed medications in dementia. Unfortunately, increasing acetylcholine levels during the night decreases NREM sleep, with associated impairment in episodic memory consolidation, and makes vivid dreams more prevalent, paralleling REM sleep increase.85–87 Daytime acetylcholine administration mitigates such side effects.88 Finally, use of benzodiazepines and benzodiazepine receptor agonists, such as zolpidem, should be avoided in patients with dementia due to their side effect profile with confusion and cognitive worsening the next day.

A closing consideration relates to behavioral interventions that promote sleep-wake consolidation. Unfortunately, there are no studies on cognitive-behavioral therapy of insomnia for patients with cognitive impairment. Tested interventions, however, can be divided in two groups: sleep hygiene and daytime activation (Table 2). A few deserve special reference. For example, daytime light exposure allows for effective entrainment of the suprachiasmatic nucleus in people without dementia, but dementia studies have yielded conflicting results.89 This could reflect the differential timing of light therapy during morning and/or afternoon hours between trials, the variable suprachiasmatic nucleus degeneration between patients across disease stages, or even incorrect assumptions of pathological diagnosis.43 Generally, daytime administration of light therapy, and if needed nighttime trazodone, can better consolidate sleep-wake cycles and increase vitamin D levels; the latter also showing a positive association to cognition, but evidence is lacking for definite causality.90 Another useful intervention is a warm shower 1 to 2 hours prior to bedtime, as passive body heating and the subsequent drop in core body temperature as patients enter a colder room promote sleep. Stimulant administration, including coffee, abides by the rule of 2's: avoid after 2 pm, do not consume no more than twice a week to avoid tolerance, and do not consume more than 2 times daily. Similarly, alcohol is best avoided near bedtime, as rebound insomnia and worsening of SDB are not uncommon, even though it may help induce sleep. Finally, allowing for improved sleep quality in patients may also help caregivers, whose sleep is known to suffer and can improve when patient sleep improves.91

Conclusion

In summary, sleep disorders precede overt cognitive impairment by years, indicating that early degeneration involves sleep-wake regulatory nuclei of the brainstem. Inversely, recent findings implicate sleep disorders, especially lack of deep sleep and hypoxia, as promoters of proteinopathies and vascular pathologies leading to degeneration. Helpful interventions range from pharmacologic optimization to behavioral changes focusing on sleep-wake consolidation. A future avenue of research with a goal of proper cycling through sleep stages, and thus memory consolidation, could involve the timed administration of medications during sleep, such as orexin during periods of desired NREM sleep and acetylcholine during periods of desired REM sleep. Finally, emerging evidence links early neurofibrillary pathology at the brainstem, through increased levels of brain activity during sleep, to increased accumulation and decreased clearance of amyloid later in the disease course.

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Sleep Disturbance Prevalence in Dementia Disorders

Disturbance AD PSP PDD and DLB FTD VaD
Insomnia 46–53 ∼100 66–72 48–89 47–67
Daytime somnolence 5–48 See footnote b 57–100 11–64 16–58
SDB 40–70 55 50–76 68 74
Sleep fragmentation 18 57 See footnote c See footnote c See footnote c
REMd and NREM parasomnias 20–22 35–85 65–95 24–89 26–73
Leg restlessnesse 4–24 57 50–83 8–78 5–11
Sleep architecture Reduced REM and SWS, more arousals, degraded sleep features (spindles/K-complex) Decreased REM; increased sleep-onset latency; decreased efficiency Decreased REM; decreased efficiency Decreased REM; less N2; less NREM/REM cycles Disrupted sleep-wakecycles
Poor quality sleep See footnote c 43 54–63 See footnote c See footnote c

Practical Considerations When Treating Patients with Dementia

Pre-visit evaluations <list-item>

Sleep questionnaires (PSQI, SACS, Berlin sleep questionnaire, ESS)

</list-item><list-item>

Choice depends on purpose (eg, SDB vs clarifying sleep patterns)

</list-item>
Visit evaluation clarifying questions <list-item>

In-bed and out-of-bed habits over the 24-hour cycle <list-item>

Time in and out of bed?

</list-item><list-item>

What happens upon lying in bed (eg, reading on a tablet, watching television, eating)?

</list-item><list-item>

Number of bathroom visits? (As a risk factor for sleep apnea)

</list-item>

</list-item><list-item>

Total sleep time and daytime somnolence (night and daytime nap duration) <list-item>

How long until falling asleep?

</list-item><list-item>

Identify both the short sleeper (<6 hours) and the “great” sleeper (>9 hours)

</list-item><list-item>

How long are the naps (ie, >1 hour)?

</list-item>

</list-item><list-item>

Morning rested feeling <list-item>

Poorly informative even in people without dementia

</list-item>

</list-item><list-item>

Clarifications on dream enactment and whether the patient is “living the dream” <list-item>

Avoid overdiagnosing RBD on the basis of sleeptalking, sleepwalking, brief myoclonic jerks

</list-item><list-item>

Is there a dream that can be described (usually violent)? Does it correlate with persistent motor activity? Are there injuries to the patient or the bed partner?

</list-item>

</list-item><list-item>

Medications, medications, medications <list-item>

Which drugs (eg, cholinesterase inhibitors, benzodiazepines, benzodiazepine receptor agonists, melatonin, antihistamines and “PM” drugs)?

</list-item><list-item>

Time of administration (eg, morning vs nighttime dosing of cholinesterase inhibitors)

</list-item>

</list-item> End-of-visit instructions <list-item>

Sleep hygiene <list-item>

Maintain regular schedule, avoid unnecessary naps, avoid stimulants after 2 pm (rule of 2's), daytime exercise and social engagement, avoid heavy meals and alcohol near bedtime, sunlight exposure or light box use (10,000 lux for 30 minutes) in the morning, go to bed when sleepy (avoid eating, watching TV, or reading from a tablet while in bed), comfortable sleep environment (slightly cool room), avoid middle of the night snacks, warm shower 1–2 hours prior to bedtime

</list-item>

</list-item><list-item>

Medications <list-item>

Trazodone for insomnia and sleep consolidation; melatonin also considered according to open-label studies (but failed in randomized controlled trial of moderate to severe AD)

</list-item><list-item>

Cholinesterase inhibitor dosing in the morning rather than nighttime

</list-item><list-item>

Remove offending agents (eg, benzodiazepines, benzodiazepine receptor agonists, antihistamines)

</list-item>

</list-item><list-item>

Family education <list-item>

Interventions in dementia are primarily managed by family and caregivers. Explain importance and relevance, as well as provide education in communicating with patients, to allow for better compliance

</list-item>

</list-item><list-item>

Sleep clinic referral if indicated

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Authors

Elissaios Karageorgiou, MD, PhD, is an Adjunct Assistant Professor, Memory and Aging Center, Department of Neurology, University of California San Francisco; and a Scientific Advisor, Neurological Institute of Athens. Christine M. Walsh, PhD, is an Assistant Professor, Memory and Aging Center, Department of Neurology, University of California San Francisco. Kristine Yaffe, MD, is a Professor of Neurology, Psychiatry, Epidemiology, and the Roy and Marie Scola Endowed Chair and Vice Chair of Research in Psychiatry, University of California San Francisco; and the Chief, Geriatric Psychiatry, and the Director, Memory Disorders Clinic, San Francisco Veterans Affairs Medical Center. Thomas C. Neylan, MD, is a Professor of Psychiatry, University of California San Francisco; and the Director, Post-Traumatic Stress Disorders Program, San Francisco Veterans Affairs Medical Center. Bruce L. Miller, MD, is the A.W. and Mary Margaret Clausen Distinguished Professor in Neurology, and the Director, Memory and Aging Center, University of California San Francisco.

Address correspondence to Elissaios Karageorgiou, MD, PhD, Memory and Aging Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158; email: Elissaios.Karageorgiou@ucsf.edu.

This work was supported by grants from the American Brain Foundation, the Alzheimer's Association, the J.D. French Alzheimer's Foundation, and the Tau Consortium to E. K.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20170407-01

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