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Comparison of polysomnography in people with Alzheimer's disease and insomnia versus non-demented elderly people with insomnia
Abstract
Background
We used baseline polysomnography (PSG) data obtained during the clinical program development for suvorexant to compare the PSG profiles of people with Alzheimer's disease and insomnia (ADI) versus age-matched elderly individuals with insomnia (EI).
Methods
Sleep laboratory Baseline PSG data from participants age 55–80 years from 2 trials in people with insomnia and a trial in people with ADI were included. ADI participants had dementia of mild-to-moderate severity. Diagnostic criteria for insomnia, exclusion for other sleep problems, PSG recording procedures, and endpoint derivations were similar across the trials. All participants underwent a night of in-laboratory PSG prior to the Baseline night to allow for screening/adaptation. Participants in the EI and ADI groups were compared with regard to sleep architecture, sleep micro-structure, and quantitative EEG power spectral endpoints. The analysis was performed on a post hoc basis using propensity score matching to compare sleep parameters separately in women and men while accounting for age group and total sleep time.
Results
A total of 837 EI people and 239 ADI people were included, with the majority in each population (∼65%) being women. Compared to EI, those with ADI had a lower percentage of time spent in slow wave sleep (and a corresponding higher percentage of time spent in the lighter N1 sleep), a lower number of spindles per minute of N2 sleep, and lower absolute EEG power during NREM sleep, particularly in the lower-frequency bands. Trends for lower REM sleep percentage in ADI did not reach statistical significance.
Conclusions
Our findings in this large data set, in which the influence of sleep problems was effectively subtracted out (since both groups had insomnia), provide strong confirmatory support of results from previous smaller studies in indicating that AD of mild-to-moderate severity is associated with less slow wave sleep, spindles, and lower-frequency EEG power.
Trial registration
ClinicalTrials.gov, numbers NCT01097616, NCT01097629, NCT02750306;
... PSG in AD and MCI reveals shortened durations of REM sleep and SWS to a far greater extent than in normal aging (116,117). Decreases in delta and theta EEG power, increases in wake after sleep onset (WASO), increased REM-sleep latency, and decreased sleep efficiency are also observed (117,118). Sleep spindles and K-complexes are reduced in amplitude and frequency, that is, number and quality (116,117). ...
... PSG in AD and MCI reveals shortened durations of REM sleep and SWS to a far greater extent than in normal aging (116,117). Decreases in delta and theta EEG power, increases in wake after sleep onset (WASO), increased REM-sleep latency, and decreased sleep efficiency are also observed (117,118). Sleep spindles and K-complexes are reduced in amplitude and frequency, that is, number and quality (116,117). Furthermore, distinguishing between N1 and N2 NREM sleep often becomes increasingly difficult as the disease progresses (113,116). ...
... Decreases in delta and theta EEG power, increases in wake after sleep onset (WASO), increased REM-sleep latency, and decreased sleep efficiency are also observed (117,118). Sleep spindles and K-complexes are reduced in amplitude and frequency, that is, number and quality (116,117). Furthermore, distinguishing between N1 and N2 NREM sleep often becomes increasingly difficult as the disease progresses (113,116). ...
Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.
Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... The results showed that multimodal ML can help predict the outcome of CSF biomarkers in early AD, the impact of hypoxemia on higher CSF amyloid levels, and hypopnoea and apnoea events associated with levels of pathological AD markers and cognitive decline. Tao et al. [100] used baseline PSG data from mild-to-moderate AD patients and older healthy controls, with AD patients showing a lower percentage of time spent in slow-wave sleep (and a correspondingly higher percentage of time spent in lighter NREM 1 sleep), lower spindles per minute of NREM 2 sleep, and lower absolute EEG power during NREM sleep, particularly in the low-frequency bands. ...
This paper explores the progressive era of sleep monitoring, focusing on wearable and remote devices contributing to advances in the concept of home polysomnography. We begin by exploring the basic physiology of sleep, establishing a theoretical basis for understanding sleep stages and associated changes in physiological variables. The review then moves on to an analysis of specific cutting-edge devices and technologies, with an emphasis on their practical applications, user comfort, and accuracy. Attention is also given to the ability of these devices to predict neurological disorders, particularly Alzheimer’s and Parkinson’s disease. The paper highlights the integration of hardware innovations, targeted sleep parameters, and partially advanced algorithms, illustrating how these elements converge to provide reliable sleep health information. By bridging the gap between clinical diagnosis and real-world applicability, this review aims to elucidate the role of modern sleep monitoring tools in improving personalised healthcare and proactive disease management.
... [14][15][16] Reduced spindle activity has also been demonstrated in adults with Alzheimer's disease. 17 The incidence of OSA is far higher in children with Down syndrome (DS), where the condition has been reported in 31-97%, depending on patient selection criteria, definitions and methodologies used. 18 The distinct dysmorphic features of DS, such as mid-face and mandibular hypoplasia, relatively large and medially positioned tonsils, and relative macroglossia result in a significant reduction in the size of the upper airway in children with DS when compared to TD children, thus increasing the risk of SDB. ...
Background
Children with Down syndrome (DS) are at increased risk of sleep-disordered breathing (SDB). We investigated sleep spindle activity, as a marker of sleep quality, and its relationship with daytime functioning in children with DS compared to typically developing (TD) children.
Methods
Children with DS and SDB ( n = 44) and TD children matched for age, sex and SDB severity underwent overnight polysomnography. Fast or Slow sleep spindles were identified manually during N2/N3 sleep. Spindle activity was characterized as spindle number, density (number of spindles/h) and intensity (density × average duration) on central (C) and frontal (F) electrodes. Parents completed the Child Behavior Check List and OSA-18 questionnaires.
Results
In children with DS, spindle activity was lower compared to TD children for F Slow and F Slow&Fast spindles combined ( p < 0.001 for all). Furthermore, there were no correlations between spindle activity and CBCL subscales; however, spindle activity for C Fast and C Slow&Fast was negatively correlated with OSA-18 emotional symptoms and caregiver concerns and C Fast activity was also negatively correlated with daytime function and total problems.
Conclusions
Reduced spindle activity in children with DS may underpin the increased sleep disruption and negative effects of SDB on quality of life and behavior.
Impact
Children with Down syndrome (DS) are at increased risk of sleep-disordered breathing (SDB), which is associated with sleep disruption affecting daytime functioning.
Sleep spindles are a sensitive marker of sleep quality.
We identified for the first time that children with DS had reduced sleep spindle activity compared to typically developing children matched for SDB severity.
The reduced spindle activity likely underpins the more disrupted sleep and may be associated with reduced daytime functioning and quality of life and may also be an early biomarker for an increased risk of developing dementia later in life in children with DS.
Substantial sleep impairment in patients with Alzheimer’s disease (AD) is one of the emerging points for continued efforts to better understand the disease. Individuals without cognitive decline, an important marker of the clinical phase of AD, may show early alterations in the sleep-wake cycle. The objective of this critical narrative review is to explore the bidirectional pathophysiological correlation between sleep disturbances and Alzheimer’s Disease. Specifically, it examines how the disruption of sleep homeostasis in individuals without dementia could contribute to the pathogenesis of AD, and conversely, how neurodegeneration in individuals with Alzheimer’s Disease might lead to dysregulation of the sleep-wake cycle. Recent scientific results indicate that sleep disturbances, particularly those related to impaired glymphatic clearance, may act as an important mechanism associated with the genesis of Alzheimer’s Disease. Additionally, amyloid deposition and tau protein hyperphosphorylation, along with astrocytic hyperactivation, appear to trigger changes in neurotransmission dynamics in areas related to sleep, which may explain the onset of sleep disturbances in individuals with AD. Disruption of sleep homeostasis appears to be a modifiable risk factor in Alzheimer’s disease. Whenever possible, the use of non-pharmacological strategies becomes important in this context. From a different perspective, additional research is needed to understand and treat the dysfunction of the sleep-wake cycle in individuals already affected by AD. Early recognition and correction of sleep disturbances in this population could poten-tially mitigate the progression of dementia and improve the quality of life for those with AD.
Old age is a sensitive period of life, characterized by a wide range of physiological and psychological changes that cause the loss of some states, including cognitive weakness, gradual deterioration of the body, memory and social function. The elderly in this period are facing many challenges, the identification of which can be of great help in the preparation of support and rehabilitation programs. Therefore, the purpose of this research was to explain the phenomenological challenges of the elderly living in Kashan, Iran. The research population included the elderly over 62 years old living in Kashan city. The sampling method was purposeful, during which 14 aged people were interviewed and the sampling was saturated. The data were collected using semi-structured interviews and analyzed by the seven-step Claesian method. The result indicated two main themes and 14 Sub-themes. The main themes were (1) individual challenges and (2) social challenges. Sub-themes included (1) concerns about physical health and diseases, (2) feelings of loneliness, (3) concerns about children's future, (4) support for children, (5) lack of support for children, (6) mental and emotional problems, (7) maintaining authority and respect, (8) positive hope, (9) negative hope, (10) disability, (11) receiving support from social institutions and providing welfare for the elderly, (12) economic problems, (13) positive attitude towards the nursing home and (14) negative attitude towards the nursing home. According to the results, it was found that it is necessary to deal with the problems and challenges of the elderly, and therefore, providing supportive, educational and health services for the elderly can reduce their problems. Research Article
The growth of biomedical engineering has made depression diagnosis via electroencephalography (EEG) a trendy issue. The two significant challenges to this application are EEG signals’ complexity and non-stationarity. Additionally, the effects caused by individual variances may hamper the generalization of detection systems. Given the association between EEG signals and particular demographics, such as gender and age, and the influences of these demographic characteristics on the incidence of depression, it would be preferable to include demographic factors during EEG modeling and depression detection. The main objective of this work is to develop an algorithm that can recognize depression patterns by studying EEG data. Following a multiband analysis of such signals, machine learning and deep learning techniques were used to detect depression patients automatically. EEG signal data are collected from the multi-modal open dataset MODMA and employed in studying mental diseases. The EEG dataset contains information from a traditional 128-electrode elastic cap and a cutting-edge wearable 3-electrode EEG collector for widespread applications. In this project, resting EEG readings of 128 channels are considered. According to CNN, training with 25 epoch iterations had a 97% accuracy rate. The patient’s status has to be divided into two basic categories: major depressive disorder (MDD) and healthy control. Additional MDD include the following six classes: obsessive-compulsive disorders, addiction disorders, conditions brought on by trauma and stress, mood disorders, schizophrenia, and the anxiety disorders discussed in this paper are a few examples of mental illnesses. According to the study, a natural combination of EEG signals and demographic data is promising for the diagnosis of depression.
Polysomnography (PSG) studies of sleep changes in Alzheimer's disease (AD) have reported but not fully established the relationship between sleep disturbances and AD. To better detail this relationship, we conducted a systematic review and meta-analysis of reported PSG differences between AD patients and healthy controls. An electronic literature search was conducted in EMBASE, MEDLINE, All EBM databases, CINAHL, and PsycINFO inception to Mar 2021. Twenty-eight studies were identified for systematic review, 24 of which were used for meta-analysis. Meta-analyses revealed significant reductions in total sleep time, sleep efficiency, and percentage of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and increases in sleep latency, wake time after sleep onset, number of awakenings, and REM latency in AD compared to controls. Importantly, both decreased SWS and REM were significantly associated with the severity of cognitive impairment in AD patients. Alterations in electroencephalogram (EEG) frequency components and sleep spindles were also observed in AD, although the supporting evidence for these changes was limited. Sleep in AD is compromised with increased measures of wake and decreased TST, SWS, and REM sleep relative to controls. AD-related reductions in SWS and REM sleep correlate with the degree of cognitive impairment. Alterations in sleep EEG frequency components such as sleep spindles may be possible biomarkers with relevance for diagnosing AD although their sensitivity and specificity remain to be clearly delineated. AD-related sleep changes are potential targets for early therapeutic intervention aimed at improving sleep and slowing cognitive decline.
Insomnia is a pervasive sleep disorder affecting numerous patients across diverse demographical populations and comorbid disease states. Contributing factors are often a complex interaction of biological, psychological, and social components, requiring a multifaceted approach in terms of both diagnosis and management. In the setting of Alzheimer’s disease, insomnia is an even more complicated issue, with a higher overall prevalence than in the general population, greater complexity of contributing etiologies, and differences in diagnosis (at times based on caregiver observation of sleep disruption rather than subjective complaints by the individual with the disorder), and requiring more discretion in terms of treatment, particularly in regard to adverse effect profile concerns. There also is growing evidence of the bidirectional nature of sleep disruption and Alzheimer’s disease, with insomnia potentially contributing to disease progression, making the condition even more paramount to address. The objective of this review was to provide the clinician with an overview of treatment strategies that may have value in the treatment of disturbed sleep in Alzheimer’s disease. Nonpharmacological approaches to treatment should be exhausted foremost; however, pharmacotherapy may be needed in certain clinical scenarios, which can be a challenge for clinicians given the paucity of evidence and guidelines for treatment in the subpopulation of Alzheimer’s disease. Agents such as sedating antidepressants, melatonin, and site-specific γ-aminobutyric acid agonists are often employed based on historical usage but are not necessarily supported by high-quality trials. Newer agents such as dual orexin receptor antagonists have demonstrated some promise but still need further evaluation.
AD patients undergo a slowing of waking EEG rhythms since prodromal stages, which could be ascribed to poor sleep quality. We examined the relationship between wake and sleep alterations by assessing EEG activity during (NREM/REM) sleep and (pre-sleep/post-sleep) wakefulness in AD, MCI and healthy controls. AD and MCI show high sleep latency and less slow-wave sleep. Reduced sigma activity characterizes NREM sleep, reflecting sleep spindles loss. The EEG slowing characterizes REM sleep and wakefulness of AD and MCI, with strong correlations among the two phenomena suggesting common neuropathological mechanisms. Evening-to-morning variations in waking EEG revealed the gradual disappearance in MCI and AD of overnight changes in delta activity, indicating a progressive decay of sleep restorative functions on diurnal activity, that correlates with the impairment of sleep high-frequency activity in AD. Our findings support a linkage between wake and sleep alterations, and the importance of sleep-related processes in Alzheimer’s disease progression.
Suboptimal sleep causes cognitive decline and probably accelerates Alzheimer's Disease (AD) progression. Several sleep interventions have been tested in established AD dementia cases. However early intervention is needed in the course of AD at Mild Cognitive Impairment (MCI) or mild dementia stages to help prevent decline and maintain good quality of life. This systematic review aims to summarize evidence on sleep interventions in MCI and mild AD dementia. Seven databases were systematically searched for interventional studies where ≥ 75% of participants met diagnostic criteria for MCI/mild AD dementia, with a control group and validated sleep outcome measures. Studies with a majority of participants diagnosed with Moderate to Severe AD were excluded. After removal of duplicates, 22,133 references were returned in two separate searches (August 2019 and September 2020). 325 full papers were reviewed with 18 retained. Included papers reported 16 separate studies, total sample (n = 1,056), mean age 73.5 years. 13 interventions were represented: Cognitive Behavioural Therapy – Insomnia (CBT‐I), A Multi‐Component Group Based Therapy, A Structured Limbs Exercise Programme, Aromatherapy, Phase Locked Loop Acoustic Stimulation, Transcranial Stimulation, Suvorexant, Melatonin, Donepezil, Galantamine, Rivastigmine, Tetrahydroaminoacridine and Continuous Positive Airway Pressure (CPAP). Psychotherapeutic approaches utilising adapted CBT‐I and a Structured Limbs Exercise Programme each achieved statistically significant improvements in the Pittsburgh Sleep Quality Index with one study reporting co‐existent improved actigraphy variables. Suvorexant significantly increased Total Sleep Time and Sleep Efficiency whilst reducing Wake After Sleep Onset time. Transcranial Stimulation enhanced cortical slow oscillations and spindle power during daytime naps. Melatonin significantly reduced sleep latency in two small studies and sleep to wakefulness transitions in a small sample. CPAP demonstrated efficacy in participants with Obstructive Sleep Apnoea. Evidence to support other interventions was limited. Whilst new evidence is emerging, there remains a paucity of evidence for sleep interventions in MCI and mild AD highlighting a pressing need for high quality experimental studies exploring alternative sleep interventions.
Even prior to the onset of the prodromal stages of Alzheimer’s disease (AD), a constellation of sleep disturbances are apparent. A series of epidemiological studies indicate that multiple forms of these sleep disturbances are associated with increased risk for developing mild cognitive impairment (MCI) and AD, even triggering disease onset at an earlier age. Through the combination of causal manipulation studies in humans and rodents, as well as targeted examination of sleep disturbance with respect to AD biomarkers, mechanisms linking sleep disturbance to AD are beginning to emerge. In this review, we explore recent evidence linking local deficits in brain oscillatory function during sleep with local AD pathological burden and circuit-level dysfunction and degeneration. In short, three deficits in the local expression of sleep oscillations have been identified in relation to AD pathophysiology: (1) frequency-specific frontal deficits in slow wave expression during non-rapid eye movement (NREM) sleep, (2) deficits in parietal sleep spindle expression, and (3) deficits in the quality of electroencephalographic (EEG) desynchrony characteristic of REM sleep. These deficits are noteworthy since they differ from that seen in normal aging, indicating the potential presence of an abnormal aging process. How each of these are associated with β-amyloid (Aβ) and tau pathology, as well as neurodegeneration of circuits sensitive to AD pathophysiology, are examined in the present review, with a focus on the role of dysfunction within fronto-hippocampal and subcortical sleep-wake circuits. It is hypothesized that each of these local sleep deficits arise from distinct network-specific dysfunctions driven by regionally-specific accumulation of AD pathologies, as well as their associated neurodegeneration. Overall, the evolution of these local sleep deficits offer unique windows into the circuit-specific progression of distinct AD pathophysiological processes prior to AD onset, as well as their impact on brain function. This includes the potential erosion of sleep-dependent memory mechanisms, which may contribute to memory decline in AD. This review closes with a discussion of the remaining critical knowledge gaps and implications of this work for future mechanistic studies and studies implementing sleep-based treatment interventions.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an asymptomatic period of amyloid-β (Aβ) deposition as insoluble extracellular plaque, intracellular tau aggregation, neuronal and synaptic loss, and subsequent cognitive dysfunction and dementia. A growing public health crisis, the worldwide prevalence of AD is expected to rise from 46.8 million individuals affected in 2015 to 131.5 million in 2050. Sleep disturbances have been associated with increased future risk of AD. A bi-directional relationship is hypothesized between sleep and AD with sleep disturbances as either markers for AD pathology and/or a mechanism mediating increased risk of AD. In this review, the evidence in humans supporting this complex relationship between sleep and AD will be discussed as well as the therapeutic potential and challenges of treating sleep disturbances to prevent or delay the onset of AD.
Introduction:
We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia.
Methods:
Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4.
Results:
Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients.
Discussion:
Suvorexant improved TST in patients with probable AD dementia and insomnia.
The association between Alzheimer's disease (AD) and sleep disturbances has received increasing scientific attention in the last decades. However, little is known about the impact of sleep and its disturbances on the development of preclinical AD stages, such as mild cognitive impairment. This review describes the evolution of knowledge about the potential bidirectional relationships between AD and sleep disturbances exploring recent large prospective studies and meta-analyses and studies of the possible mechanisms through which sleep and the neurodegenerative process could be associated. The review also makes a comprehensive exploration of the sleep characteristics of older people, ranging from cognitively normal individuals, through patients with mild cognitive impairment, up to the those with dementia with AD.
Purpose:
Sleep disturbances are common in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients. Non-rapid eye movement stage 3 (N3), rapid eye movement stage (REM), spindle density, and K-complex (KC) density are decreased in MCI and AD patients. Periodic limb movements in sleep (PLMS) are increased in other neurodegenerative diseases. We aimed to distinguish amnestic mild cognitive impairment (aMCI) patients from the overall population of MCI patients by comparing the N3 and REM proportions, the morphological characteristics of spindles and KCs and the periodic limb movement index (PLMI) among control, aMCI and AD subjects.
Methods:
In 92 subjects (30 controls, 32 aMCI and 30 AD), sleep stages, spindles, KCs and PLMS were recorded during the second of two nights of polysomnography (PSG). We compared the above parameters among the three groups.
Results:
AD and aMCI subjects had lower proportions of N3 and REM, poorer spindle and KC activities and more frequent PLMS than controls. These alterations were associated with decreased Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. We determined cut-off values for distinguishing aMCI and AD using logistic regression and receiver operating characteristic (ROC) analyses.
Conclusions:
AD and aMCI patients have abnormal sleep stage proportions, spindles, KCs and PLMS. The combination of the above alterations may distinguish aMCI and AD patients from controls with high specificity and sensitivity.
The K-complex (KC) is one of the hallmarks of Non-Rapid Eye Movement (NREM) sleep. Recent observations point to a drastic decrease of spontaneous KCs in Alzheimer's disease (AD). However, no study has investigated when, in the development of AD, this phenomenon starts. The assessment of KC density in mild cognitive impairment (MCI), a clinical condition considered a possible transitional stage between normal cognitive function and probable AD, is still lacking. The aim of the present study was to compare KC density in AD/MCI patients and healthy controls (HCs), also assessing the relationship between KC density and cognitive decline. Twenty amnesic MCI patients underwent a polysomnographic recording of a nocturnal sleep. Their data were compared to those of previously recorded 20 HCs and 20 AD patients. KCs during stage 2 NREM sleep were visually identified and KC densities of the three groups were compared. AD patients showed a significant KC density decrease compared with MCI patients and HCs, while no differences were observed between MCI patients and HCs. KC density was positively correlated with Mini-Mental State Examination (MMSE) scores. Our results point to the existence of an alteration of KC density only in a full-blown phase of AD, which was not observable in the early stage of the pathology (MCI), but linked with cognitive deterioration.
Although a slowing of electroencephalographic (EEG) activity during wakefulness and –to some extent- sleep of Alzheimer disease (AD) patients (i.e., increased slow-frequency activity) was documented, recent findings in healthy elderly show a decreased 0.6–1 Hz slow wave activity (SWA) during NREM, which was associated to β-amyloid deposition and impaired hippocampal memory consolidation. We hypothesize that the apparent contradiction may be explained by the partial overlap between 0.6–1 Hz EEG activity and K-Complex (KC). According to this view, we studied both frontal KCs and SWA in 20 AD patients and 20 healthy age-matched controls (HC) during nightly sleep, under the hypothesis that KCs better discriminate patients from healthy elderly than ≤1 Hz SWA. A drastic decrease of KC density during stage 2 NREM was found in AD compared to HC. Patients show more than 40% reduction of the KC density, allowing a correct classification of 80%. On the other hand, ≤1 Hz SWA of AD patients is slightly (not significantly) higher in most cortical areas compared to HC. Although no significant changes of ≤1 Hz SWA are detectable over frontal areas in AD, KC density decreases over the same location, and its decrease is related to the cognitive decline.
Historically, pharmacological therapies have used mechanisms such as γ- aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAA receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage-specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 57 is January 06, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Men and women sleep differently. While much is known about the mechanisms that drive sleep, the reason for these sex differences in sleep behaviour is unknown and understudied. Historically, women and female animals are underrepresented in studies of sleep and its disorders. Nevertheless, there is a growing recognition of sex disparities in sleep and rhythm disorders. Women typically report poorer quality and more disrupted sleep across various stages of life. Findings from clinical and basic research studies strongly implicate a role for sex steroids in sleep modulation. Understanding how neuroendocrine mediators and sex differences influence sleep is central to advancing our understanding of sleep-related disorders. The investigation into sex differences and sex steroid modulation of sleep is in its infancy. Identifying the mechanisms underlying sex and gender differences in sleep will provide valuable insights leading to tailored therapeutics that benefit each sex. The goal of this review is to discuss our current understanding of how biological sex and sex steroids influence sleep behaviour from both the clinical and pre-clinical perspective.
Study objectives:
Suvorexant, an orexin receptor antagonist, improves sleep in healthy subjects (HS) and patients with insomnia. We compared the electroencephalographic (EEG) power spectral density (PSD) profile of suvorexant with placebo using data from a phase 2 trial in patients with insomnia. We also compared suvorexant's PSD profile with the profiles of other insomnia treatments using data from 3 HS studies.
Design:
Phase 2 trial--randomized, double-blind, two-period (4 w per period) crossover. HS studies--randomized, double-blind, crossover.
Setting:
Sleep laboratories.
Participants:
Insomnia patients (n = 229) or HS (n = 124).
Interventions:
Phase 2 trial--suvorexant 10 mg, 20 mg, 40 mg, 80 mg, placebo; HS study 1--suvorexant 10 mg, 50 mg, placebo; HS study 2--gaboxadol 15 mg, zolpidem 10 mg, placebo; HS study 3--trazodone 150 mg, placebo.
Measurements and results:
The PSD of the EEG signal at 1-32 Hz of each PSG recording during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were calculated. The day 1 and day 28 PSD profiles of suvorexant at all four doses during NREM and REM sleep in patients with insomnia were generally flat and close to 1.0 (placebo) at all frequencies. The day 1 PSD profile of suvorexant in HS was similar to that in insomnia patients. In contrast, the other three drugs had distinct PSD profiles in HS that differed from each other.
Conclusions:
Suvorexant at clinically effective doses had limited effects on power spectral density compared with placebo in healthy subjects and in patients with insomnia, in contrast to the three comparison insomnia treatments. These findings suggest the possibility that antagonism of the orexin pathway might lead to improvements in sleep without major changes in the patient's neurophysiology as assessed by electroencephalographic.
Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid-β (Aβ) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleep-wake cycle directly influences levels of Aβ in the brain. In experimental models, sleep deprivation increases the concentration of soluble Aβ and results in chronic accumulation of Aβ, whereas sleep extension has the opposite effect. Furthermore, once Aβ accumulates, increased wakefulness and altered sleep patterns develop. Individuals with early Aβ deposition who still have normal cognitive function report sleep abnormalities, as do individuals with very mild dementia due to AD. Thus, sleep and neurodegenerative disease may influence each other in many ways that have important implications for the diagnosis and treatment of AD.
The propensity score is the conditional probability of assignment to a particular treatment given a vector of observed covariates. Both large and small sample theory show that adjustment for the scalar propensity score is sufficient to remove bias due to all observed covariates. Applications include: (i) matched sampling on the univariate propensity score, which is a generalization of discriminant matching, (ii) multivariate adjustment by subclassification on the propensity score where the same subclasses are used to estimate treatment effects for all outcome variables and in all subpopulations, and (iii) visual representation of multivariate covariance adjustment by a two- dimensional plot.
MatchIt implements the suggestions of Ho, Imai, King, and Stuart (2007) for improving parametric statistical models by preprocessing data with nonparametric matching methods. MatchIt implements a wide range of sophisticated matching methods, making it possible to greatly reduce the dependence of causal inferences on hard-to-justify, but commonly made, statistical modeling assumptions. The software also easily fits into existing research practices since, after preprocessing data with MatchIt, researchers can use whatever parametric model they would have used without MatchIt, but produce inferences with substantially more robustness and less sensitivity to modeling assumptions. MatchIt is an R program, and also works seamlessly with Zelig.
To compare NREM EEG power in primary insomnia (PI) and good sleeper controls (GSC), examining both sex and NREM period effects; to examine relationships between EEG power, clinical characteristics, and self-reports of sleep.
Overnight polysomnographic study.
Sleep laboratory.
PI (n=48; 29 women) and GSC (n=25; 15 women).
None.
EEG power from 1-50 Hz was computed for artifact-free sleep epochs across four NREM periods. Repeated measures mixed effect models contrasted differences between groups, EEG frequency bands, and NREM periods. EEG power-frequency curves were modeled using regressions with fixed knot splines.
Mixed models showed no significant group (PI vs. GSC) differences; marginal sex differences (delta and theta bands); significant differences across NREM periods; and group*sex and group*NREM period interactions, particularly in beta and gamma bands. Modeled power-frequency curves showed no group difference in whole-night NREM, but PI had higher power than GSC from 18-40 Hz in the first NREM period. Among women, PI had higher 16 to 44-Hz power than GSC in the first 3 NREM periods, and higher 3 to 5-Hz power across all NREM periods. PI and GSC men showed no consistent differences in EEG power. High-frequency EEG power was not related to clinical or subjective sleep ratings in PI.
Women with PI, but not men, showed increased high-frequency and low-frequency EEG activity during NREM sleep compared to GSC, particularly in early NREM periods. Sex and NREM period may moderate quantitative EEG differences between PI and GSC.
The 1968 Rechtschaffen and Kales (R & K) sleep scoring manual was published 15 years after REM sleep was discovered. Advances in the ensuing 28 years warranted a re-look at visual scoring of sleep stages. This paper describes the work of the AASM Visual Scoring Task Force, including methodology, a literature review and the rationale behind the new rules. Reliability studies of R & K scoring were reviewed; reliability was low for stage one and moderate for slow wave sleep. Evidence indicated that K complexes and slow waves are expressed maximal frontally, spindles centrally and alpha rhythm over the occipital region. Three derivations of EEG, two of electro-oculography, and one of chin EMG were recommended. Scoring by 30-second epochs was retained. New terminology for sleep stages was proposed. Attenuation of alpha rhythm was determined to be the most valid electrophysiological marker of sleep onset. Alternative measures were proposed for non-alpha generating subjects. K complexes associated with arousals were determined to be insufficient alone to define the new stage N2. No evidence was found to justify dividing slow wave sleep into two stages. No reasons were found to alter the current slow wave amplitude criteria at any age. The phenomena of REM sleep were defined. The rules for defining onset and termination of REM sleep periods were simplified. Movement time was eliminated and major body movements defined. Studies are needed to test the reliability of the new rules. Future advances in technology may require modification of these rules with time.
A majority of patients with Alzheimer’s disease (AD) experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (SWS, stage N3), and decreased rapid-eye-movement sleep (REM). Clinical studies are investigating whether such sleep disturbances are a consequence of the underlying disease, and whether they also contribute to the clinical and pathological manifestations of AD. Emerging research has provided a direct link between several of these sleep disruptions and AD pathophysiology, suggesting that treating sleep disorders in this population may target basic mechanisms of the disease. Here, we provide a comprehensive review of sleep disturbances associated with the spectrum of AD, ranging from the preclinical stages through dementia. We discuss how sleep interacts with AD pathophysiology and, critically, whether sleep impairments can be targeted to modify the disease course in a subgroup of affected AD patients. Ultimately, larger studies that fully utilize new diagnostic and experimental tools will be required to better define the most relevant sleep disturbance to target in AD, the interventions that best modulate this target symptom, and whether successful early intervention can modify AD risk and prevent dementia.
Accumulating evidence supports a bidirectional relationship between sleep disruption and Alzheimer’s disease (AD) pathology. Among various sleep electroencephalography activities, the sleep spindle is one specific electroencephalographic rhythm that has potential to be a biomarker for AD. This review explores the association between sleep spindles and AD-related dementia from a neuropsychological perspective by a systematic re-examining of recent findings. In general, sleep spindles, characterized by density, amplitude, duration, and frequency, are disrupted in AD. Moreover, its functional coupling with slow oscillation also suffers in AD. While preliminary, our observations and comparisons suggest that spindle density rather than frequency and fast spindles rather than slow spindles could be more sensitive to AD-related dementia, and spindle plasticity provides possibilities for targeted interference. In conclusion, quantitative and qualitative features of sleep spindles represent potential non-invasive and cost-effective biomarkers for AD and provide both therapeutic and public health implications.
As we age, sleep patterns undergo significant modifications in micro and macrostructure, worsening cognition, and quality of life. These are associated with remarkable brain changes, like deterioration in synaptic plasticity, gray and white matter, and significant modifications in hormone levels. Sleep alterations are also a core component of mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). AD night time is characterized by a gradual decrease in slow-wave activity and a substantial reduction of REM sleep. Sleep abnormalities can accelerate AD pathophysiology, promoting the accumulation of amyloid-β (Aβ) and phosphorylated tau. Thus, interventions that target sleep disturbances in elderly people and MCI patients have been suggested as a possible strategy to prevent or decelerate conversion to dementia. Although cognitive-behavioral therapy and pharmacological medications are still first-line treatments, despite being scarcely effective, new interventions have been proposed, such as sensory stimulation and Noninvasive Brain Stimulation (NiBS). The present review outlines the current state of the art of the relationship between sleep modifications in healthy aging and the neurobiological mechanisms underlying age-related changes. Furthermore, we provide a critical analysis showing how sleep abnormalities influence the prognosis of AD pathology by intensifying Aβ and tau protein accumulation. We discuss potential therapeutic strategies to target sleep disruptions and conclude that there is an urgent need for testing new therapeutic sleep interventions.
Older adults with mild cognitive impairment (MCI) are at-risk of developing dementia, particularly Alzheimer’s disease. While some research suggests that alterations in sleep architecture may mediate cognitive decline, the nature and magnitude of changes to sleep macro- (sleep stages) and micro-architecture (electroencephalography (EEG) oscillations) in MCI is not yet clear. This study aimed to systematically review and meta-analyse case-control studies objectively measuring sleep in MCI. A systematic search was conducted using PubMed, Scopus, Web of Science, Embase and Psycinfo databases and after review, a total of 10 studies met inclusion criteria. Of these, all reported sleep macro-architecture and four reported micro-architecture outcomes. A combined total of 430participants (209 with and 221 without MCI) underwent objective sleep assessments in the included full-text articles. Findings show that compared to healthy controls, those with MCI have pronounced changes in sleep macro-architecture with greater wake after sleep onset, reduced total sleep time, lower sleep efficiency, longer sleep onset latency, longer rapid eye movement sleep (REM) latency, reduced REM sleep, greater N1 sleep, and worse severity of hypoxemia. Pooling of sleep micro-architecture EEG measures was not possible due to limited studies, however reduced spindles in non-REM sleep and greater EEG slowing in REM sleep were reported.
As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer’s disease (AD) can develop sleep problems even before memory and other cognitive deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep−wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep−wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.
Objective:
Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS).
Methods:
Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 ± 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 ± 5 years).
Results:
We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk.
Conclusions:
Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia.
Observational studies are often the only viable options in many clinical settings, especially when it is unethical or infeasible to randomly assign participants to different treatment régimes. In such case propensity score (PS) analysis can be applied to accounting for possible selection bias and thereby addressing questions of causal inference. Many PS methods exist, yet few guidelines are available to aid applied researchers in their conduct and evaluation of a PS analysis. In this article we give an overview of available techniques for PS estimation and application, balance diagnostic, treatment effect estimation, and sensitivity assessment, as well as recent advances. We also offer a tutorial that can be used to emulate the steps of PS analysis. Our goal is to provide information that will bring PS analysis within the reach of applied clinical researchers and practitioners.
Previous studies of the differences between patients with insomnia and good sleepers with regard to quantitative electroencephalographic measures have mostly utilized small samples and consequently had limited ability to account for potentially important confounding factors of age, sex and part of the night. We conducted a power spectral analysis using a large database of sleep electroencephalographic recordings to evaluate differences between patients with insomnia (N = 803) and good sleepers (N = 811), while simultaneously accounting for these factors and their interaction. Comparisons of power as a function of age and part of the night were made between cohorts (patients with insomnia versus good sleepers) by sex. Absolute power in the delta, theta and sigma bands declined with age for both females and males. Females had significantly greater power than males at all ages, and for each band, cohort and part of the night. These sex differences were much greater than differences between patients with insomnia and good sleepers. Compared with good sleepers, patients with insomnia under age 40-45 years had reduced delta band power during Part 1 of the night. Females with insomnia over age 45 years had increased delta and theta band power in Parts 2 and 3 of the night, and males with insomnia under age 40 years had reduced theta power in Part 1. Females with insomnia had increased beta2 power in all parts of the night, and males with insomnia had reduced alpha power during all parts of the night. Relative power (the proportion that an individual frequency band contributes to the total power) decreased in the delta band and increased in all other bands with age for both cohorts, sexes and all parts of the night. This analysis provides a unique resource for quantitative information on the differences in power spectra between patients with insomnia and good sleepers accounting for age, sex and part of the night.
Sleep disruption appears to be a core component of Alzheimer's disease (AD) and its pathophysiology. Signature abnormalities of sleep emerge before clinical onset of AD. Moreover, insufficient sleep facilitates accumulation of amyloid-β (Aβ), potentially triggering earlier cognitive decline and conversion to AD. Building on such findings, this review has four goals: evaluating (i) associations and plausible mechanisms linking non-rapid-eye-movement (NREM) sleep disruption, Aβ, and AD; (ii) a role for NREM sleep disruption as a novel factor linking cortical Aβ to impaired hippocampus-dependent memory consolidation; (iii) the potential diagnostic utility of NREM sleep disruption as a new biomarker of AD; and (iv) the possibility of sleep as a new treatment target in aging, affording preventative and therapeutic benefits.
Background:
Neuropsychiatric symptoms (NPS) are being increasingly recognized as common serious problems in Alzheimer's disease (AD). However, published data on the prevalence of NPS in persons with AD are conflicting. This meta-analysis aimed to estimate the prevalence of NPS in persons with AD.
Methods:
Studies published from 1964 to September 30, 2014, were identified from PubMed and Embase database, reference lists and conference abstracts. We calculated prevalence rates and conducted meta-regression analysis with random-effects model, according to study characteristics, population demographics or condition information.
Results:
We identified 48 eligible articles, which provided data for 12 NPS reported in Neuropsychiatric Inventory (NPI). The most frequent NPS was apathy, with an overall prevalence of 49% (95% CI 41-57%), followed by depression, aggression, anxiety and sleep disorder, the pooled prevalence estimates of which were 42% (95% CI 37-46%), 40% (95% CI 33-46%), 39% (95% CI 32-46%) and 39% (95% CI 30-47%), respectively. The less prevalent NPS were irritability (36%, 31-41%), appetite disorder (34%, 27-41%), aberrant motor behavior (32%, 25-38%), delusion (31%, 27-35%), disinhibition (17%, 12-21%) and hallucination (16%, 13-18%). Least common was euphoria, with an overall prevalence of 7% (95% CI 5-9%).
Limitations:
Several aspects, such as the quality of included studies were not always optimal and there was significant heterogeneity of prevalence estimate across studies.
Conclusions:
NPS were observed to be highly prevalent in AD patients. Disease duration, age, education level, population origin and the severity of cognitive impairment had influence on the prevalence of some NPS.
Background
Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal Phase-3 trials.
Methods
Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30mg (non-elderly/elderly) and 20/15mg (non-elderly/elderly) were evaluated. The primary focus was 40/30mg, with fewer patients randomized to 20/15mg. There was an optional 3-month double-blind extension in Trial-1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at Week-1, Month-1, and Month-3 by patient-reported subjective total-sleep-time (sTST) and time-to-sleep-onset (sTSO), and in a subset of patients at Night-1, Month-1, and Month-3 by polysomnographic (PSG) endpoints of Wakefulness-After-persistent-Sleep-Onset (WASO) and Latency-to-onset-of-Persistent-Sleep (LPS). 1021 patients were randomized in Trial-1 and 1019 patients in Trial-2.
Results
Suvorexant 40/30mg was superior to placebo on all subjective and PSG endpoints at Night-1/Week-1, Month-1 and Month-3 in both trials, except for LPS at Month-3 in Trial-2. Suvorexant 20/15mg was superior to placebo on sTST and WASO at Night-1/Week-1, Month-1 and Month-3 in both trials and at most individual timepoints for sTSO and LPS in each trial. Both doses of suvorexant were generally well-tolerated, with <5% of patients discontinuing due to adverse events over 3-months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued.
Conclusions
Suvorexant improved sleep onset and maintenance over 3-months of nightly treatment and was generally safe and well-tolerated.
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Patients with dementias, such as Alzheimer's disease (AD), often have nocturnally disrupted sleep. Clinically, this may present as agitation during the nighttime hours, which may affect as many as a quarter of AD patients during some stage of their illness. Sleep disturbance in AD may be multifactorial and involve sleep-disordered breathing and disrupted chronobiology, both often characterized by excessive daytime napping. Polysomnographically, AD patients show decreased rapid eye movement (REM) sleep in proportion to the extent of their dementia; some evidence suggests that cholinesterase inhibitors, commonly used pharmacologic agents for cognitive loss in AD, may increase REM sleep measures. Unfortunately, such agents may also induce insomnia and vivid dreams. There have been no randomized clinical trials of sedative-hypnotic medications specifically targeted at AD patients with sleep problems. Evidence suggests that sedative-hypnotics, such as benzodiazepine site-specific agonists, may have a role in some cases, whereas atypical antipsychotics may be necessary in other cases. There are also reports of successful interventions with nonpharmacologic options (eg, exercise, illumination). The utility of melatonin as a hypnotic in this population appears equivocal.
The effects of age and gender on sleep EEG power spectral density in the middle years of life (ages 20-60 years old)
- Carrier