Suvorexant Acutely Decreases Tau Phosphorylation and Aß in the Human CNS.

OBJECTIVE: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-ß levels and amyloid plaques in mouse models overexpressing amyloid-ß, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-ß, tau, and phospho-tau. METHODS: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-ß, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry. RESULTS: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-ß ~10% to 20% compared to placebo starting 5 hours after drug administration. INTERPRETATION: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-ß concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27-40.

Mapping sleep's oscillatory events as a biomarker of Alzheimer's disease.

INTRODUCTION: Memory-associated neural circuits produce oscillatory events including theta bursts (TBs), sleep spindles (SPs), and slow waves (SWs) in sleep electroencephalography (EEG). Changes in the "coupling" of these events may indicate early Alzheimer's disease (AD) pathogenesis. METHODS: We analyzed 205 aging adults using single-channel sleep EEG, cerebrospinal fluid (CSF) AD biomarkers, and Clinical Dementia Rating® (CDR®) scale. We mapped SW-TB and SW-SP neural circuit coupling precision to amyloid positivity, cognitive impairment, and CSF AD biomarkers. RESULTS: Cognitive impairment correlated with lower TB spectral power in SW-TB coupling. Cognitively unimpaired, amyloid positive individuals demonstrated lower precision in SW-TB and SW-SP coupling compared to amyloid negative individuals. Significant biomarker correlations were found in oscillatory event coupling with CSF Aß42 /Aß40 , phosphorylated- tau181 , and total-tau. DISCUSSION: Sleep-dependent memory processing integrity in neural circuits can be measured for both SW-TB and SW-SP coupling. This breakdown associates with amyloid positivity, increased AD pathology, and cognitive impairment. HIGHLIGHTS: At-home sleep EEG is a potential biomarker of neural circuits linked to memory. Circuit precision is associated with amyloid positivity in asymptomatic aging adults. Levels of CSF amyloid and tau also correlate with circuit precision in sleep EEG. Theta burst EEG power is decreased in very early mild cognitive impairment. This technique may enable inexpensive wearable EEGs for monitoring brain health.

Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer's disease.

Sleep monitoring may provide markers for future Alzheimer's disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer's disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer's disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer's disease biomarkers, total tau and amyloid-ß42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-ß42 ratio, APOE ε4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer's disease.

Effect of sleep on overnight cerebrospinal fluid amyloid ß kinetics.

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid ß, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C6 -leucine to measure amyloid ß kinetics. We found that sleep deprivation increased overnight amyloid ß38, amyloid ß40, and amyloid ß42 levels by 25 to 30% via increased overnight amyloid ß production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid ß production. Ann Neurol 2018;83:197-204.

Comparison of a single-channel EEG sleep study to polysomnography.

An accurate home sleep study to assess electroencephalography (EEG)-based sleep stages and EEG power would be advantageous for both clinical and research purposes, such as for longitudinal studies measuring changes in sleep stages over time. The purpose of this study was to compare sleep scoring of a single-channel EEG recorded simultaneously on the forehead against attended polysomnography. Participants were recruited from both a clinical sleep centre and a longitudinal research study investigating cognitively normal ageing and Alzheimer's disease. Analysis for overall epoch-by-epoch agreement found strong and substantial agreement between the single-channel EEG compared to polysomnography (κ = 0.67). Slow wave activity in the frontal regions was also similar when comparing the single-channel EEG device to polysomnography. As expected, Stage N1 showed poor agreement (sensitivity 0.2) due to lack of occipital electrodes. Other sleep parameters, such as sleep latency and rapid eye movement (REM) onset latency, had decreased agreement. Participants with disrupted sleep consolidation, such as from obstructive sleep apnea, also had poor agreement. We suspect that disagreement in sleep parameters between the single-channel EEG and polysomnography is due partially to altered waveform morphology and/or poorer signal quality in the single-channel derivation. Our results show that single-channel EEG provides comparable results to polysomnography in assessing REM, combined Stages N2 and N3 sleep and several other parameters, including frontal slow wave activity. The data establish that single-channel EEG can be a useful research tool.

Midpoint of sleep is associated with sleep quality in older adults with and without symptomatic Alzheimer's disease.

Introduction: Disrupted sleep is common in individuals with Alzheimer's disease (AD) and may be a marker for AD risk. The timing of sleep affects sleep-wake activity and is also associated with AD, but little is known about links between sleep architecture and the midpoint of sleep in older adults. In this study, we tested if the midpoint of sleep is associated with different measures of sleep architecture, AD biomarkers, and cognitive status among older adults with and without symptomatic AD. Methods: Participants (N = 243) with a mean age of 74 underwent standardized cognitive assessments, measurement of CSF AD biomarkers, and sleep monitoring via single-channel EEG, actigraphy, a home sleep apnea test, and self-reported sleep logs. The midpoint of sleep was defined by actigraphy. Results: A later midpoint of sleep was associated with African-American race and greater night-to-night variability in the sleep midpoint. After adjusting for multiple potential confounding factors, a later sleep midpoint was associated with longer rapid-eye movement (REM) onset latency, decreased REM sleep time, more actigraphic awakenings at night, and higher < 2 Hz non-REM slow-wave activity. Conclusions: Noninvasive in vivo markers of brain function, such as sleep, are needed to track both future risk of cognitive impairment and response to interventions in older adults at risk for AD. Sleep timing is associated with multiple other sleep measures and may affect their utility as markers of AD. The midpoint of sleep may be changed through behavioral intervention and should be taken into account when using sleep as a marker for AD risk.

Chronotype is Associated with Sleep Quality in Older Adults.

Introduction: Disrupted sleep is common in individuals with Alzheimer's disease (AD) and may be a marker for AD risk. The timing of sleep or chronotype affects sleep-wake activity and is also associated with AD, but little is known about links between sleep and chronotype in older adults. In this study, we tested if different measures of sleep and chronotype are associated among older adults even after adjusting for multiple potentially confounding variables. Methods: Participants (N=243) with a mean age of 74 underwent standardized cognitive assessments, measurement of CSF AD biomarkers, and sleep monitoring via single-channel EEG, actigraphy, and self-reported sleep logs. Chronotype was defined as the midpoint of sleep measured by actigraphy. Results: Later mid-point of sleep (i.e., late chronotype) was associated with African American race and greater night-to-night variability in the sleep mid-point. After controlling for age, race, sex, cognitive status, AD biomarkers, and sleep disorders, a later mid-point of sleep was associated with longer rapid eye movement (REM) onset latency, decreased REM sleep time, lower sleep efficiency, increased sleep onset latency, and more awakenings at night. Late chronotype was also associated with increased <2 Hz non-REM slow-wave activity. Conclusions: To identify individuals at risk for cognitive impairment before symptoms onset, non-invasive in vivo markers of brain function, such as sleep, are needed to track both future risk of cognitive impairment and response to interventions. Chronotype is a potential modifiable AD risk factor and should also be taken into account when using sleep as a marker for AD risk.

Mapping Sleep's Oscillatory Events as a Biomarker of Alzheimer's Disease.

Objective: Memory-associated neural circuits produce oscillatory events within single-channel sleep electroencephalography (EEG), including theta bursts (TBs), sleep spindles (SPs) and multiple subtypes of slow waves (SWs). Changes in the temporal "coupling" of these events are proposed to serve as a biomarker for early stages of Alzheimer's disease (AD) pathogenesis. Methods: We analyzed data from 205 aging adults, including single-channel sleep EEG, cerebrospinal fluid (CSF) AD-associated biomarkers, and Clinical Dementia Rating® (CDR®) scale. Individual SW events were sorted into high and low transition frequencies (TF) subtypes. We utilized time-frequency spectrogram locations within sleep EEG to "map" the precision of SW-TB and SW-SP neural circuit coupling in relation to amyloid positivity (by CSF Aß 42 /Aß 40 threshold), cognitive impairment (by CDR), and CSF levels of AD-associated biomarkers. Results: Cognitive impairment was associated with lower TB spectral power in both high and low TF SW-TB coupling (p<0.001, p=0.001). Cognitively unimpaired, amyloid positive aging adults demonstrated lower precision of the neural circuits propagating high TF SW-TB (p<0.05) and low TF SW-SP (p<0.005) event coupling, compared to cognitively unimpaired amyloid negative individuals. Biomarker correlations were significant for high TF SW-TB coupling with CSF Aß 42 /Aß 40 (p=0.005), phosphorylated-tau 181 (p<0.005), and total-tau (p<0.05). Low TF SW-SP coupling was also correlated with CSF Aß 42 /Aß 40 (p<0.01). Interpretation: Loss of integrity in neural circuits underlying sleep-dependent memory processing can be measured for both SW-TB and SW-SP coupling in spectral time-frequency space. Breakdown of sleep's memory circuit integrity is associated with amyloid positivity, higher levels of AD-associated pathology, and cognitive impairment.

Adverse driving behaviors are associated with sleep apnea severity and age in cognitively normal older adults at risk for Alzheimer's disease.

Alzheimer's disease (AD) pathology accumulates for decades before the onset of cognitive decline. Cognitively normal individuals with biomarker evidence of AD brain pathology (i.e. biomarker + or preclinical AD) can be differentiated from individuals without AD brain pathology based on naturalistic driving data, such as hard acceleration or braking and speeding, measured using in-vehicle dataloggers. Older adults are at increased risk of injury and death from motor vehicle crashes and driving cessation is also linked to negative health outcomes. Identifying potentially modifiable risk factors that increase driving risk may prolong safe driving in old age. Sleep apnea is associated with adverse driving behaviors across the age span. In this study, we hypothesized that high-risk driving behaviors would be associated with increased sleep apnea severity and AD pathology. We found that higher sleep apnea severity measured by a home sleep apnea test was associated with a higher incidence of adverse driving behaviors even after controlling for multiple confounders (ß = 0.24 ±â€…0.09, p < 0.01). This association was independent of AD biomarker positivity (i.e. increased t-tau/Aß 42 ratio). Increasing age was associated with a higher likelihood of high-risk driving behaviors in individuals with AD brain pathology (ß = 0.12 ±â€…0.04, p < 0.01), but a lower likelihood in individuals without AD brain pathology (ß = -0.06 ±â€…0.03, p < 0.05). These findings suggest that adverse driving behaviors linked to a higher rate of traffic crashes in older adults are associated with sleep apnea severity and AD pathology even in cognitively unimpaired individuals. Further studies are needed to determine if treatment of sleep apnea decreases high-risk driving behaviors and therefore motor vehicle crashes.

Comparison of single-channel EEG, actigraphy, and sleep diary in cognitively normal and mildly impaired older adults.

STUDY OBJECTIVES: Multiple methods for monitoring sleep-wake activity have identified sleep disturbances as risk factors for Alzheimer disease (AD). In order to identify the level of agreement between different methods, we compared sleep parameters derived from single-channel EEG (scEEG), actigraphy, and sleep diaries in cognitively normal and mildly impaired older adults. METHODS: Two hundred ninety-three participants were monitored at home for up to six nights with scEEG, actigraphy, and sleep diaries. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), and wake after sleep onset (WASO) were calculated using each of these methods. In 109 of the 293 participants, the ratio of cerebrospinal fluid concentrations of phosphorylated tau (p-tau) and amyloid-ß-42 (Aß42) was used as a biomarker for AD pathology. RESULTS: Agreement was highest for TST across instruments, especially in cognitively normal older adults. Overall, scEEG and actigraphy appeared to have greater agreement for multiple sleep parameters than for scEEG and diary or actigraphy and diary. Levels of agreement between scEEG and actigraphy overall decreased in mildly impaired participants and those with biomarker evidence of AD pathology, especially for measurements of TST. CONCLUSIONS: Caution should be exercised when comparing scEEG and actigraphy in individuals with mild cognitive impairment or with AD pathology. Sleep diaries may capture different aspects of sleep compared to scEEG and actigraphy. Additional studies comparing different methods of measuring sleep-wake activity in older adults are necessary to allow for comparison between studies using different methods.

Increased Cerebrospinal Fluid Amyloid-ß During Sleep Deprivation in Healthy Middle-Aged Adults Is Not Due to Stress or Circadian Disruption.

BACKGROUND: Concentrations of soluble amyloid-ß (Aß) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aß in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aß levels. Cortisol is a marker for stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aß. OBJECTIVE: In this exploratory study, we used samples collected in a previous study to examine how sleep deprivation affects Aß, cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (N = 11). METHODS: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aß were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. RESULTS: One night of sleep deprivation increases the overnight concentration of Aß in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. CONCLUSION: These data suggest that sleep deprivation-related changes in CSF Aß are not mediated by stress or circadian disruption as measured by cortisol.

Multi-Modal Home Sleep Monitoring in Older Adults.

The gold standard for sleep monitoring is attended in-lab polysomnography; however, this method may be cost-prohibitive and inconvenient for patients and research participants. Home sleep testing has gained momentum in the field of sleep medicine due to its convenience and lower cost, as well as being more naturalistic. The accuracy and quality of home sleep testing, however, may be variable because studies are not monitored by sleep technologists. There has been some success in improving the accuracy of home sleep studies by having trained sleep technicians assist participants inside their homes with putting on the devices, but this can be intrusive and time-consuming for those involved. In this protocol, participants undergo at-home sleep monitoring with multiple devices: 1) a single-channel EEG device; 2) a home sleep test for sleep-disordered breathing and periodic limb movements; 3) actigraphy; and 4) sleep logs. A major challenge of this study is obtaining high-quality sleep monitoring data on the first attempt in order to minimize participant burden. This protocol describes the implementation of educational manuals with step-by-step instructions and photos. The goal is to improve the quality of home sleep testing.

Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease.

In Alzheimer's disease (AD), deposition of insoluble amyloid-ß (Aß) is followed by intracellular aggregation of tau in the neocortex and subsequent neuronal cell loss, synaptic loss, brain atrophy, and cognitive impairment. By the time even the earliest clinical symptoms are detectable, Aß accumulation is close to reaching its peak and neocortical tau pathology is frequently already present. The period in which AD pathology is accumulating in the absence of cognitive symptoms represents a clinically relevant time window for therapeutic intervention. Sleep is increasingly recognized as a potential marker for AD pathology and future risk of cognitive impairment. Previous studies in animal models and humans have associated decreased non-rapid eye movement (NREM) sleep slow wave activity (SWA) with Aß deposition. In this study, we analyzed cognitive performance, brain imaging, and cerebrospinal fluid (CSF) AD biomarkers in participants enrolled in longitudinal studies of aging. In addition, we monitored their sleep using a single-channel electroencephalography (EEG) device worn on the forehead. After adjusting for multiple covariates such as age and sex, we found that NREM SWA showed an inverse relationship with AD pathology, particularly tauopathy, and that this association was most evident at the lowest frequencies of NREM SWA. Given that our study participants were predominantly cognitively normal, this suggested that changes in NREM SWA, especially at 1 to 2 Hz, might be able to discriminate tau pathology and cognitive impairment either before or at the earliest stages of symptomatic AD.

Sleep quality and preclinical Alzheimer disease.

IMPORTANCE: Sleep and circadian problems are very common in Alzheimer disease (AD). Recent animal studies suggest a bidirectional relationship between sleep and ß-amyloid (Aß), a key molecule involved in AD pathogenesis. OBJECTIVE: To test whether Aß deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep. DESIGN: Cross-sectional study conducted from October 2010 to June 2012. SETTING: General community volunteers at the Washington University Knight Alzheimer's Disease Research Center. PARTICIPANTS: Cognitively normal individuals (n = 145) 45 years and older were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. Valid actigraphy data were recorded in 142. The majority (124 of 142) were recruited from the Adult Children Study, in which all were aged 45 to 75 years at baseline and 50% have a parental history of late-onset AD. The rest were recruited from a community volunteer cohort in which all were older than 60 years and healthy at baseline. MAIN OUTCOME MEASURES: Sleep was objectively measured using actigraphy for 2 weeks. Sleep efficiency, which is the percentage of time in bed spent asleep, was the primary measure of sleep quality. Total sleep time was the primary measure of sleep quantity. Cerebrospinal fluid Aß42 levels were used to determine whether amyloid deposition was present or absent. Concurrent sleep diaries provided nap information. RESULTS: Amyloid deposition, as assessed by Aß42 levels, was present in 32 participants (22.5%). This group had worse sleep quality, as measured by sleep efficiency (80.4% vs 83.7%), compared with those without amyloid deposition, after correction for age, sex, and APOEε4 allele carrier status (P = .04). In contrast, quantity of sleep was not significantly different between groups, as measured by total sleep time. Frequent napping, 3 or more days per week, was associated with amyloid deposition (31.2% vs 14.7%; P = .03). CONCLUSIONS AND RELEVANCE: Amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality but not with changes in sleep quantity.