Is Sleep Disruption a Cause or Consequence of Alzheimer's Disease? Reviewing Its Possible Role as a Biomarker.

In recent years, the idea that sleep is critical for cognitive processing has gained strength. Alzheimer's disease (AD) is the most common form of dementia worldwide and presents a high prevalence of sleep disturbances. However, it is difficult to establish causal relations, since a vicious circle emerges between different aspects of the disease. Nowadays, we know that sleep is crucial to consolidate memory and to remove the excess of beta-amyloid and hyperphosphorilated tau accumulated in AD patients' brains. In this review, we discuss how sleep disturbances often precede in years some pathological traits, as well as cognitive decline, in AD. We describe the relevance of sleep to memory consolidation, focusing on changes in sleep patterns in AD in contrast to normal aging. We also analyze whether sleep alterations could be useful biomarkers to predict the risk of developing AD and we compile some sleep-related proposed biomarkers. The relevance of the analysis of the sleep microstructure is highlighted to detect specific oscillatory patterns that could be useful as AD biomarkers.

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.

Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy.

Sleep problems relate to brain changes in aging and disease, but the mechanisms are unknown. Studies suggest a relationship between ß-amyloid (Aß) accumulation and sleep, which is likely augmented by interactions with multiple variables. Here, we tested how different cerebrospinal fluid (CSF) biomarkers for brain pathophysiology, brain atrophy, memory function, and depressive symptoms predicted self-reported sleep patterns in 91 cognitively healthy older adults over a 3-year period. The results showed that CSF levels of total- and phosphorylated (P) tau, and YKL-40-a marker of neuroinflammation/astroglial activation-predicted poor sleep in Aß positive older adults. Interestingly, although brain atrophy was strongly predictive of poor sleep, the relationships between CSF biomarkers and sleep were completely independent of atrophy. A joint analysis showed that unique variance in sleep was explained by P-tau and the P-tau × Aß interaction, memory function, depressive symptoms, and brain atrophy. The results demonstrate that sleep relates to a range of different pathophysiological processes, underscoring the importance of understanding its impact on neurocognitive changes in aging and people with increased risk of Alzheimer's disease.

Lack of correlation between CSF glutamate levels and PSQI scores in heavy smokers.

OBJECTIVE: Glutamate is an excitatory neurotransmitter in the central nervous system that participates in initiation and maintenance of sleep and wakefulness. The mechanisms involved occur in the brainstem, lateral hypothalamus, and basal forebrain. Our previous study suggested that higher levels of glutamate in cerebrospinal fluid (CSF) contributed to poorer sleep quality. Smoking has been shown to be harmful to sleep quality. In the present study, we recruited non-smokers and heavy smokers and measured the concentration of CSF glutamate in order to investigate the associations among smoking status, sleep quality, and CSF glutamate levels. METHODS: We recruited 147 men (n = 68 non-smokers, 30.31 ± 9.10 years; n = 79 heavy smokers, 34.54 ± 10.71 years). Glutamate concentrations in CSF were measured by spectrophotometry, and subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: PSQI total scores were significantly higher in heavy smokers than that in non-smokers (p < 0.001). Glutamate concentrations in CSF were lower in heavy smokers than that in non-smokers (p < 0.001). CSF glutamate levels positively correlated with PSQI total scores in the non-smokers group (r = 0.313, p = 0.011, effect size = 0.324). No correlation was found between CSF glutamate levels and PSQI total scores in the heavy smokers group (p > 0.05). Multivariable linear regression analysis showed that years of smoking was contributed to the PSQI total scores (p = 0.008), and cigarettes smoked per day contributed to the decreased CSF glutamate levels in heavy smokers (p = 0.001). CONCLUSION: Poorer subjective sleep quality and lower CSF glutamate concentrations were observed in the heavy smokers group than in the non-smokers group. In addition, lack of correlation was observed between CSF glutamate levels and PSQI scores in the heavy smokers.

The study of sleep disorder factors in patients with Guillain-Barré syndrome.

In this study, we explore the sleep disorders and its associated factors in patients with Guillain-Barré syndrome (GBS), so as to work out appropriate interventions to promote early recovery of the patients. This study subjects included 49 patients with GBS who had been admitted to the Department of Neurology at The Affiliated Hospital of Hebei University, fulfilling National Institute of Neurological and Communicative Diseases and Stroke (NINCDS) criteria for GBS; 37 cases were male and 12 female (age: 27-68 years). Patients were evaluated once daily for two consecutive weeks. By using Wong and Baker Face Scale (WBFS) to evaluate the numbness and pain in patients, 0 points representing completely no pain and 10 points represents the most severity of the pain reactions; the same applies for numbness. The GBS Disability Scale (GBS DS) is used to evaluate the severity of GBS. The Hospital Anxiety and Depression Scale (HADS) is used to evaluate the anxiety and depression the patient is experiencing. All patients take routine EMG and sleep EEG. The sleep quality of the subjects was evaluated by the Pittsburgh Sleep Quality Index Scale (PSQI) and Richard Campbell Sleep Rating Scale. This study found that the application of ventilators, numbness, anxiety and severe limb movement disorders are the main factors causing sleep disorders. Cerebrospinal fluid (CSF) protein concentration is also associated with sleep disorders. But, no obvious abnormalities were found in sleep EEG. The application of the ventilator, numbness, anxiety and severe limb movement disorder are main factors causing sleep disorders. CSF protein concentration is also associated with sleep disorders.

HIV Tat protein affects circadian rhythmicity by interfering with the circadian system.

OBJECTIVES: Sleep disorders are common in patients with HIV/AIDS, and can lead to poor quality of life. Although many studies have investigated the aetiology of these disorders, it is still unclear whether impaired sleep quality is associated with HIV itself, social problems, or side effects of antiretroviral therapy (ART). Moreover, despite its known neurological associations, little is known about the role of the trans-activator of transcription (Tat) protein in sleep disorders in patients with HIV/AIDS. The purpose of this study was to test the hypothesis that the sleep quality of patients with HIV/AIDS affected by an altered circadian rhythm correlates with cerebrospinal HIV Tat protein concentration. METHODS: Ninety-six patients with HIV/AIDS between 20 and 69 years old completed the Pittsburgh Sleep Quality Index. Their circadian rhythm parameters of blood pressure, Tat concentration in cerebrospinal fluid, melatonin concentration, CD4 cell count and HIV RNA viral load in serum were measured. RESULTS: The circadian amplitude of systolic blood pressure and the score for sleep quality (Pittsburgh Sleep Quality Index) were negatively correlated with HIV Tat protein concentration, while the melatonin value was positively correlated with Tat protein concentration. CONCLUSIONS: The HIV Tat protein affects circadian rhythmicity by interfering with the circadian system in patients with HIV/AIDS and further increases the melatonin excretion value. A Tat protein-related high melatonin value may counteract HIV-related poor sleep quality during the progression of HIV infection. This study provides the first clinical evidence offering an explanation for why sleep quality did not show an association with progression of HIV infection in previous studies.

Correlations among serum alpha-(1,6)-fucosyltransferase and early symptoms associated with Parkinson's disease: A cross-sectional retrospective study.

Alpha-(1,6)-fucosyltransferase (FUT8) has been found to play a role in modulating the central immune system and inflammatory responses. Limited studies have assessed the correlations between serum FUT8 levels and various non-motor symptoms associated with early Parkinson's disease (PD). Therefore, our research aims to investigate the associations between serum FUT8 levels and symptoms such as smell dysfunction, sleep duration, sleep problems, and MMSE scores in PD patients. FUT8 and neurofilament light chain (NfL) levels were measured using enzyme-linked immunosorbent assays (ELISA). We analyzed the correlations between serum FUT8 levels, NfL, and early symptoms of PD using Spearman's correlation, multiple linear regression, and logistic regression models. The expression of FUT8 in CSF samples from PD patients was significantly upregulated, with its protein levels in CSF being positively associated with serum levels. Furthermore, there were significant positive associations between serum FUT8 levels with NfL levels, smell dysfunction, short sleep duration, and long sleep duration. However, a significant inverse relationship was observed between FUT8 levels and MMSE scores. Additionally, we explored gender and age differences in the correlations of FUT8 levels and early symptoms in patients. This study reveals that increased FUT8 levels are positively correlated with a higher risk of early PD-associated symptoms. These findings suggest that serum FUT8 could serve as a promising biomarker for the early detection of PD.

Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness?

Sleep-wake disturbances are frequent in patients with Parkinson's disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep-wake disturbances in Parkinson's disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson's disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson's disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin-deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson's disease. Poorer sleep quality is linked to dopamine deficiency and other disease-related factors. Despite hypocretin cell loss in Parkinson's disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

Sleep Characteristics and Cerebrospinal Fluid Progranulin in Older Adults: The CABLE Study.

Cerebrospinal fluid (CSF) progranulin (PGRN) is related to various neurodegeneration diseases. And sleep problems can cause abnormality in protein metabolism in vivo. We aim to explore the potential associations between the self-reported sleep characteristics and CSF PGRN in cognitively intact older adults. Our study recruited 747 participants (mean (standard deviation (SD)) age, 61.99 (10.52) years, 329 (42.89%) females) who had normal cognition from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF PGRN and sleep characteristics measured. The multiple linear regression and nonlinear regression adjusted for age, gender, education, and apolipoprotein E-epsilon 4 gene (APOE4) status were used to assess the associations between sleep characteristics and PGRN. Interaction effects were explored between APOE4 status and sleep characteristics on CSF PGRN level. Sleep disturbances indicated lower CSF PGRN (ß = - 0.0186, p = 0.0160). For detailed items in sleep disturbances, lower CSF PGRN was found in males who woke up during sleep (ß = - 0.0121, p = 0.0062) and in females who had breathing difficulties (ß = - 0.0258, p = 0.0271). Meanwhile, sleep efficiency was associated with CSF PGRN (ß = - 0.0512, p = 0.0497). No significant interaction effects between sleep characteristics and APOE4 status were found. Meanwhile, we did not find a nonlinear relationship between nocturnal sleep duration and CSF PGRN. Sleep problems may influence the metabolism of PGRN, thus attenuating the protective effects of PGRN on neurodegeneration diseases.

Sleep dysregulation, memory impairment, and CSF biomarkers during different levels of neurocognitive functioning in Alzheimer's disease course.

BACKGROUND: Alzheimer's disease (AD) is frequently accompanied by sleep impairment, which can induce AD-related neurodegeneration. We herein investigated the sleep architecture, cognition, and cerebrospinal fluid (CSF) biomarkers (tau proteins and ß-amyloid42) during AD progression from subjective cognitive impairment (SCI) to mild cognitive impairment (MCI) and eventually to AD dementia, and compared the results with cognitively normal (CN) subjects. METHODS: We included patients affected by SCI, MCI, mild AD, and moderate-to-severe AD in our study along with CN subjects as controls. All the subjects underwent nocturnal polysomnography to investigate sleep, neuropsychological testing to evaluate cognition, and lumbar puncture for CSF AD biomarkers assessment. RESULTS: Sleep (both rapid eye movement (REM) and non-REM sleep) and memory function are both progressively impaired during the course of AD from SCI to mild and subsequently to moderate AD. Further, sleep dysregulation appears earlier than cognitive deterioration, with a reduction of CSF ß-amyloid42 level. CONCLUSION: Sleep, memory, and CSF AD biomarkers are closely interrelated in AD progression from the earliest asymptomatic and preclinical stages of the disease related in AD since the earliest and preclinical stages of the disease.

Cardiorespiratory Fitness Modifies Influence of Sleep Problems on Cerebrospinal Fluid Biomarkers in an At-Risk Cohort.

BACKGROUND: Previous studies indicate that cardiorespiratory fitness (CRF) and sleep are each favorably associated with Alzheimer's disease (AD) pathophysiology, including reduced amyloid-ß (Aß) and tau pathology. However, few studies have examined CRF and sleep in the same analysis. OBJECTIVE: To examine the relationship between sleep and core AD cerebrospinal fluid (CSF) biomarkers among at-risk healthy late-middle-aged adults and determine whether CRF modifies this association. METHODS: Seventy-four adults (age = 64.38±5.48, 68.9% female) from the Wisconsin Registry for Alzheimer's Prevention participated. Sleep was evaluated using the Medical Outcomes Study Sleep Scale, specifically the Sleep Problems Index I (SPI), which incorporates domains of sleep disturbance, somnolence, sleep adequacy, and shortness of breath. Higher scores indicate greater sleep problems. To assess CRF, participants underwent a graded exercise test. CSF was collected via lumbar puncture, from which Aß42, total-tau (t-tau), and phosphorylated-tau (p-tau) were immunoassayed. Regression analyses examined the association between SPI and CSF biomarkers, and the interaction between SPI and CRF on these same biomarkers, adjusting for relevant covariates. RESULTS: Higher SPI scores were associated with greater p-tau (p = 0.027) and higher t-tau/Aß42 (p = 0.021) and p-tau/Aß42 (p = 0.009) ratios. Analyses revealed significant SPI*CRF interactions for t-tau (p = 0.016), p-tau (p = 0.008), and p-tau/Aß42 (p = 0.041); with a trend for t-tau/Aß42 (p = 0.061). Specifically, the relationship between poorer sleep and these biomarkers was significant among less fit individuals, but not among those who were more fit. CONCLUSION: In a late-middle-aged at-risk cohort, CRF attenuated the association between poor sleep and levels of select CSF biomarkers. This suggests fitness may play an important role in preventing AD by protecting against pathology, even in impaired sleep.

Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults.

OBJECTIVE: To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife. METHODS: We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal. Sleep quality was measured with the Medical Outcomes Study Sleep Scale. CSF was assayed for biomarkers of amyloid metabolism and plaques (ß-amyloid 42 [Aß42]), tau pathology (phosphorylated tau [p-tau] 181), neuronal/axonal degeneration (total tau [t-tau], neurofilament light [NFL]), neuroinflammation/astroglial activation (monocyte chemoattractant protein-1 [MCP-1], chitinase-3-like protein 1 [YKL-40]), and synaptic dysfunction/degeneration (neurogranin). To adjust for individual differences in total amyloid production, Aß42 was expressed relative to Aß40. To assess cumulative pathology, CSF biomarkers were expressed in ratio to Aß42. Relationships among sleep scores and CSF biomarkers were assessed with multiple regression, controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch. RESULTS: Worse subjective sleep quality, more sleep problems, and daytime somnolence were associated with greater AD pathology, indicated by lower CSF Aß42/Aß40 and higher t-tau/Aß42, p-tau/Aß42, MCP-1/Aß42, and YKL-40/Aß42. There were no significant associations between sleep and NFL or neurogranin. CONCLUSIONS: Self-report of poor sleep was associated with greater AD-related pathology in cognitively healthy adults at risk for AD. Effective strategies exist for improving sleep; therefore sleep health may be a tractable target for early intervention to attenuate AD pathogenesis.

Novel method for evaluation of eye movements in patients with narcolepsy.

BACKGROUND: Narcolepsy causes abnormalities in the control of wake-sleep, non-rapid-eye-movement (non-REM) sleep and REM sleep, which includes specific eye movements (EMs). In this study, we aim to evaluate EM characteristics in narcolepsy as compared to controls using an automated detector. METHODS: We developed a data-driven method to detect EMs during sleep based on two EOG signals recorded as part of a polysomnography (PSG). The method was optimized using the manually scored hypnograms from 36 control subjects. The detector was applied on a clinical sample with subjects suspected for central hypersomnias. Based on PSG, multiple sleep latency test and cerebrospinal fluid hypocretin-1 measures, they were divided into clinical controls (N = 20), narcolepsy type 2 (NT2, N = 19), and narcolepsy type 1 (NT1, N = 28). We investigated the distribution of EMs across sleep stages and cycles. RESULTS: NT1 patients had significantly less EMs during wake, N1, and N2 sleep and more EMs during REM sleep compared to clinical controls, and significantly less EMs during wake and N1 sleep compared to NT2 patients. Furthermore, NT1 patients showed less EMs during NREM sleep in the first sleep cycle and more EMs during NREM sleep in the second sleep cycle compared to clinical controls and NT2 patients. CONCLUSIONS: NT1 patients show an altered distribution of EMs across sleep stages and cycles compared to NT2 patients and clinical controls, suggesting that EMs are directly or indirectly controlled by the hypocretinergic system. A data-driven EM detector may contribute to the evaluation of narcolepsy and other disorders involving the control of EMs.

CSF orexin levels of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration.

Excessive daytime sleepiness has been widely accepted as a common problem not only in Parkinson's disease (PD) but also in other related disorders. Lowered excretion of orexin A (hypocretin 1) into the cerebrospinal fluid (CSF) is known to play a pathological role in narcolepsy and secondary hypersomnia due to hypothalamic dysfunction. Although the levels of CSF orexin in PD have been previously examined, the results have been controversial, and no systematic investigation of CSF orexin excretion has been conducted on PD related disorders. In this study, orexin was measured in CSF collected by lumbar puncture in 62 patients with PD, 13 patients with dementia with Lewy bodies (DLB), 16 patients with progressive supranuclear palsy (PSP), and 7 patients with corticobasal degeneration (CBD). Levels of CSF orexin (mean+/-SD pg/ml) were 302+/-38 in PD, 297+/-48 in DLB, 258+/-37 in PSP, 246+/-90 in CBD. The occurrence of low orexin levels (

Rapid eye movement sleep disruption and sleep fragmentation are associated with increased orexin-A cerebrospinal-fluid levels in mild cognitive impairment due to Alzheimer's disease.

The orexin system has been investigated in patients affected by mild cognitive impairment (MCI) due to Alzheimer's disease (AD) by measuring orexin-A concentrations in the cerebrospinal fluid (CSF), and correlated to subjective and objective sleep parameters, quantified by questionnaires and polysomnography, respectively. Twenty drug-naïve patients with MCI due to AD were studied and compared with a population of 26 age and/or sex matched controls, divided into subgroups on the basis of the Pittsburgh Sleep Quality Index (PSQI) score. Increased CSF-orexin levels were detected in patients with MCI due to AD in comparison with controls (p < 0.05). In particular, CSF-orexin concentrations were higher in MCI patients suffering from sleep complaints (PSQI ≥5, n = 10) compared with MCI patients with a regular sleep-wake cycle (PSQI <5, n = 10, p < 0.001) and compared with both control groups (with sleep complaints, PSQI ≥5, n = 11, p < 0.001; without sleep complaints, PSQI <5, n = 15, p < 0.001). Moreover, REM sleep was reduced in MCI patients compared with controls (p < 0.01), and had a negative correlation coupled with a reciprocal influence at the multiple regression analysis with CSF-orexin levels (R = -0.65; ß = -8.90). REM sleep disruption and sleep fragmentation are related to higher CSF-orexin levels in patients with MCI due to AD, thus suggesting that the orexin system may be involved even in the earliest stages of AD, resulting in prolonged sleep latency, reduced sleep efficiency, and REM sleep impairment.

Increased cerebrospinal fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in Kleine-Levin syndrome.

A 17-year-old man with the Kleine-Levin syndrome died unexpectedly of cardiopulmonary arrest during a period of autonomic instability that followed an episode of megaphagia. At autopsy, the only pertinent finding was mild depigmentation of the locus ceruleus and substantia nigra. Premortem CSF levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were elevated. These findings indicate that many symptoms of the Kleine-Levin syndrome are a result of a neurotransmitter imbalance in the serotonergic pathway of the brainstem.

Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture.

Sleep abnormalities have been consistently observed in patients with schizophrenia. Elevated levels of corticotropin releasing factor (CRF) and prostaglandins (PGs) in the cerebrospinal fluid (CSF) of patients with schizophrenia have been reported, and these neurochemical substances, known to modulate sleep in experimental animals, may play a role in these sleep abnormalities. In this study, we measured PGD2, PGE2, PGF2alpha and CRF levels in the CSF of 14 unmedicated schizophrenic patients and 14 age- and sex-matched control subjects. Polysomnographic recordings were also carried out for each subject. As expected, the sleep of the schizophrenic subjects significantly differed from that of the controls; schizophrenic subjects had a longer sleep onset latency, slept less, spent fewer minutes in stage 2 sleep and had a lower sleep efficiency. We could not, however, detect any differences in CSF CRF and PG levels between normal and schizophrenic subjects, nor could we find any correlation between CSF variables and sleep parameters in the schizophrenic subjects and the non-psychiatric controls. These results do not favor the hypothesis of a role for CRF or PGs in the pathophysiology of sleep disturbances in schizophrenia.

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease.

IMPORTANCE: Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. OBJECTIVES: To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and ß-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, ≥21), whereas 27 were included in the moderate to severe AD group (score, <21). The control group consisted of 29 nondemented participants of similar age and sex. EXPOSURE: Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and ß-amyloid 1-42 and polysomnographic assessment of sleep variables. MAIN OUTCOMES AND MEASURES: Levels of orexin, tau proteins, and ß-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores. RESULTS: Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD. On the other hand, in the global AD group, orexin levels were positively correlated with total tau protein levels (r = 0.32; P = .03) and strictly related to sleep impairment. Finally, cognitive impairment, as measured by the Mini-Mental State Examination, was correlated with sleep structure deterioration. CONCLUSIONS AND RELEVANCE: Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.

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.

Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency.

IMPORTANCE: Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically. OBJECTIVE: To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency. DESIGN, SETTING, AND PARTICIPANTS: Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels. MAIN OUTCOME AND MEASURES: Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level. RESULTS: Short REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%). CONCLUSIONS AND RELEVANCE: Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.