Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease

BACKGROUND: The prevalence and characteristics of sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. METHODS: Seven consecutive patients with definite sCJD underwent a systematic assessment of sleep-wake disturbances, including clinical history, video-polysomnography, and actigraphy. Extent and distribution of neurodegeneration was estimated by brain autopsy in six patients. Western blot analyses enabling classification and quantification of the protease-resistant isoform of the prion protein, PrPSc, in thalamus and occipital cortex was available in four patients. RESULTS: Sleep-wake symptoms were observed in all patients, and were prominent in four of them. All patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep. The correlation between different methods to assess sleep-wake functions (history, polysomnography, actigraphy, videography) was generally poor. Brain autopsy revealed prominent changes in cortical areas, but only mild changes in the thalamus. No mutation of the PRNP gene was found. CONCLUSIONS: This study demonstrates in sporadic Creutzfeldt-Jakob disease, first, the existence of sleep-wake disturbances similar to those reported in fatal familial insomnia in the absence of prominent and isolated thalamic neuronal loss, and second, the need of a multimodal approach for the unambiguous assessment of sleep-wake functions in these patients.

Sleep-wake habits and disorders in a series of 100 adult epilepsy patients--a prospective study

The aim of the study was to assess sleep-wake habits and disorders and excessive daytime sleepiness (EDS) in an unselected outpatient epilepsy population. Sleep-wake habits and presence of sleep disorders were assessed by means of a clinical interview and a standard questionnaire in 100 consecutive patients with epilepsy and 90 controls. The questionnaire includes three validated instruments: the Epworth Sleepiness Scale (ESS) for EDS, SA-SDQ for sleep apnea (SA), and the Ullanlinna Narcolepsy Scale (UNS) for narcolepsy. Sleep complaints were reported by 30% of epilepsy patients compared to 10% of controls (p=0.001). The average total sleep time was similar in both groups. Insufficient sleep times were suspected in 24% of patients and 33% of controls. Sleep maintenance insomnia was more frequent in epilepsy patients (52% vs. 38%, p=0.06), whereas nightmares (6% vs. 16%, p=0.04) and bruxism (10% vs. 19%, p=0.07) were more frequent in controls. Sleep onset insomnia (34% vs. 28%), EDS (ESS >or=10, 19% vs. 14%), SA (9% vs. 3%), restless legs symptoms (RL-symptoms, 18% vs. 12%) and most parasomnias were similarly frequent in both groups. In a stepwise logistic regression model loud snoring and RL-symptoms were found to be the only independent predictors of EDS in epilepsy patients. In conclusion, sleep-wake habits and the frequency of most sleep disorders are similar in non-selected epilepsy patients as compared to controls. In epilepsy patients, EDS was predicted by a history of loud snoring and RL-symptoms but not by SA or epilepsy-related variables (including type of epilepsy, frequency of seizures, and number of antiepileptic drugs).

Effect of short-wave (6-22 MHz) magnetic fields on sleep quality and melatonin cycle in humans: the Schwarzenburg shut-down study

This paper describes the results of a unique "natural experiment" of the operation and cessation of a broadcast transmitter with its short-wave electromagnetic fields (6-22 MHz) on sleep quality and melatonin cycle in a general human population sample. In 1998, 54 volunteers (21 men, 33 women) were followed for 1 week each before and after shut-down of the short-wave radio transmitter at Schwarzenburg (Switzerland). Salivary melatonin was sampled five times a day and total daily excretion and acrophase were estimated using complex cosinor analysis. Sleep quality was recorded daily using a visual analogue scale. Before shut down, self-rated sleep quality was reduced by 3.9 units (95% CI: 1.7-6.0) per mA/m increase in magnetic field exposure. The corresponding decrease in melatonin excretion was 10% (95% CI: -32 to 20%). After shutdown, sleep quality improved by 1.7 units (95% CI: 0.1-3.4) per mA/m decrease in magnetic field exposure. Melatonin excretion increased by 15% (95% CI: -3 to 36%) compared to baseline values suggesting a rebound effect. Stratified analyses showed an exposure effect on melatonin excretion in poor sleepers (26% increase; 95% CI: 8-47%) but not in good sleepers. Change in sleep quality and melatonin excretion was related to the extent of magnetic field reduction after the transmitter's shut down in poor but not good sleepers. However, blinding of exposure was not possible in this observational study and this may have affected the outcome measurements in a direct or indirect (psychological) way.

Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats.

OBJECTIVE Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch). METHODS Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep-wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining. RESULTS Repeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group. CONCLUSION Delayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery.

Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized

OBJECTIVE This study is a prospective, controlled clinical and electrophysiologic trial examining the chronic course of posttraumatic sleep-wake disturbances (SWD). METHODS We screened 140 patients with acute, first-ever traumatic brain injury of any severity and included 60 patients for prospective follow-up examinations. Patients with prior brain trauma, other neurologic or systemic disease, drug abuse, or psychiatric comorbidities were excluded. Eighteen months after trauma, we performed detailed sleep assessment in 31 participants. As a control group, we enrolled healthy individuals without prior brain trauma matched for age, sex, and sleep satiation. RESULTS In the chronic state after traumatic brain injury, sleep need per 24 hours was persistently increased in trauma patients (8.1 ± 0.5 hours) as compared to healthy controls (7.1 ± 0.7 hours). The prevalence of chronic objective excessive daytime sleepiness was 67% in patients with brain trauma compared to 19% in controls. Patients significantly underestimated excessive daytime sleepiness and sleep need, emphasizing the unreliability of self-assessments on SWD in trauma patients. CONCLUSIONS This study provides prospective, controlled, and objective evidence for chronic persistence of posttraumatic SWD, which remain underestimated by patients. These results have clinical and medicolegal implications given that SWD can exacerbate other outcomes of traumatic brain injury, impair quality of life, and are associated with public safety hazards.

Neural correlates of sleepiness induced by catecholamine depletion

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups. The CD-induced prolactin increase significantly correlated with CD-induced sleepiness but not with CD-induced mood and anxiety symptoms. CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep.

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.

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

Poor sleep is associated with higher plasma proinflammatory cytokine interleukin-6 and procoagulant marker fibrin D-dimer in older caregivers of people with Alzheimer's disease

OBJECTIVES: To determine whether objective measures of sleep correlate with plasma levels of the proinflammatory cytokine interleukin (IL)-6 and the procoagulant marker fibrin D-dimer in caregivers of patients with dementia. DESIGN: Cross-sectional study. SETTING: Subjects' homes. PARTICIPANTS: Sixty-four community-dwelling spousal caregivers (69% women, mean age+/-standard deviation 72+/-9) and 36 sex-matched noncaregiving controls. MEASUREMENTS: All participants underwent in-home full-night polysomnography. Demographic and lifestyle factors, depression, diseases, and medication that could affect inflammation, coagulation, and sleep were controlled for in analyses regressing sleep variables and caregiver status and their interaction on plasma levels of IL-6 and D-dimer. RESULTS: Caregivers had higher levels of D-dimer (781+/-591 vs 463+/-214 ng/mL, P=.001) and IL-6 (1.42+/-1.52 vs 0.99+/-0.86 pg/mL, P<.06) and lower levels of total sleep time (369+/-70 vs 393+/-51 minutes, P=.049) and sleep efficiency (77+/-11 vs 82+/-9%, P=.04) than controls. After controlling for age and body mass index, longer wake time after sleep onset (change in coefficient of determination (DeltaR2)=0.039, P=.04) and the interaction between caregiver status and higher apnea-hypopnea index (DeltaR2=0.054, P=.01) were predictors of IL-6. Controlling for age, caregiver status independently predicted D-dimer levels (DeltaR2=0.047, P=.01). Controlling for age and caregiver status, lower sleep efficiency (DeltaR2=0.032, P=.03) and the interaction between caregiver status and more Stage 2 sleep (DeltaR2=0.037, P=.02) independently predicted plasma D-dimer levels. CONCLUSION: Poor sleep was associated with higher plasma IL-6 and D-dimer levels. These effects were most pronounced in caregivers of subjects with Alzheimer's disease. The findings suggest a mechanism that may explain how disturbed sleep might be associated downstream with cardiovascular risk, particularly in older people under chronic stress.

Sleepless night, the moon is bright: longitudinal study of lunar phase and sleep

Popular belief holds that the lunar cycle affects human physiology, behaviour and health. We examined the influence of moon phase on sleep duration in a secondary analysis of a feasibility study of mobile telephone base stations and sleep quality. We studied 31 volunteers (18 women and 13 men, mean age 50 years) from a suburban area of Switzerland longitudinally over 6 weeks, including two full moons. Subjective sleep duration was calculated from sleep diary data. Data were analysed using multiple linear regression models with random effects. Mean sleep duration was 6 h 49 min. Subjective sleep duration varied with the lunar cycle, from 6 h 41 min at full moon to 7 h 00 min at new moon (P < 0.001). Average sleep duration was shortened by 68 min during the week compared with weekends (P < 0.001). Men slept 17 min longer than women (P < 0.001) and sleep duration decreased with age (P < 0.001). There was also evidence that rating of fatigue in the morning was associated with moon phase, with more tiredness (P = 0.027) at full moon. The study was designed for other purposes and the association between lunar cycle and sleep duration will need to be confirmed in further studies.

Sleep disturbance, norepinephrine, and D-dimer are all related in elderly caregivers of people with Alzheimer disease

STUDY OBJECTIVE: Caregiving for a relative with Alzheimer disease has been associated with sympathoadrenal medullary arousal and morbidity and mortality. In this study, we examined if sleep disturbance of elderly caregivers was associated with physiologic markers of cardiovascular risk, including plasma norepinephrine, epinephrine, and the hemostasis marker D-dimer. DESIGN: Cross-sectional. SETTING: Community-based sample of elderly caregivers of spouses with Alzheimer disease assessed within their homes. PARTICIPANTS: A sample of 40 elderly spousal caregivers of patients with Alzheimer disease. MEASUREMENTS AND RESULTS: Participants underwent in-home full-night polysomnography and had plasma assayed for norepinephrine and epinephrine. Using multiple regression analyses and controlling for a number of cardiovascular risk factors (e.g., age, sex, blood pressure, body mass index), increased wake after sleep onset was positively associated with norepinephrine levels (beta = .35; t = 2.45, df = 32, p = .020) and plasma D-dimer (beta = .31; t = 2.18, df = 29, p = .038). Further, plasma norepinephrine was significantly associated with D-dimer (beta = .34; t = 2.11, df = 29, p = .044). Additional analyses indicated that norepinephrine accounted for 28% of the relationship between wake after sleep onset and D-dimer. No association was observed between sleep variables and epinephrine. CONCLUSIONS: These findings provide preliminary evidence that sleep disturbance may contribute to morbidity in caregivers through sympathoadrenal medullary arousal and downstream physiologic effects such as altering the hemostasis environment.

Positive Affect and Sleep in Spousal Alzheimer Caregivers: A Longitudinal Study.

This article examines the longitudinal relation between positive affect (PA) and sleep in 126 spousal Alzheimer's disease caregivers. Caregivers underwent 4 yearly assessments for the Positive and Negative Affect Schedule, the self-rated Pittsburgh Sleep Quality Index, and actigraphy to objectify nighttime total sleep time, wake after sleep onset, and percentage of sleep. Increased levels of PA and a greater positivity (i.e., positive-to-negative affect) ratio were significantly associated with better subjective sleep over the entire study period. Yearly increases in PA-even when controlling for negative affect (NA)-and in the positivity ratio were also associated with better subjective sleep. PA and actigraphy measures showed no significant relations. Increased PA is longitudinally associated with better sleep in dementia caregivers largely independent of NA.

Endothelial function and sleep: associations of flow-mediated dilation with perceived sleep quality and rapid eye movement (REM) sleep.

Endothelial function typically precedes clinical manifestations of cardiovascular disease and provides a potential mechanism for the associations observed between cardiovascular disease and sleep quality. This study examined how subjective and objective indicators of sleep quality relate to endothelial function, as measured by brachial artery flow-mediated dilation (FMD). In a clinical research centre, 100 non-shift working adults (mean age: 36 years) completed FMD testing and the Pittsburgh Sleep Quality Index, along with a polysomnography assessment to obtain the following measures: slow wave sleep, percentage rapid eye movement (REM) sleep, REM sleep latency, total arousal index, total sleep time, wake after sleep onset, sleep efficiency and apnea-hypopnea index. Bivariate correlations and follow-up multiple regressions examined how FMD related to subjective (i.e., Pittsburgh Sleep Quality Index scores) and objective (i.e., polysomnography-derived) indicators of sleep quality. After FMD showed bivariate correlations with Pittsburgh Sleep Quality Index scores, percentage REM sleep and REM latency, further examination with separate regression models indicated that these associations remained significant after adjustments for sex, age, race, hypertension, body mass index, apnea-hypopnea index, smoking and income (Ps < 0.05). Specifically, as FMD decreased, scores on the Pittsburgh Sleep Quality Index increased (indicating decreased subjective sleep quality) and percentage REM sleep decreased, while REM sleep latency increased (Ps < 0.05). Poorer subjective sleep quality and adverse changes in REM sleep were associated with diminished vasodilation, which could link sleep disturbances to cardiovascular disease.

Impact of Acetazolamide and CPAP on Cortical Activity in Obstructive Sleep Apnea Patients

STUDY OBJECTIVES 1) To investigate the impact of acetazolamide, a drug commonly prescribed for altitude sickness, on cortical oscillations in patients with obstructive sleep apnea syndrome (OSAS). 2) To examine alterations in the sleep EEG after short-term discontinuation of continuous positive airway pressure (CPAP) therapy. DESIGN Data from two double-blind, placebo-controlled randomized cross-over design studies were analyzed. SETTING Polysomnographic recordings in sleep laboratory at 490 m and at moderate altitudes in the Swiss Alps: 1630 or 1860 m and 2590 m. PATIENTS Study 1: 39 OSAS patients. Study 2: 41 OSAS patients. INTERVENTIONS Study 1: OSAS patients withdrawn from treatment with CPAP. Study 2: OSAS patients treated with autoCPAP. Treatment with acetazolamide (500-750 mg) or placebo at moderate altitudes. MEASUREMENTS AND RESULTS An evening dose of 500 mg acetazolamide reduced slow-wave activity (SWA; approximately 10%) and increased spindle activity (approximately 10%) during non-REM sleep. In addition, alpha activity during wake after lights out was increased. An evening dose of 250 mg did not affect these cortical oscillations. Discontinuation of CPAP therapy revealed a reduction in SWA (5-10%) and increase in beta activity (approximately 25%). CONCLUSIONS The higher evening dose of 500 mg acetazolamide showed the "spectral fingerprint" of Benzodiazepines, while 250 mg acetazolamide had no impact on cortical oscillations. However, both doses had beneficial effects on oxygen saturation and sleep quality.