Sabra M. Abbott

Circadian Rhythm Sleep-Wake Disorders

The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options.

Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health

Janet M. Mullington, PhD1; Sabra M. Abbott, MD, PhD2; Judith E. Carroll, PhD3; Christopher J. Davis, MS, PhD4; Derk-Jan Dijk, PhD5; David F. Dinges, PhD6; Philip R. Gehrman, PhD7; Geoffrey S. Ginsburg, MD, PhD8; David Gozal, MD, MBA9; Monika Haack, PhD1; Diane C. Lim, MD10; Madalina Macrea, MD, MPH, PhD11,12; Allan I. Pack, MBChB, PhD, FRCP13; David T. Plante, MD14; Jennifer A. Teske, PhD15; Phyllis C. Zee, MD, PhD2

Chronic sleep disturbance and neural injury: links to neurodegenerative disease

Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are often accompanied by neurodegenerative or neurotransmitter changes. However, in addition to being a symptom of the underlying neurodegenerative condition, there is also emerging evidence that sleep disturbance itself may contribute to the development and facilitate the progression of several of these disorders. Due to its impact both as an early symptom and as a potential factor contributing to ongoing neurodegeneration, the sleep–wake cycle is an ideal target for further study for potential interventions not only to lessen the burden of these diseases but also to slow their progression. In this review, we will highlight the sleep phenotypes associated with some of the major neurodegenerative disorders, focusing on the circadian disruption associated with Alzheimer’s disease, the rapid eye movement behavior disorder and sleep fragmentation associated with Parkinson’s disease, and the insomnia and circadian dysregulation associated with Huntington’s disease.

Sleep Disorders in Atypical Parkinsonism

Sleep disorders are commonly observed in atypical parkinsonism, with particular disorders occurring more frequently in specific parkinsonian disorders. Multiple system atrophy (MSA) is a synucleinopathy often associated with nocturnal stridor, which is a serious, but treatable, condition highly specific to MSA. In addition, this disorder is strongly associated with rapid eye movement sleep behavior disorder (RBD), which is also observed in dementia with Lewy bodies. RBD is far less prevalent in progressive supranuclear palsy (PSP), which is a tauopathy. Insomnia and impaired sleep architecture are the most common sleep abnormalities observed in PSP. Corticobasilar degeneration is also a tauopathy, but has far fewer sleep complaints associated with it than PSP. In this article, we review the spectrum of sleep dysfunction across the atypical parkinsonian disorders, emphasize the importance of evaluating for sleep disorders in patients with parkinsonian symptoms, and point to sleep characteristics that can provide diagnostic clues to the underlying parkinsonian disorder.

Jet Lag and Shift Work Disorder

Jet lag and shift work disorder are circadian rhythm sleep-wake disorders resulting from behaviorally altering the sleep-wake schedule in relation to the external environment. Not everyone who experiences trans-meridian travel or performs shift work has a disorder. The prevalence of jet lag disorder is unclear, approximately 5%-10% of shift workers have shift work disorder. Treatment aims to realign the internal circadian clock with the external environment. Behavioral therapies include sleep hygiene and management of the light-dark and sleep schedule. Pharmacologic agents are used to treat insomnia and excessive sleepiness, and melatonin is used to facilitate sleep and circadian realignment.

Sleep disorders in perinatal women

Insufficient sleep is common in the general population, and can result from environmental and psychosocial factors, medical and psychiatric disorders, and sleep disorders, such as insomnia, circadian rhythm disorders, sleep apnoea and restless legs. Women are particularly at risk for sleep disorders, and complaints of sleep disturbance are more prevalent among women than men across the life span. During the perinatal period, many common sleep disorders, such as obstructive sleep apnoea or restless legs may be exacerbated, or in the case of insomnia or narcolepsy, treatment options may change. In addition, the role of circadian rhythms in fertility and perinatal health is just beginning to be appreciated. In this chapter, we provide an overview of the current knowledge of the unique aspects of diagnosis and treatment of sleep disorders during the perinatal period.

Signals from the Brainstem Sleep/Wake Centers Regulate Behavioral Timing via the Circadian Clock

Sleep-wake cycling is controlled by the complex interplay between two brain systems, one which controls vigilance state, regulating the transition between sleep and wake, and the other circadian, which communicates time-of-day. Together, they align sleep appropriately with energetic need and the day-night cycle. Neural circuits connect brain stem sites that regulate vigilance state with the suprachiasmatic nucleus (SCN), the master circadian clock, but the function of these connections has been unknown. Coupling discrete stimulation of pontine nuclei controlling vigilance state with analytical chemical measurements of intra-SCN microdialysates in mouse, we found significant neurotransmitter release at the SCN and, concomitantly, resetting of behavioral circadian rhythms. Depending upon stimulus conditions and time-of-day, SCN acetylcholine and/or glutamate levels were augmented and generated shifts of behavioral rhythms. These results establish modes of neurochemical communication from brain regions controlling vigilance state to the central circadian clock, with behavioral consequences. They suggest a basis for dynamic integration across brain systems that regulate vigilance states, and a potential vulnerability to altered communication in sleep disorders.

Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea

Study Objectives There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully blinded parallel groups, placebo-controlled randomized trial of dronabinol in people with moderate or severe OSA. Methods By random assignment, 73 adults with moderate or severe OSA received either placebo (N = 25), 2.5 mg dronabinol (N = 21), or 10 mg dronabinol (N = 27) daily, 1 hour before bedtime for up to 6 weeks. Results At baseline, overall apnea-hypopnea index (AHI) was 25.9 ± 11.3, Epworth Sleepiness Scale (ESS) score was 11.45 ± 3.8, maintenance of wakefulness test (MWT) mean latency was 19.2 ± 11.8 minutes, body mass index was 33.4 ± 5.4 kg/m2, and age was 53.6 ± 9.0 years. The number and severity of adverse events, and treatment adherence (0.3 ± 0.6 missed doses/week) were equivalent among all treatment groups. Participants receiving 10 mg/day of dronabinol expressed the highest overall satisfaction with treatment (p = .04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7 ± 4.4 (p = .02) and 12.9 ± 4.3 (p = .003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8 ± 0.8 points from baseline (p < .0001) and by -2.3 ± 1.2 points in comparison to placebo (p = .05). MWT sleep latencies, gross sleep architecture, and overnight oxygenation parameters were unchanged from baseline in any treatment group. Conclusions These findings support the therapeutic potential of cannabinoids in people with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved self-reported sleepiness, and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA.

Basic mechanisms of circadian rhythms and their relation to the sleep/wake cycle

Organisms exhibit cyclic variations in a variety of essential functions, including the sleep-wake cycle, hormonal regulation, and reproduction. A primary environmental signal regulating these functions is the daily alternation of darkness and light exerted by the rotation of the earth. Superimposed upon the daily light-dark cycle is a seasonal influence that modifies the relative durations of day and night over the course of a year. These environmental changes make it necessary for organisms to be able to modify their behavior so that they are active during times when the opportunity to acquire nutritional resources exceeds the risk of predation, and resting during times when the need for vigilance is minimized. Be they day-active or night-active, all organisms need a means of keeping time in a 24-hour world and adjusting to changes in day length or transition times that may occur

Circadian Disruption Associated with Alzheimer’s Disease

Alzheimer’s disease (AD) is increasing in prevalence and has a significant impact on caregivers and the healthcare system. One of the many physiologic process affected by AD is the circadian system, with disruption reflected in abnormalities of the sleep-wake cycle. This interaction is bidirectional, with circadian and sleep disruption influencing disease progression. Understanding the bidirectional relationship between AD and circadian disruption may allow for earlier recognition of the potential to develop dementia as well as improved targeted approaches for therapy. Therapies including melatonin and bright light therapy may be advantageous in improving sleep and circadian rhythms and preventing the progression of disease. However, unfortunately, these modalities are not curative, and additional research is needed to improve treatment options for these individuals.