Unlocking Therapeutic Potential: Targeting Sleep to Combat Neurodegenerative Diseases and Aging

By Samantha A. Keil, PhD & Deidre Jansson, MSc, PhD

The intricate relationship between sleep and aging has gained increasing interest, with growing evidence of sleep disruption years before the development of cardinal neurodegenerative disease symptoms. Over the last few decades, our understanding of the bidirectional relationship between sleep disorders and comorbid illnesses, including hypertension, cardiovascular disease, depression, and neurodegenerative disease states, has continued to evolve. This article explores the consequences of sleep disruption within clinical populations and highlights how targeting sleep could hold transformative therapeutic potential.

Age-related Sleep Changes

As we age, sleep undergoes noticeable changes that can influence neurologic health. Clinically, alterations in sleep have long been considered a natural part of the aging process, with patients expressing alterations in sleep architecture (non-Rapid Eye Movement [REM], Rapid Eye Movement [REM]), circadian rhythm disruptions, and shifts in total sleep time as they grow older.1-3 Often approached as distinct from sleep disorders, changes including reductions in slow-wave sleep and increased sleep fragmentation with nighttime waking and early rise times have been associated with increased age-related decline in cognitive performance. Research suggests that these age-related changes stem from physiological alterations in sleep regulatory mechanisms within the brain, changes in neuroendocrine levels, and altered function of the suprachiasmatic nucleus.2-4 However, as the scope of sleep research grows, emerging evidence suggests that these age-related sleep changes may have far-reaching implications for both neuropathologic disease and comorbid illness.

Comorbid Illness and Sleep Disturbance

Importantly, these sleep changes occur concurrently with other comorbid disease states, becoming more prevalent with age. Further, comorbid illnesses can also significantly contribute to sleep disturbances. Patients suffering from conditions including chronic pain, metabolic dysfunction, and respiratory disorders often experience alterations in sleep, with higher levels of reported insomnia, sleep apnea, and increased sleep fragmentation with difficulty falling and staying asleep.5-8 When experienced chronically, these sleep changes have been associated with increased inflammation, chronic intermittent hypoxia, and oxidative stress.9-11 Similarly, mounting evidence shows that the increased sympathetic nervous system activity and altered vascular function caused by chronic sleep apnea and disrupted sleep impact cardiovascular and cerebrovascular disease progression and risk.12

Additionally, research supports an intricate and cyclic link between sleep and depression. Not only are sleep disturbances a common symptom of depression, but chronic sleep deprivation can precipitate or exacerbate mood symptoms. Depressive symptoms have been shown to result in insomnia or hypersomnia, altered sleep architecture, and disrupted circadian rhythms.13 As depression is itself a prevalent comorbidity in neurodegenerative disease states, the bidirectional relationship between sleep disruption and depression should be addressed.

Neurodegenerative Diseases and Sleep

The connection between sleep and neurodegenerative disease progression is a rapidly evolving field of research. While neurodegenerative diseases are characterized by cardinal cognitive and motor function impairment, patients also experience substantial sleep changes. In fact, these sleep disturbances often precede clinical manifestations of these diseases, hinting at their potential role as prodromal markers.

Sleep fragmentation altered sleep architecture, and disturbances in circadian rhythms are commonly expressed in patients across neurodegenerative disease states. Importantly, emerging research supports that these disturbances are not only a symptom of disease but are also likely to contribute to disease progression. Fragmented and decreased slow-wave sleep is associated with decreased glymphatic function or brain waste clearance.14 This is thought to lead to increased levels of neuropathologic protein deposits such as amyloid-beta and neurofibrillary tau,15 the pathologic hallmarks of Alzheimer’s disease. In Parkinson’s and Huntington’s disease, REM sleep abnormalities, sleep fragmentation, and daytime sleepiness are thought to be early signs of disease, with these sleep changes influencing the progression of motor symptoms and loss of quality of life.16-17 Patients with Amyotrophic Lateral Sclerosis (ALS), a motor neuron disease, often experience disrupted sleep patterns due to physical limitations and respiratory compromise.18 Similarly, the impact of demyelination in patients with Multiple Sclerosis has been associated with increased prevalence of fatigue and chronic sleep disturbance.19 While this is not an exhaustive list, these conditions highlight the complicated relationship between sleep, aging, and neurodegenerative disease. Each disorder is uniquely tied to changes in sleep architecture, circadian rhythm, and sleep-related symptoms.

The Glymphatic System, Sleep, and Neurodegenerative Disease

Beyond the alterations in sleep architecture and circadian rhythms associated with aging and neurodegenerative diseases, a critical player in this complex relationship is the glymphatic system. This recently discovered system functions to distribute and remove interstitial solutes and waste within the brain. It is thought to be primarily active during slow-wave sleep.20-21 Reduction in slow-wave sleep and increased sleep fragmentation, common in aging and neurodegenerative disease conditions, have been linked to glymphatic clearance efficiency.22 Consequently, this impairment can lead to the accumulation of toxic metabolites, including the amyloid-beta and neurofibrillary tau proteins implicated in Alzheimer’s disease, potentially accelerating neurodegenerative disease progression.23 Understanding the intricate interplay between sleep, the glymphatic system, and neurodegenerative diseases highlights the therapeutic potential of targeting sleep to mitigate the onset and progression of these devastating conditions.24-25

Measuring and Addressing Sleep Clinically

Understanding and clinically addressing the impact of chronic sleep disruptions on neurodegenerative disease and comorbid conditions is paramount. Historically, evaluating a patient’s sleep experience has relied heavily on self-reporting via standardized sleep questionnaires such as the Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index.26-27 While these self-reports continue to provide valuable insight into a patient’s current sleep experience, technological advances can highlight sleep more objectively. Polysomnography (PSG), currently the gold standard for evaluating objective sleep, provides the multi-modal monitoring of brain activity (EEG), eye movements (EOG), muscle activity (EMG), heart rate, respiratory rate, and oxygen saturation.28 This comprehensive approach allows for a detailed assessment of sleep stages and related physiological parameters. Alternatively, while not as detailed as a PSG, physiologic monitors, including actigraphy watches, bed and mattress sensors, and even biometric wearables like fitness watches, can provide information about sleep patterns, heart rate, and movement patterns across time. When paired with subjective self-report, these technologies offer crucial insight into a patient’s sleep.

Addressing any identified sleep disturbances in a clinical setting requires a multidisciplinary approach that integrates the patient’s neurological, psychological, and sleep health factors. Often, these sleep disturbances are managed pharmacologically, using either prescription or over-the-counter sleep aids.29-30 While pharmacological intervention can successfully increase sleep duration, it must be approached with careful consideration of potential interactions with existing medications and disease-specific factors. Moreover, it is becoming increasingly evident that when prescribing medications, care should be taken into consideration of the impact on not only sleep quality but also sleep architecture.31

The emergence of non-pharmacologic sleep interventions has demonstrated their effectiveness in addressing primary sleep disorders and sleep disturbances secondary to neurodegenerative disease. At their most basic, these interventions predominantly focus on enhancing sleep hygiene by promoting healthier sleep habits, including maintaining a consistent sleep schedule, creating a comfortable sleeping environment, and avoiding stimulants and electronics before bedtime. One notable approach is cognitive-behavioral therapy of insomnia (CBT-I), which utilizes a structured therapeutic approach to encourage better cognitive and behavioral habits toward improved sleep quality.32

Additionally, interventions targeting overall physical and mental health can profoundly impact sleep. Adjustments in diet and nutrition, incorporating a regular exercise regime, and managing weight can also positively influence sleep health. Moreover, reducing stress and anxiety through techniques such as progressive muscle relaxation, deep breathing exercises, and mindfulness meditation provides individuals with tools conducive to healthy sleep.33 For example, incorporating regular yoga or tai-chi to target breathing, synchronize heart rate and movement, and improve vascular function may enhance glymphatic clearance and offer a complementary intervention for age-associated changes in sleep.34-35 In essence, by establishing an active role in their sleep optimization, these non-pharmacological sleep interventions empower patients with multi-modal strategies towards improving their sleep health and overall well-being.

Furthermore, as sleep research continues to underscore the role of chronic sleep disruption in comorbid disease progression, innovative non-invasive techniques are actively under exploration. For instance, light exposure therapy, originally developed for seasonal affective disorder, utilizes bright light in the morning to regulate circadian rhythm and sleep-wake cycles.36 Noninvasive brain stimulation techniques, including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), predominantly known for their use with mood disorders like depression, also show promise for sleep disruption intervention.37-38 Utilizing non-invasive neurostimulation, they modulate neural activity and potentially enhance glymphatic clearance, a process vital for solute distribution and brain waste removal. Additionally, acoustic and auditory stimulation, featuring elements like binaural beats, are being evaluated for their ability to influence brain wave states and the potential to foster deep and restorative sleep.39 Even virtual and augmented reality (VR/AR) have entered the therapeutic arena, offering immersive, relaxing environments to promote relaxation and facilitate sleep.40

Conclusion

The nexus of sleep disruption, aging, and comorbid illnesses with neurodegenerative disease underscores the need for comprehensive management strategies that address sleep health within the multifaced nature of these conditions. As the research delves deeper into the intricate relationship between sleep and health, our potential to alleviate suffering and improve patient outcomes expands exponentially. It presents an opportunity to reshape the approach to patient care. Harnessing improved sleep health as a therapeutic tool by integrating sleep-focused interventions into our strategies for holistic patient care provides new horizons for improving patient well-being.

Dr. Samantha Keil, Ph.D., is a senior postdoctoral researcher in Weill Cornell Medicine’s Department of Radiology.

Dr. Deidre Jansson, MSc, Ph.D., is an acting instructor at the University of Washington, VA, Puget Sound Health Center System.

This article first appeared in the Sleep Lab Magazine Sept/Oct 2023.

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