Sleep & Arousal Disorders

SLEEP AND AROUSAL DISORDERS OF ALZHEIMER'S DISEASE:
WE NOW THINK THE SYMPTOMS THEMSELVES DRIVE THE PATHOLOGY
Cliff Singer, MD; Chief, Geriatric Neuropsychiatry, Acadia Hospital, Bangor Maine, USA

Key Highlights:

• Sleep and wake disorders are common symptoms of AD
• Sleep disorders accelerate neurodegeneration
• Sleep fragmentation may “lesion” arousal mechanisms
• IPA has recognized the need for education and practice guidelines in sleep, wake and circadian disorders of older adults

Introduction
Insomnia and daytime sleepiness are now known to be more than symptoms of dementia. They are drivers of somatic illness and cognitive decline. Sleep and wake disorders are also fascinating and frustrating areas of clinical practice. We need to integrate new scientific findings with old knowledge to create updated guidelines for the assessment and treatment of sleep and arousal disorders, especially in dementia (Guarnieri and Sorbi 2015). In this brief review, I will introduce what will be a special focus of IPA in the coming year.

Sleep as a Symptom of Alzheimer’s Disease (AD)
Sleep disturbances have long been recognized as a common problem for patients with AD (Prinz PN et al. 1982). AD is associated with variable changes in total sleep time (increased and decreased), nocturnal arousals and irregular or reversed circadian sleep-wake cycles (McCurry SM et al. 1999). Nighttime awakenings are common and distressing to family caregivers, but arousal disorders may be even more common. In a community sample of well-diagnosed AD subjects versus healthy elderly control subjects, time spent in bed during the day was the most significant difference in sleep pattern by subjective report of caregivers, although caregivers may be less aware and less likely to report nighttime sleep symptoms (Tractenberg RE et al. 2006). Changes in sleep present in the preclinical stages of AD may indicate risk of progression to cognitive impairment within several years (Ju YE et al. 2013). Nighttime sleep disruption and daytime sleepiness have been associated with cortical amyloid deposition occurring early in the pathogenesis of AD before cognitive symptoms are seen (Spira AP et al. 2013). Whereas investigators have focused on sleep disorder as a stressor for caregivers in the past, increasing attention is being paid to sleep disruption as a key factor in the pathologic process of AD (Lim AS et al. 2013).

Sleep Disorders and Neurodegeneration
Recent discoveries that sleep promotes clearance of potentially toxic metabolites from the brain through the lymphatic system have “awakened” us to the importance of sleep to clearance of Aβ (Xie L et al. 2013). There is normally a circadian rhythm in CSF Aβ levels, with high daytime levels and low nighttime levels. Sleep fragmentation may disrupt the nocturnal clearance of amyloid (Huang et al. 2012). Cortical amyloid deposition has been associated with decreased sleep efficiency and longer sleep latency (time to fall asleep) in subjects with normal cognition but at risk for AD (Spira et al. 2013; Brown et al. 2016). Although impaired NREM sleep, REM and wake mechanisms early in the disease process have been extensively documented, correlations with AD pathology (amyloid plaques and neurofibrillary tangles) in sleep-promoting hypothalamic and brain stem nuclei are still lacking (Holth JK et al. 2017). It’s interesting to note that some of the tauopathies, such as frontotemporal dementia with TAU G389R mutation and those with progressive supranuclear palsy, show similar sleep disturbances to AD patients (Holth JK et al. 2017). Patients with Lewy body disease and Parkinson’s disease have a full spectrum of sleep and wake problems, with nighttime awakenings, daytime sleepiness and the parasomnia, REM behavior disorder, which is highly correlated with synucleinopathies (Boeve BF et al. 2013).

Arousal Disorders and Cognition in AD and other Dementias
Most clinicians are aware of conditions that cause daytime sleepiness, such as insomnia, sleep-related breathing disorders, sedating medications, circadian rhythm disturbances and the many things that contribute to non-restorative sleep. But we have always assumed that that daytime sleepiness is a reversible consequence of sleep loss. In fact, sleep disruption itself may have direct and persistent neuropathological effects on wake-promoting centers. Primary arousal disorders and daytime sleepiness can occur early in the disease process from abnormal tau formation (Holth JK et al. 2017). Experimentally-induced sleep fragmentation without a reduction in total sleep time over 14 weeks in mice leads to loss of orexinergic neurons of the hypothalamus and noradrenergic neurons of the locus coeruleus (Zhu Y et al. 2015). These findings suggest that sleep fragmentation in old age and dementia may induce persistent impairment of alertness beyond what can be compensated for by increased sleep time. That is, we don’t yet know whether sustained improvement in sleep (if clinically possible) can reverse this process. Daytime sleepiness contributes to the low initiative, apathy, impaired attention and slow cognitive processing that are themselves core symptoms of most dementias.

Chronobiologic Disorders in AD
The nighttime awakenings so stressful for family caregivers are the most obvious manifestations of chronobiologic disorders associated with the disease. The output of the suprachiasmatic nucleus (SCN or the master circadian pacemaker) is affected either directly or indirectly by AD pathology (Musiek, ES et al. 2015). Disturbances in circadian timing of sleep can disrupt basic sleep processes REM sleep, slow wave sleep, sleep spindles) that have been shown to be important in memory consolidation (Van Someren EJW et al. 2015). In fact, disrupted circadian sleep-wake cycles may precede cognitive symptoms, (Musiek, ES et al. 2015) and also have very large effects on gene transcription and endocrine function, potentially affecting many processes essential to health (Archer SN and Oster H 2015). Although chronobiologic interventions (bright light and melatonin) have generally not been effective as monotherapy, melatonin may be helpful for the irregular sleep wake cycle rhythm that is sometimes seen in AD (Singer C et al. 2002).

IPA Symposium on Sleep and Health in Aging
Recognizing the importance of new findings from the neuroscience of sleep to clinical practice, IPA President Mary Sano has called for a special IPA symposium on sleep and aging. The symposium will take place 14-15 September 2018 in picturesque (it is!) Hoboken, NJ, USA and will bring together a very distinguished faculty and multidisciplinary audience of scientists and clinical providers. See the IPA website for details of the program and registration.

For further reading:

• Archer SN and Oster H. How sleep and wakefulness influence circadian rhythmicity: effects of insufficient and mistimed sleep on the animal and human transcriptome. J Sleep Research 2015; Oct 24(5)476-493
• Boeve BF, Silber MH, Ferman TJ, Lin SC, Benarroch EE et al. Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without coexisting neurologic disorder. Sleep Med 2013; Aug; 14:8:754-62
• Brown B, Rainey-Smith S, Villemagne V, Weinborn M, Bucks R, Sohrabi H, Laws S, Taddei K, Macaulay S, Ames D, Fowler C, Maruff P, Masters C, Rowe C, Martins R, Group A. The relationship between sleep quality and brain amyloid burden. Sleep 2016; 39:1063-8
• Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol 2013; 70:587–593
• Guarnieri B and Sorbi S. Sleep and cognitive decline: A strong bidirectional relationship. Is it time for specific recommendations on routine assessment and the management of sleep disorders in patients with mild cognitive impairment and dementia? Eur Neurol 2015; 74:43-48
• Holth JK, Patel TK, Holtzman DM. Sleep in Alzheimer’s disease: Beyond amyloid. Neurobiology of sleep and circadian rhythms 2017; 2:4-14
• Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju YE, Katen T, Morris JC, Mintun M, Duntley S, Bateman RJ. Arch Neurol 2012; 69:51-8
• Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep fragmentation and the risk of incident Alzheimer's disease and cognitive decline in older persons. Sleep 2013; 36: 1027–1032
• McCurry SM, Logsdon RG, Teri L, Gibbons LE, Kukull WA, Bowen JD, McCormick WC, Larson EB. Characteristics of sleep disturbance in community-dwelling Alzheimer’s disease patients. Psychiatry Neurology 1999: 12:53-9
• Musiek, E.S., Xiong, D.D., Holtzman, D.M., 2015. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp. Mol. Med 47, e148
• Prinz PN, Peskind ER, Vitaliano PP, Raskind MA, Eisdorfer C, Zemcuznikov N et al. Changes in the sleep and waking EEGs of nondemented and demented elderly subjects. J Am Geriatr Soc 1982; 30:86–93.
• Singer C, Colling E, Tractenberg R, Grundman M, Gamst A, Thomas R, Thal L. The ADCS clinical trial of meltonin for sleep disturbance of Alzheimer’s disease: Case report of an unusual sleep/wake cycle and response to melatonin. Am J Geri Psychiatry Supp 1 2002; 10:2:92
• Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M et al. Self-reported sleep and beta-amyloid deposition in community-dwelling older adults. JAMA Neurol 2013; 70: 1537–1543
• Tractenberg RE, Singer CM and Kaye JA. Characterizing sleep problems in person with Alzheimer’s disease and normal elderly. J sleep Research 2006; 15:97-103
• Van Someren EJW, Cirelli C, Dijk DJ, Cauter EV, Schwartz S, Chee MWL. Disrupted Sleep: From Molecules to Cognition. J Neuroscience 2015; 35:41:13889-13895
• Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnel J, Christensen DJ, Nicholson C, Illiff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science 2013; Oct 18; 342:6156:373-7
• Zhu Y, Fenik P, Zhan G, Xin R, Veasey SC. Degeneration in arousal neurons in chronic sleep disruption modeling sleep apnea. Front Neurol 2015;6:109

Dr. Cliff Singer is the Chief of Geriatric Mental Health and Neuropsychiatry at Acadia Hospital and Eastern Maine Medical Center (EMMC). Dr. Singer is also an Adjunct Professor at the University of Maine in Orono. He was the recipient of an award in 2005 for his contributions to older adults with dementia and mental illness. He has been voted to the "Best Doctors in America" list every year since 2003 and has made national television and radio appearances speaking on topics related to aging. Dr. Singer is the Course Director for the IPA Sleep and Health in Aging Symposium, 14-15 September 2018 in Hoboken, NJ, USA.

IPA Bulletin, Volume 35, Number 2: IPA Members can download the full PDF issue here