Rev. Neurosci. 2015; 26(1): 31–38
Alberto Raggi*, Walter Neri and Raffaele Ferri
Sleep-related behaviors in Alzheimer’s disease and dementia with Lewy bodies Abstract: Prevalence studies suggest that Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common dementing illnesses in the elderly. The aim of this narrative review was to provide data on sleeprelated behaviors in AD and DLB. This paper contains arguments, with a clinical approach, on both circadian rhythm changes and dissociated states of wakefulness and sleep in these two conditions. Keywords: Alzheimer’s disease; dementia with Lewy bodies; dissociated states of wakefulness and sleep; rapid eye movement sleep behavior disorder; sundown syndrome. DOI 10.1515/revneuro-2014-0050 Received July 24, 2014; accepted August 16, 2014; previously published online September 16, 2014
Introduction Alzheimer’s disease (AD) is a tauopathy and represents the most common cause of dementia. It is a progressive cognitive-behavioral disease that initially presents with short-term memory deficit and gradually worsens over time, progressing to widespread brain impairment. The intracellular neurofibrillary lesions consisting of tau protein and extracellular β-amyloid peptide deposits are the defining lesions in AD (Dickson, 1997; Williams, 2006). Dementia with Lewy bodies (DLB) is a synucleinopathy; prevalence studies suggest that it is the second most common dementing illness in the elderly. It is associated with cognitive decline, fluctuations in alertness and cognition, visual hallucinations, dysautonomia, and parkinsonism. The pathological criteria of DLB are associated with the location of Lewy bodies from the brainstem to *Corresponding author: Alberto Raggi, Unit of Neurology, Morgagni-Pierantoni Hospital, 34 Via Carlo Forlanini, I-47121 Forlì, Italy, e-mail: [email protected] Walter Neri: Unit of Neurology, Morgagni-Pierantoni Hospital, 34 Via Carlo Forlanini, I-47121 Forlì, Italy Raffaele Ferri: Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), I-94018, Troina, Italy
the cortex (Weisman and McKeith, 2007; Fujishiro et al., 2008). Both diseases have sleep-related behaviors, with prominent circadian rhythm changes (‘sundowning’) in AD and rapid eye movement (REM) sleep behavior disorder (RBD) in DLB (Raggi and Ferri, 2010). The aim of this brief narrative review was to provide data on these sleep disturbances according to a tutorial design and a clinical approach.
Sundown syndrome in AD The suprachiasmatic nucleus (SCN) is a small region located in the hypothalamus. It is responsible for controlling circadian rhythms (Saper, 2013). As for other brain regions, SCN is the object of age-related functional changes causing a reduction in amplitude of the circadian timing signal and a decreased precision of daily rhythms in physiology and behavior (Farajnia et al., 2014). The alteration in biorhythms relates with various health problems such as depression and can bring about neurodegeneration (Campos Costa et al., 2013). Cholinergic efferents from the nucleus basalis magnocellularis (NBM) play a direct role in the regulation of neuropeptide synthesis and expression by neurons in the SCN (Madeira et al., 2004). Physiological studies have yielded some rather consistent findings on the fact that also melatonin, which is a hormone produced by the pineal gland in darkness and during sleep in light active organisms, has a pivotal role in the regulation of the mechanisms underlying the circadian rhythms (Cajochen et al., 2003). The phenomenon of sundowning can be described as a nighttime worsening of disruptive behavior in elderly people (Vitiello et al., 1992). Patients present symptoms such as agitation, confusion, anxiety, screaming, moaning, hallucinations, mood swings, abnormally demanding attitude, suspiciousness, and aggressiveness in the late afternoon, in the evening, or at night (Vitiello et al., 1992). It has been estimated that 2.4–25% of AD patients have sundown syndrome, which is considered the second cause of disruptive behavior in institutionalized patients, after wandering (Khachiyants et al., 2011).
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32 A. Raggi et al.: Sleep-related behaviors in AD and DLB Sleep in AD patients is characterized by increased duration and frequency of awakenings, decreased slowwave sleep (SWS) and REM sleep, and more daytime napping (Vitiello et al., 1992; Vitiello and Borson, 2001). However, daytime sleep consists essentially of non-REM (NREM) stages 1 and 2 and does not compensate effectively for the loss of SWS and REM sleep (Vitiello et al., 1991, 1992; Vitiello and Borson, 2001). Some variables, both endogenous and environmental, seem to be responsible for sleep architecture alterations and for the predisposition to sundowning of AD patients. First, there is deterioration of the SCN because of senile plaque deposits with consequent disruption of circadian rhythms (Stopa et al., 1999) that have also been observed in aged plated-derived β-amyloid precursor protein transgenic mice (Huitrón-Reséndiz et al., 2002). It is noteworthy that neurodegeneration involves the NBM since the early phases of AD (Mesulam et al., 2004) with consequent SCN dysfunction (Bliwise, 2004). Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, AD, and apolipoprotein E-ε4 homozygote genotype have been found as well (Liu et al., 1999). Disruption of the circadian distribution of motor activity and of the basal temperature (Satlin et al., 1995), such as temporal variation in pain and mood in the evening hours (Bachman and Rabins, 2006), which are biological patterns of dementia, possibly explains some cases of sundown syndrome. Among the external factors that predispose patients to the sundown syndrome are the following: poor quality social networks in nursing home residents (Cohen-Mansfield et al., 1990), low-level assistance by staff in institutions or absence of available caregivers at night at home (Khachiyants et al., 2011), caregiver burden (GallagherThompson et al., 1992), and overstimulation by the environment (Khachiyants et al., 2011). Moreover, paradoxical agitation induced by benzodiazepines (Dell’Osso and Lader, 2013), worsening cognition caused sometimes by the anticholinergic side effect of some medications (Koyama et al. 2014), and restlessness and akathisia as side effects of antidepressants and antipsychotics (Bachman and Rabins, 2006) are often relevant iatrogenic factors triggering sundowning.
REM sleep behavior disorder in DLB The most frequent sleep disturbances in Parkinson’s disease (PD) are difficulty initiating sleep, frequent
nighttime awakening and sleep fragmentation, nocturia, restless legs syndrome/periodic limb movements during sleep, sleep breathing disorders, drug-induced symptoms, narcolepsy-like features, sleep attacks and excessive daytime sleepiness, and REM sleep parasomnia (Raggi et al., 2013). In PD and DLB, sleep disruption may be even more prominent than in AD and also include sundown symptoms (Bliwise, 2004; Raggi and Ferri, 2010). DLB includes symptoms of both AD (cognitive impairment) and PD (extrapyramidal features) (Weisman and McKeith, 2007; Fujishiro et al., 2008), and it is no coincidence that sleep disorders may overlap between the two diseases. However, above all sleep disorders, RBD is nowadays considered to be a suggestive manifestation in the clinical diagnostic criteria of DLB (Fujishiro et al., 2008). RBD is frequent in DLB (Uchiyama et al., 1995; Boeve et al., 1998, 2003, 2004, 2007a; Ferman et al., 2002; Iranzo et al., 2006; Ratti et al., 2012). In a recent study on neuropathologic findings of 172 cases of RBD, with or without coexisting neurological disorder, 77 diagnoses were of DLB and 59 were of combined DLB and AD (Boeve et al., 2013). It is assumed that RBD may precede any other clinical manifestation of synucleinopathies by more than 10 years (Boeve et al., 2007b; Postuma et al., 2009; McCarter et al., 2012). The ability to identify this prodrome may be critical in the development and eventual use of neuroprotective therapy. RBD is a REM sleep parasomnia characterized by loss of physiological atonia (REM sleep without atonia, or RSWA) and the appearance of behaviors reproducing the content of dreams. Even though acting out of dreams with appetitive behaviors has been described, in most of the cases, the movements reflect defense or aggression scenarios. The behaviors include yelling, talking, swearing, kicking, punching, or jumping out of the bed (Schenck et al., 1986; Mahowald and Schenck, 2005; Schenck and Mahowald, 2005). Absence of electroencephalographic epileptiform activity during REM sleep is needed unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder (Ferini-Strambi and Zucconi, 2000; Schenck et al., 2013). It has been demonstrated that, in the cat brain, a reciprocal inhibition exists between GABAergic REM-on neurons (sublaterodorsal tegmental nucleus [SLD]) and GABAergic REM-off neurons (ventrolateral periacqueductal gray matter and lateral pontine tegmentum) (Lu et al., 2006; Fuller et al., 2007). Among REM-on neurons, some glutamatergic cells project to the basal forebrain and regulate electro-cortical components of REM sleep, while other
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A. Raggi et al.: Sleep-related behaviors in AD and DLB 33
neurons project to the ventromedial medulla and spinal cord and regulate muscular atonia during REM sleep. It has also been hypothesized that there might be structures and networks in humans similar to those described in cats with SLD (or analogous nucleus) projecting to spinal interneurons through a direct pathway and causing active inhibition of skeletal muscles during REM sleep. Additionally, an indirect pathway from SLD to spinal interneurons, passing through the magnocellular reticular formation is believed to regulate muscular tone in REM sleep (Boeve et al., 2007b). Lesional and imaging studies indicate the existence of a dysfunction of SLD or analogous nucleus (within the coeruleus/subcoeruleus brainstem complex), which possibly causes RSWA and RBD in synucleinopathies (Boeve et al., 2007b). The spatial and temporal spread of α-synuclein pathology in PD with or without dementia seems to be characterized by a caudo-rostral development, starting from the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus toward the neocortex. RSWA and RBD might appear as an effect of dysfunction in the caudal portion of the brainstem during the presymptomatic stage. This would explain why RBD precedes the clinical symptoms of synucleinopathies (Braak et al., 2003, 2004; Brunnström et al., 2012). Recent experimental studies have demonstrated that α-synuclein can transfer from cell to cell with a ‘prion-like mechanism’ (George et al., 2013). There are also acute forms of RBD that are often due to undesirable side effects of prescribed medications, particularly with increasing age, such as tryciclic antidepressants, serotonin reuptake inhibitors, anticholinesterase inhibitors, or that are associated with alcohol, barbiturate, and meprobamate withdrawal (Winkelman and James, 2004; Mahowald and Schenck, 2005; Yeh et al., 2010; Manni et al., 2011).
Treatment Both sundown syndrome and RBD require nonpharmacological and pharmacological treatments.
Nonpharmacological treatment A comprehensive treatment program (cognitive-behavioral-motor) for demented patients may have beneficial effects on cognitive, functional, and in particular neuropsychiatric outcomes in both hospital and outdoor
settings (Olazarán et al., 2004; Raggi et al., 2007). Therefore, it is plausible that stability in cognition should improve the nocturnal exacerbation of disruptive behavior typical of older people and AD patients (Bachman and Rabins, 2006). Physical problems, such as pain, and effects of medication are additional important medical issues (Exum et al., 1993; Bachman and Rabins, 2006). There are some encouraging results concerning light therapy on sleep-wake disorders, agitation, and reorienting in subjects with dementia (Lovell et al., 1995; Campbell et al., 1988), but there is insufficient evidence yet to assess the real value of this treatment for managing sleep, behaviors, and mood disturbances in these patients (Forbes et al., 2009). As for nonpharmacological treatment of RBD, it is required to optimize sleep circumstances in a way that can reduce accidents due to leaping from bed (Mahowald and Ettinger, 1990). Attention must be also paid for manifestations that, because of violent behaviors acted out, could have potential forensic implications because of the risk of misinterpretation of RBD as suicidal or homicidal behavior (Mahowald and Schenck, 1995; Schenck et al., 2009; Siclari et al., 2010).
Melatonin Melatonin has been reported to be effective to treat sundowning in AD, although controversial data on this point exist. Indeed, large interindividual differences between AD patients exist and can explain these erratic results (Cardinali et al., 2011). With similar uncertainty and more in general, a systematic review of studies on empirical treatment data has concluded that there is sufficient evidence that low doses of melatonin improve initial sleep quality in selected elderly insomniacs (Olde Rikkert and Rigaud, 2001). One study on melatonin (3 mg at bedtime) in a patient with severe RBD suggests that melatonin might be able to reinforce over time REM sleep in RBD patients by enhancing its active inhibition of motor activity (Kunz and Bes, 1997). In a double-blind placebo-controlled trial of RBD that utilized melatonin at the same dosage of 3 mg, four patients had complete resolution of the disturbance, two had marked improvement, one showed a little improvement, and one remained unchanged (Kunz and Mahlberg, 2010). A much higher dosage (15 mg at bedtime) has been reported to be effective (Schenck and Mahowald, 2011). A clinical impression is that melatonin may induce sustained benefit over time (Kunz and Bes, 1997; Schenck et al., 2013).
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34 A. Raggi et al.: Sleep-related behaviors in AD and DLB
Antipsychotic medications
Sleep neurology
Atypical antipsychotics, better if used at low dosages, may have beneficial effect on sundowning because of their sedative properties without some of the common side effects of typical agents (Parnetti, 2000; Standridge, 2004). Atypical antipsychotics offer several advanced treatment options for psychotic symptoms in patients with parkinsonism, but there is no rationale in the usage of antipsychotic medications for the treatment of RBD in these diseases (Larsen and Tandberg, 2001).
It belongs to the experience of every physician in any field of medicine that in many hospitals or institutions for elderly/demented residents, there is an overuse of sedation at night because of agitation and not enough attention to the environmental factors that might improve cognition, behavior, and circadian rhythms in these patients. There is insufficient evidence yet to assess the value of light therapy for managing sleep, behavior, and mood disturbances in AD patients (Forbes et al., 2009). The research agenda should include more of these studies, but of course, it is reasonable and intuitive that in both homes and institutions, daily and evening light should be always available for every old subject. Extensive literature concerns RBD, but not all hospitals have sleep medicine, centers and this parasomnia tends to be underestimated. Therefore, simple solutions such as avoiding some medications in the evening or setting adequately the patients’ bedroom are not observed very often. Analyzing and knowing sleep disorders in neurodegenerative diseases call attention to the still insufficiently known ‘sleep neurology’ (Raggi and Ferri, 2010). Fisher (2003) suggests, in a fascinating article, that ‘Neurologists experienced in the interpretation of disease in terms of disordered action of the nervous system should be well suited to extend their field of interest to the more complex disorders of human behavior, including hysteria, delirium, ill-defined pain syndromes, unexplained fatigue, disorders of thought, atypical depression, and delusions… Inquiry into complex disorders of behavior is inseparable from the broad subject of normal mental activity, the neural organization subserving all human thought, emotion, and action’. It is worthwhile to include into the complex behavioral disorders also sleep-related ones such as sundown syndrome and RBD.
Benzodiazepines As for the sundown syndrome, benzodiazepines are effective hypnotics, but their use in elderly people is limited by the risk of falls, memory impairment, and worsening of sleep apnea (Culebras, 1992). Clonazepam, with a therapeutic range between 0.25 and 4.00 mg, is the treatment of choice for RBD; this drug is efficacious and has a low incidence of adverse effects, and it is possible to use it in association with melatonin (Ferini-Strambi and Zucconi, 2000; Gugger and Wagner, 2007; Ramar and Olson, 2013; Schenck et al. 2013).
Acetylcholinesterase inhibitors There is no evidence that acetylcholinesterase inhibitors (AChEIs) are beneficial in controlling sundowning, and some patients treated with these experience insomnia and nightmares (Ross and Shua-Haim, 1998; Khachiyants et al., 2011). AChEI-induced RBD has been described (Yeh et al., 2010). Best practice guide is to attenuate these adverse effects of AChEIs on sleep by slow-dose titration and switching from evening to morning use (Jackson et al., 2004). AChEIs may be considered to treat RBD in patients with a concomitant synucleinopathy, although limited data are available yet (Aurora et al., 2010).
Conclusion It is interesting to conclude arguing a very practical issue (‘sleep neurology’) and a theoretical one (‘dissociated states of wakefulness and sleep’).
Dissociated states of wakefulness and sleep The primary states of being (wakefulness, NREM sleep, and REM sleep) are not necessarily mutually exclusive, and components of these states may appear in various combinations, with intriguing phenomenological consequences in both normality and pathology (Schenck et al., 1986; Mahowald and Schenck, 1991, 1992, 2001; Raggi et al., 2010). The concept of ‘covert REM’ (Nielsen, 2000), anticipated in part by that of ‘intermediate sleep’ (Lairy et al., 1967), concerns the presence of mentation not only in REM but also in NREM sleep, which is an example of incompleteness of state boundaries already in physiology.
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A. Raggi et al.: Sleep-related behaviors in AD and DLB 35
According to Mahowald and Schenck (1992), areas of overlap among states in pathology can be wake-NREM combinations (disorders of arousal such as sleepwalking, sleep terror, confusional arousals; psychogenic dissociation), wake-REM combinations (cataplexy, hypnagogic hallucinations, sleep paralysis; RBD; lucid dreaming; delirium), wake-NREM-REM combinations (status dissociatus, parasomnia overlap syndromes), and NREM-REM combinations, which are theoretically possible but not accompanied by conscious awareness. The study of RBD has been instrumental in promoting the concept of boundary dyscontrol conditions: patients with RBD show violent dream enacting behaviors, which represent the acting out of dream mentation and are possible because of the absence of typical somatic muscle atonia during REM sleep. Another example of dissociated states could be that of narcolepsy when sleep attacks, and hallucinations represent an intrusion of REM sleep into wakefulness and paralysis in the morning is when REM atonia persists after awakening (Raggi et al., 2010). Very often, RBD and narcolepsy overlap (Mahowald and Schenck, 2005; Raggi et al., 2010). Elderly persons have an earlier onset of dream periods and more frequent and rapid awakening episodes (Feinberg et al., 1965), and AD patients have a higher nocturnal activity than controls do (Satlin et al., 1995); sundowners among institutionalized increase restless and verbal behavior as evening approaches (Evans, 1987). Moreover, patients with sundown syndrome are more likely to be demented, with greater mental impairment and organic involvement than those without sundown syndrome (Evans, 1987). It is reasonable to hypothesize that, sometimes, nocturnal psychopathology might represent a transitional state from dreaming to wakefulness and a sudden intrusion of sleep into wakefulness (Feinberg et al., 1965; Culebras, 1992), allowing the conclusive assertion that both RBD and sundowning are examples of dissociated states of wakefulness and sleep in patients with dementia. Acknowledgments: This work was partially supported by the Italian Ministry of Health (‘Ricerca Corrente’). Conflict of interest statement: None.
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Schenck, C.H. and Mahowald, M.W. (2011). REM sleep parasomnias in adults: REM sleep behavior disorder (RBD), isolated sleep paralysis and nightmare disorder. Therapy in Sleep Medicine. Matheson, J., Ferber, R.F., and Doghramji, K., eds. (Philadelphia, PA: Elsevier Press), pp. 549–558. Schenck, C.H., Bundlie, S.R., Ettinger, M.G., and Mahowald, M.W. (1986). Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 9, 293–308. Schenck, C.H., Lee, S.A., Bornemann, M.A., and Mahowald, M.W. (2009). Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder: review of the literature and forensic implications. J. Forensic Sci. 54, 1475–1484. Schenck, C.H., Montplaisir, J.Y., Frauscher, B., Hogl, B., Gagnon, J.F., Postuma, R., Sonka, K., Jennum, P., Partinen, M., Arnulf, I., et al. (2013). Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med. 14, 795–806. Siclari, F., Khatami, R., Urbaniok, F., Nobili, L., Mahowald, M.W., Schenck, C.H., Cramer Bornemann, M.A., and Bassetti, C.L. (2010). Violence in sleep. Brain 133, 3494–3509. Standridge, J.B. (2004). Pharmacotherapeutic approaches to the treatment of Alzheimer’s disease. Clin. Ther. 26, 615–630. Stopa, E.G., Volicer, L., Kuo-Leblanc, V., Harper, D., Lathi, D., Tate, B., and Satlin, A. (1999). Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J. Neuropathol. Exp. Neurol. 58, 29–39. Uchiyama, M., Isse, K., Tanaka, K., Yokota, N., Hamamoto, M., Aida, S., Ito, Y., Yoshimura, M., and Okawa, M. (1995). Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 45, 709–712. Vitiello, M.V. and Borson, S. (2001). Sleep disturbances in patients with Alzheimer’s disease: epidemiology, pathophysiology and treatment. CNS Drugs 15, 777–796. Vitiello, M.V., Poceta, J.S., and Prinz, P.N. (1991). Sleep in Alzheimer’s disease and other dementing disorders. Can. J. Psychol. 45, 221–239. Vitiello, M.V., Bliwise, D.L., and Prinz, P.N. (1992). Sleep in Alzheimer’s disease and the sundown syndrome. Neurology 42, 83–93. Weisman, D. and McKeith, I. (2007). Dementia with Lewy bodies. Semin. Neurol. 27, 42–47. Williams, D.R. (2006). Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern. Med. J. 36, 652–660. Winkelman, J.W. and James, L. (2004). Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27, 317–321. Yeh, S.B., Yeh, P.Y., and Schenck, C.H. (2010). Rivastigmine-induced REM sleep behavior disorder (RBD) in a 88-year-old man with Alzheimer’s disease. J. Clin. Sleep Med. 6, 192–195.
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38 A. Raggi et al.: Sleep-related behaviors in AD and DLB He has practiced Neurology at the Morgagni-Pierantoni public hospital of Forlì to date. He has been Chief of the Neurophysiology Laboratory for many years and he is the Director of the Unit of Neurology since 2000. Dr. Neri is involved in both clinical neurology and neurophysiology, with a large spectrum of interests including neuroimmunology, peripheral neuropathy, neurodegenerative and cerebrovascular disorders. He is the author of publications in both international and national scientific journals. Alberto Raggi studied Medicine at the University of Bologna. He served his residency in Psychiatry at the University of Modena and in Neurology at the University of Florence and is board certified in both specialties. He has worked as a staff neurologist for some public hospitals (Borgomanero, Faenza, Piacenza), the Neurology and Neurorehabilitation Unit of the San Raffaele Turro Hospital in Milan and the Department of Neurology of the Oasi Institute for Research on Mental Retardation and Brain Aging in Troina. He works at the Neurology Unit of the Morgagni–Pierantoni public Hospital of Forlì since 2012. His main research focus is in behavioural neurology. He has authored publications in both international and national scientific journals. He has served as occasional reviewer for several neuroscience journals.
Walter Neri received his MD at the University of Bologna in 1977 where he also received the specialization in Neurology in 1981.
Raffaele Ferri has been involved in the scientific study of the neurophysiological aspects of Alzheimer’s disease and other dementias and is the Head of a clinical unit specifically devoted to the diagnosis and treatment of these conditions. His specific areas of interest cover also the description, analysis and understanding of various aspects of human sleep and sleep disorders such restless legs syndrome, narcolepsy, and REM sleep behavior disorder. He has published over 300 papers in international peer-reviewed scientific journals, in addition to book chapters. Currently Scientific Secretary of the European Restless Legs Syndrome Study Group and member-at-large of the International Restless Legs Syndrome Study Group, Dr. Ferri is also Associate Editor for the journal Sleep, Action Editor for the International Journal of Psychophysiology, Academic Editor for PlosONE, and is member of the editorial board of Clinical Neurophysiology, Sleep Medicine, and Sleep Medicine Reviews.
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Alberto Raggi*, Walter Neri and Raffaele Ferri
Sleep-related behaviors in Alzheimer’s disease and dementia with Lewy bodies Abstract: Prevalence studies suggest that Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common dementing illnesses in the elderly. The aim of this narrative review was to provide data on sleeprelated behaviors in AD and DLB. This paper contains arguments, with a clinical approach, on both circadian rhythm changes and dissociated states of wakefulness and sleep in these two conditions. Keywords: Alzheimer’s disease; dementia with Lewy bodies; dissociated states of wakefulness and sleep; rapid eye movement sleep behavior disorder; sundown syndrome. DOI 10.1515/revneuro-2014-0050 Received July 24, 2014; accepted August 16, 2014; previously published online September 16, 2014
Introduction Alzheimer’s disease (AD) is a tauopathy and represents the most common cause of dementia. It is a progressive cognitive-behavioral disease that initially presents with short-term memory deficit and gradually worsens over time, progressing to widespread brain impairment. The intracellular neurofibrillary lesions consisting of tau protein and extracellular β-amyloid peptide deposits are the defining lesions in AD (Dickson, 1997; Williams, 2006). Dementia with Lewy bodies (DLB) is a synucleinopathy; prevalence studies suggest that it is the second most common dementing illness in the elderly. It is associated with cognitive decline, fluctuations in alertness and cognition, visual hallucinations, dysautonomia, and parkinsonism. The pathological criteria of DLB are associated with the location of Lewy bodies from the brainstem to *Corresponding author: Alberto Raggi, Unit of Neurology, Morgagni-Pierantoni Hospital, 34 Via Carlo Forlanini, I-47121 Forlì, Italy, e-mail: [email protected] Walter Neri: Unit of Neurology, Morgagni-Pierantoni Hospital, 34 Via Carlo Forlanini, I-47121 Forlì, Italy Raffaele Ferri: Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), I-94018, Troina, Italy
the cortex (Weisman and McKeith, 2007; Fujishiro et al., 2008). Both diseases have sleep-related behaviors, with prominent circadian rhythm changes (‘sundowning’) in AD and rapid eye movement (REM) sleep behavior disorder (RBD) in DLB (Raggi and Ferri, 2010). The aim of this brief narrative review was to provide data on these sleep disturbances according to a tutorial design and a clinical approach.
Sundown syndrome in AD The suprachiasmatic nucleus (SCN) is a small region located in the hypothalamus. It is responsible for controlling circadian rhythms (Saper, 2013). As for other brain regions, SCN is the object of age-related functional changes causing a reduction in amplitude of the circadian timing signal and a decreased precision of daily rhythms in physiology and behavior (Farajnia et al., 2014). The alteration in biorhythms relates with various health problems such as depression and can bring about neurodegeneration (Campos Costa et al., 2013). Cholinergic efferents from the nucleus basalis magnocellularis (NBM) play a direct role in the regulation of neuropeptide synthesis and expression by neurons in the SCN (Madeira et al., 2004). Physiological studies have yielded some rather consistent findings on the fact that also melatonin, which is a hormone produced by the pineal gland in darkness and during sleep in light active organisms, has a pivotal role in the regulation of the mechanisms underlying the circadian rhythms (Cajochen et al., 2003). The phenomenon of sundowning can be described as a nighttime worsening of disruptive behavior in elderly people (Vitiello et al., 1992). Patients present symptoms such as agitation, confusion, anxiety, screaming, moaning, hallucinations, mood swings, abnormally demanding attitude, suspiciousness, and aggressiveness in the late afternoon, in the evening, or at night (Vitiello et al., 1992). It has been estimated that 2.4–25% of AD patients have sundown syndrome, which is considered the second cause of disruptive behavior in institutionalized patients, after wandering (Khachiyants et al., 2011).
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32 A. Raggi et al.: Sleep-related behaviors in AD and DLB Sleep in AD patients is characterized by increased duration and frequency of awakenings, decreased slowwave sleep (SWS) and REM sleep, and more daytime napping (Vitiello et al., 1992; Vitiello and Borson, 2001). However, daytime sleep consists essentially of non-REM (NREM) stages 1 and 2 and does not compensate effectively for the loss of SWS and REM sleep (Vitiello et al., 1991, 1992; Vitiello and Borson, 2001). Some variables, both endogenous and environmental, seem to be responsible for sleep architecture alterations and for the predisposition to sundowning of AD patients. First, there is deterioration of the SCN because of senile plaque deposits with consequent disruption of circadian rhythms (Stopa et al., 1999) that have also been observed in aged plated-derived β-amyloid precursor protein transgenic mice (Huitrón-Reséndiz et al., 2002). It is noteworthy that neurodegeneration involves the NBM since the early phases of AD (Mesulam et al., 2004) with consequent SCN dysfunction (Bliwise, 2004). Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, AD, and apolipoprotein E-ε4 homozygote genotype have been found as well (Liu et al., 1999). Disruption of the circadian distribution of motor activity and of the basal temperature (Satlin et al., 1995), such as temporal variation in pain and mood in the evening hours (Bachman and Rabins, 2006), which are biological patterns of dementia, possibly explains some cases of sundown syndrome. Among the external factors that predispose patients to the sundown syndrome are the following: poor quality social networks in nursing home residents (Cohen-Mansfield et al., 1990), low-level assistance by staff in institutions or absence of available caregivers at night at home (Khachiyants et al., 2011), caregiver burden (GallagherThompson et al., 1992), and overstimulation by the environment (Khachiyants et al., 2011). Moreover, paradoxical agitation induced by benzodiazepines (Dell’Osso and Lader, 2013), worsening cognition caused sometimes by the anticholinergic side effect of some medications (Koyama et al. 2014), and restlessness and akathisia as side effects of antidepressants and antipsychotics (Bachman and Rabins, 2006) are often relevant iatrogenic factors triggering sundowning.
REM sleep behavior disorder in DLB The most frequent sleep disturbances in Parkinson’s disease (PD) are difficulty initiating sleep, frequent
nighttime awakening and sleep fragmentation, nocturia, restless legs syndrome/periodic limb movements during sleep, sleep breathing disorders, drug-induced symptoms, narcolepsy-like features, sleep attacks and excessive daytime sleepiness, and REM sleep parasomnia (Raggi et al., 2013). In PD and DLB, sleep disruption may be even more prominent than in AD and also include sundown symptoms (Bliwise, 2004; Raggi and Ferri, 2010). DLB includes symptoms of both AD (cognitive impairment) and PD (extrapyramidal features) (Weisman and McKeith, 2007; Fujishiro et al., 2008), and it is no coincidence that sleep disorders may overlap between the two diseases. However, above all sleep disorders, RBD is nowadays considered to be a suggestive manifestation in the clinical diagnostic criteria of DLB (Fujishiro et al., 2008). RBD is frequent in DLB (Uchiyama et al., 1995; Boeve et al., 1998, 2003, 2004, 2007a; Ferman et al., 2002; Iranzo et al., 2006; Ratti et al., 2012). In a recent study on neuropathologic findings of 172 cases of RBD, with or without coexisting neurological disorder, 77 diagnoses were of DLB and 59 were of combined DLB and AD (Boeve et al., 2013). It is assumed that RBD may precede any other clinical manifestation of synucleinopathies by more than 10 years (Boeve et al., 2007b; Postuma et al., 2009; McCarter et al., 2012). The ability to identify this prodrome may be critical in the development and eventual use of neuroprotective therapy. RBD is a REM sleep parasomnia characterized by loss of physiological atonia (REM sleep without atonia, or RSWA) and the appearance of behaviors reproducing the content of dreams. Even though acting out of dreams with appetitive behaviors has been described, in most of the cases, the movements reflect defense or aggression scenarios. The behaviors include yelling, talking, swearing, kicking, punching, or jumping out of the bed (Schenck et al., 1986; Mahowald and Schenck, 2005; Schenck and Mahowald, 2005). Absence of electroencephalographic epileptiform activity during REM sleep is needed unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder (Ferini-Strambi and Zucconi, 2000; Schenck et al., 2013). It has been demonstrated that, in the cat brain, a reciprocal inhibition exists between GABAergic REM-on neurons (sublaterodorsal tegmental nucleus [SLD]) and GABAergic REM-off neurons (ventrolateral periacqueductal gray matter and lateral pontine tegmentum) (Lu et al., 2006; Fuller et al., 2007). Among REM-on neurons, some glutamatergic cells project to the basal forebrain and regulate electro-cortical components of REM sleep, while other
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A. Raggi et al.: Sleep-related behaviors in AD and DLB 33
neurons project to the ventromedial medulla and spinal cord and regulate muscular atonia during REM sleep. It has also been hypothesized that there might be structures and networks in humans similar to those described in cats with SLD (or analogous nucleus) projecting to spinal interneurons through a direct pathway and causing active inhibition of skeletal muscles during REM sleep. Additionally, an indirect pathway from SLD to spinal interneurons, passing through the magnocellular reticular formation is believed to regulate muscular tone in REM sleep (Boeve et al., 2007b). Lesional and imaging studies indicate the existence of a dysfunction of SLD or analogous nucleus (within the coeruleus/subcoeruleus brainstem complex), which possibly causes RSWA and RBD in synucleinopathies (Boeve et al., 2007b). The spatial and temporal spread of α-synuclein pathology in PD with or without dementia seems to be characterized by a caudo-rostral development, starting from the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus toward the neocortex. RSWA and RBD might appear as an effect of dysfunction in the caudal portion of the brainstem during the presymptomatic stage. This would explain why RBD precedes the clinical symptoms of synucleinopathies (Braak et al., 2003, 2004; Brunnström et al., 2012). Recent experimental studies have demonstrated that α-synuclein can transfer from cell to cell with a ‘prion-like mechanism’ (George et al., 2013). There are also acute forms of RBD that are often due to undesirable side effects of prescribed medications, particularly with increasing age, such as tryciclic antidepressants, serotonin reuptake inhibitors, anticholinesterase inhibitors, or that are associated with alcohol, barbiturate, and meprobamate withdrawal (Winkelman and James, 2004; Mahowald and Schenck, 2005; Yeh et al., 2010; Manni et al., 2011).
Treatment Both sundown syndrome and RBD require nonpharmacological and pharmacological treatments.
Nonpharmacological treatment A comprehensive treatment program (cognitive-behavioral-motor) for demented patients may have beneficial effects on cognitive, functional, and in particular neuropsychiatric outcomes in both hospital and outdoor
settings (Olazarán et al., 2004; Raggi et al., 2007). Therefore, it is plausible that stability in cognition should improve the nocturnal exacerbation of disruptive behavior typical of older people and AD patients (Bachman and Rabins, 2006). Physical problems, such as pain, and effects of medication are additional important medical issues (Exum et al., 1993; Bachman and Rabins, 2006). There are some encouraging results concerning light therapy on sleep-wake disorders, agitation, and reorienting in subjects with dementia (Lovell et al., 1995; Campbell et al., 1988), but there is insufficient evidence yet to assess the real value of this treatment for managing sleep, behaviors, and mood disturbances in these patients (Forbes et al., 2009). As for nonpharmacological treatment of RBD, it is required to optimize sleep circumstances in a way that can reduce accidents due to leaping from bed (Mahowald and Ettinger, 1990). Attention must be also paid for manifestations that, because of violent behaviors acted out, could have potential forensic implications because of the risk of misinterpretation of RBD as suicidal or homicidal behavior (Mahowald and Schenck, 1995; Schenck et al., 2009; Siclari et al., 2010).
Melatonin Melatonin has been reported to be effective to treat sundowning in AD, although controversial data on this point exist. Indeed, large interindividual differences between AD patients exist and can explain these erratic results (Cardinali et al., 2011). With similar uncertainty and more in general, a systematic review of studies on empirical treatment data has concluded that there is sufficient evidence that low doses of melatonin improve initial sleep quality in selected elderly insomniacs (Olde Rikkert and Rigaud, 2001). One study on melatonin (3 mg at bedtime) in a patient with severe RBD suggests that melatonin might be able to reinforce over time REM sleep in RBD patients by enhancing its active inhibition of motor activity (Kunz and Bes, 1997). In a double-blind placebo-controlled trial of RBD that utilized melatonin at the same dosage of 3 mg, four patients had complete resolution of the disturbance, two had marked improvement, one showed a little improvement, and one remained unchanged (Kunz and Mahlberg, 2010). A much higher dosage (15 mg at bedtime) has been reported to be effective (Schenck and Mahowald, 2011). A clinical impression is that melatonin may induce sustained benefit over time (Kunz and Bes, 1997; Schenck et al., 2013).
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34 A. Raggi et al.: Sleep-related behaviors in AD and DLB
Antipsychotic medications
Sleep neurology
Atypical antipsychotics, better if used at low dosages, may have beneficial effect on sundowning because of their sedative properties without some of the common side effects of typical agents (Parnetti, 2000; Standridge, 2004). Atypical antipsychotics offer several advanced treatment options for psychotic symptoms in patients with parkinsonism, but there is no rationale in the usage of antipsychotic medications for the treatment of RBD in these diseases (Larsen and Tandberg, 2001).
It belongs to the experience of every physician in any field of medicine that in many hospitals or institutions for elderly/demented residents, there is an overuse of sedation at night because of agitation and not enough attention to the environmental factors that might improve cognition, behavior, and circadian rhythms in these patients. There is insufficient evidence yet to assess the value of light therapy for managing sleep, behavior, and mood disturbances in AD patients (Forbes et al., 2009). The research agenda should include more of these studies, but of course, it is reasonable and intuitive that in both homes and institutions, daily and evening light should be always available for every old subject. Extensive literature concerns RBD, but not all hospitals have sleep medicine, centers and this parasomnia tends to be underestimated. Therefore, simple solutions such as avoiding some medications in the evening or setting adequately the patients’ bedroom are not observed very often. Analyzing and knowing sleep disorders in neurodegenerative diseases call attention to the still insufficiently known ‘sleep neurology’ (Raggi and Ferri, 2010). Fisher (2003) suggests, in a fascinating article, that ‘Neurologists experienced in the interpretation of disease in terms of disordered action of the nervous system should be well suited to extend their field of interest to the more complex disorders of human behavior, including hysteria, delirium, ill-defined pain syndromes, unexplained fatigue, disorders of thought, atypical depression, and delusions… Inquiry into complex disorders of behavior is inseparable from the broad subject of normal mental activity, the neural organization subserving all human thought, emotion, and action’. It is worthwhile to include into the complex behavioral disorders also sleep-related ones such as sundown syndrome and RBD.
Benzodiazepines As for the sundown syndrome, benzodiazepines are effective hypnotics, but their use in elderly people is limited by the risk of falls, memory impairment, and worsening of sleep apnea (Culebras, 1992). Clonazepam, with a therapeutic range between 0.25 and 4.00 mg, is the treatment of choice for RBD; this drug is efficacious and has a low incidence of adverse effects, and it is possible to use it in association with melatonin (Ferini-Strambi and Zucconi, 2000; Gugger and Wagner, 2007; Ramar and Olson, 2013; Schenck et al. 2013).
Acetylcholinesterase inhibitors There is no evidence that acetylcholinesterase inhibitors (AChEIs) are beneficial in controlling sundowning, and some patients treated with these experience insomnia and nightmares (Ross and Shua-Haim, 1998; Khachiyants et al., 2011). AChEI-induced RBD has been described (Yeh et al., 2010). Best practice guide is to attenuate these adverse effects of AChEIs on sleep by slow-dose titration and switching from evening to morning use (Jackson et al., 2004). AChEIs may be considered to treat RBD in patients with a concomitant synucleinopathy, although limited data are available yet (Aurora et al., 2010).
Conclusion It is interesting to conclude arguing a very practical issue (‘sleep neurology’) and a theoretical one (‘dissociated states of wakefulness and sleep’).
Dissociated states of wakefulness and sleep The primary states of being (wakefulness, NREM sleep, and REM sleep) are not necessarily mutually exclusive, and components of these states may appear in various combinations, with intriguing phenomenological consequences in both normality and pathology (Schenck et al., 1986; Mahowald and Schenck, 1991, 1992, 2001; Raggi et al., 2010). The concept of ‘covert REM’ (Nielsen, 2000), anticipated in part by that of ‘intermediate sleep’ (Lairy et al., 1967), concerns the presence of mentation not only in REM but also in NREM sleep, which is an example of incompleteness of state boundaries already in physiology.
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A. Raggi et al.: Sleep-related behaviors in AD and DLB 35
According to Mahowald and Schenck (1992), areas of overlap among states in pathology can be wake-NREM combinations (disorders of arousal such as sleepwalking, sleep terror, confusional arousals; psychogenic dissociation), wake-REM combinations (cataplexy, hypnagogic hallucinations, sleep paralysis; RBD; lucid dreaming; delirium), wake-NREM-REM combinations (status dissociatus, parasomnia overlap syndromes), and NREM-REM combinations, which are theoretically possible but not accompanied by conscious awareness. The study of RBD has been instrumental in promoting the concept of boundary dyscontrol conditions: patients with RBD show violent dream enacting behaviors, which represent the acting out of dream mentation and are possible because of the absence of typical somatic muscle atonia during REM sleep. Another example of dissociated states could be that of narcolepsy when sleep attacks, and hallucinations represent an intrusion of REM sleep into wakefulness and paralysis in the morning is when REM atonia persists after awakening (Raggi et al., 2010). Very often, RBD and narcolepsy overlap (Mahowald and Schenck, 2005; Raggi et al., 2010). Elderly persons have an earlier onset of dream periods and more frequent and rapid awakening episodes (Feinberg et al., 1965), and AD patients have a higher nocturnal activity than controls do (Satlin et al., 1995); sundowners among institutionalized increase restless and verbal behavior as evening approaches (Evans, 1987). Moreover, patients with sundown syndrome are more likely to be demented, with greater mental impairment and organic involvement than those without sundown syndrome (Evans, 1987). It is reasonable to hypothesize that, sometimes, nocturnal psychopathology might represent a transitional state from dreaming to wakefulness and a sudden intrusion of sleep into wakefulness (Feinberg et al., 1965; Culebras, 1992), allowing the conclusive assertion that both RBD and sundowning are examples of dissociated states of wakefulness and sleep in patients with dementia. Acknowledgments: This work was partially supported by the Italian Ministry of Health (‘Ricerca Corrente’). Conflict of interest statement: None.
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38 A. Raggi et al.: Sleep-related behaviors in AD and DLB He has practiced Neurology at the Morgagni-Pierantoni public hospital of Forlì to date. He has been Chief of the Neurophysiology Laboratory for many years and he is the Director of the Unit of Neurology since 2000. Dr. Neri is involved in both clinical neurology and neurophysiology, with a large spectrum of interests including neuroimmunology, peripheral neuropathy, neurodegenerative and cerebrovascular disorders. He is the author of publications in both international and national scientific journals. Alberto Raggi studied Medicine at the University of Bologna. He served his residency in Psychiatry at the University of Modena and in Neurology at the University of Florence and is board certified in both specialties. He has worked as a staff neurologist for some public hospitals (Borgomanero, Faenza, Piacenza), the Neurology and Neurorehabilitation Unit of the San Raffaele Turro Hospital in Milan and the Department of Neurology of the Oasi Institute for Research on Mental Retardation and Brain Aging in Troina. He works at the Neurology Unit of the Morgagni–Pierantoni public Hospital of Forlì since 2012. His main research focus is in behavioural neurology. He has authored publications in both international and national scientific journals. He has served as occasional reviewer for several neuroscience journals.
Walter Neri received his MD at the University of Bologna in 1977 where he also received the specialization in Neurology in 1981.
Raffaele Ferri has been involved in the scientific study of the neurophysiological aspects of Alzheimer’s disease and other dementias and is the Head of a clinical unit specifically devoted to the diagnosis and treatment of these conditions. His specific areas of interest cover also the description, analysis and understanding of various aspects of human sleep and sleep disorders such restless legs syndrome, narcolepsy, and REM sleep behavior disorder. He has published over 300 papers in international peer-reviewed scientific journals, in addition to book chapters. Currently Scientific Secretary of the European Restless Legs Syndrome Study Group and member-at-large of the International Restless Legs Syndrome Study Group, Dr. Ferri is also Associate Editor for the journal Sleep, Action Editor for the International Journal of Psychophysiology, Academic Editor for PlosONE, and is member of the editorial board of Clinical Neurophysiology, Sleep Medicine, and Sleep Medicine Reviews.
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