Alzheimer Dementia and Sleep Disorders: Issues in Diagnosis and Treatment

TABLE 1: Nonpharmacological interventions for the management of sleep issues in dementia

TABLE 2: Pharmacological interventions for the management of sleep issues in dementia

TABLE 3: Treatment plan for Mr X

Sleep disorders occur with nearly all dementias. However, some disorders have been associated with higher rates of parasomnias and dyssomnias. In one large-scale study, nocturnal sleep disorders were found in 26.6% of patients with Alzheimer disease (AD) and were associated with higher levels of comorbid depression (48%), hallucinations (4.9%), delusions (7.5%), agitation (13.4%), and apathy (15.2%).¹ Other studies have found higher levels of nocturnal and daytime sleep disorders (44%).^2,3 Hypersomnia, nocturnal awakenings, and early morning awakenings were most frequently reported by patients’ caregivers.

Pathogenesis

Among the pathological cascade of events in the development of AD is the accumulation of β-amyloid. The buildup of β-amyloid leads (in part) to a dysregulation of neural Ca²⁺ signaling, and this alteration in Ca²⁺ results in memories acquired during wakeful periods to be rapidly erased before sleep consolidation. The changes in Ca²⁺ signaling also appear to be involved in the degradation of the sleep-wake cycle in AD with an increase in wakefulness.⁴

Sleep changes in AD occur well before the onset of cognitive decline and are likely associated with β-amyloid accumulation. In addition, some research has demonstrated that changes to brain regions involved with circadian rhythms in the early stages of AD may contribute to the emergence of sleep disorders early in the pathogenesis of AD.⁵ Levels of the neuropeptide orexin in the cerebral spinal fluid of patients with AD and impaired sleep indicate higher mean levels in moderate AD compared with mild AD or impaired sleep. These elevations are associated with decreased cognitive capacity and sleep deterioration.⁶ Convergent evidence from several biological markers shows that the systems related to sleep/wake cycles are potential areas involved in the pathology of AD.

Insomnia and circadian rhythm sleep-wake disorders

Nearly half of all older adults report difficulties with either initiation or maintenance of sleep.⁷ As a person ages, sleep decreases in quantity and quality with resulting fragmentation and daytime fatigue. Moreover, disorders and disruptions of sleep are frequently associated with increased cognitive impairments and the likelihood of dementia, which suggests a bidirectional relationship.⁸ Sleep disorders are particularly problematic in patients with AD because they are associated with increased psychiatric symptoms, daytime irritability, decreased cognitive performance, and increased risk of falls. Recent evidence also shows that increased sleep or sleepiness during the daytime appears to contribute to an increased risk of receiving a diagnosis of AD at 2-year follow-up.⁹ In addition, patients who have frequent sleep fragmentation also have a 1.5-fold increased risk of AD.¹⁰

Daytime activity in patients with AD is typically interrupted with multiple short episodes of napping. Patients also frequently experience periods of increased confusion and disruptive behaviors in the evening (sundowning).¹¹ The causes of sundowning are still unknown but are thought to be related to decreased light, fatigue, or disruption of circadian rhythms mediated by the suprachiasmatic nucleus. The total hours of sleep (day and night) is positively correlated with severity of dementia in nursing home patients, who can average over 13 hours of total sleep per 24-hour cycle. More severely demented patients show increased sleep fragmentation and daytime sleep regardless of age.

Sleep disorders in patients with AD tend to vary with disease severity and institutional placement. In those who have these disorders, rates of aggression (65% vs 40%), global behavioral problems (80% vs 58%), and anxiety (67% vs 50%) are higher than in patients with AD who do not have sleep problems.¹² For caregivers, AD patients with comorbid sleep and behavioral issues are particularly problematic. Nocturnal agitation may be the single most common reason that a patient with dementia enters a nursing home.

Obstructive sleep apnea hypopnea

Obstructive sleep apnea is common in patients with AD; the prevalence is 40% in institutionalized AD patients.¹³ If left untreated, obstructive sleep apnea can have a significant negative impact on cognition and daytime functioning, which can exacerbate the primary deficits in AD. An emerging body of evidence suggests that treatments for obstructive sleep apnea (eg, continuous positive airway pressure [CPAP]) provide significant improvements in objective sleep parameters and daytime fatigue, with modest improvements in cognitive functioning. Findings from neuropsychological testing indicate that CPAP maintained or improved general cognitive functioning, processing speed, executive functioning, and memory.¹⁴

REM sleep behavior disorder

REM sleep behavior disorder is characterized by repeated episodes of vivid and often violent dreams during REM sleep without atonia; thus, there is the capacity for complex movement during sleep. The onset of REM behavior disorder, which presents with injurious or disruptive behavior, is generally after age 50. There is a strong association with a variety of neurodegenerative disorders, including Parkinson disease, Lewy body dementia, and multisystem atrophy. AD has not been associated with REM behavior disorder, although several recent studies have suggested it may be more prevalent than once thought. These studies have found small subsets of AD patients (>10%) with violent dreams, REM sleep without atonia, and behavioral manifestations. Sinforiani and colleagues¹⁵ found increased vivid and violent dreams in patients with AD occurred more frequently in those with daytime hallucinations.

REM behavioral disorder is typically treated with long-acting hypnotics such as clonazepam, although the use of this medication in AD can lead to increased daytime fatigue and exacerbation of confusion. Anderson and colleagues¹⁶ found that melatonin was highly effective in the treatment of REM behavioral disorder and should be considered as a potential first-line treatment option given the lack of potential adverse effects. SSRIs and SNRIs may exacerbate REM behavioral disorder. It should be noted that severe sleep apnea can mimic REM behavioral disorder; thus, polysomnographic assessment is paramount prior to diagnosis. Because REM behavioral disorder can be associated with injury to self and the sleep partner, immediate treatment is indicated.

Assessment

Factors that contribute to sleep problems in patients with AD include adverse effects of medications, dosing compliance, primary or secondary psychiatric symptoms, and environmental factors (eg, community vs assisted-living placement, bed partner). Since the ultimate purpose of the assessment is to identify and treat the whole person, clinicians should start with a thorough understanding of all contributing factors that may affect nighttime sleep and daytime functioning before formulating a treatment plan.

A thorough interview and psychiatric screening measures (given the high comorbidity of psychiatric disorders and sleep changes) are required before proceeding with evidence-based pharmacological or therapeutic interventions. Careful monitoring of the patient ensures adherence and effectiveness. Slowly titrate the medications that exacerbate sleep and daytime functioning problems. Psychoeducational interventions regarding sleep hygiene (eg, consistent bedtime, morning awakening, caffeine and nicotine use, exercise, cognitive activities, and avoidance of protracted time in bed not sleeping) are a useful early step. Because sleep disorders are related to physical problems such as cardiovascular and respiratory disorders, physicians need to identify and treat early in the process.

Polysomnography in patients with AD may be difficult to obtain and to interpret. There is progressive slowing of electroencephalographic activity in AD, and this may make ascertainment of sleep stages and discrimination between wakefulness and sleep difficult.

Nonpharmacological interventions

Light physical exercise and better sleep hygiene (eg, less time spent in bed during the day, better management of nighttime incontinence) significantly improved nighttime actigraphic measures¹⁷; daily physical and social activities within the nursing home improved sleep in patients with AD¹⁸; and light exposure therapy delayed/corrected peak activity levels, consolidated nighttime sleep, and made circadian rhythms more robust.¹⁹

In one community-based study, patients with AD and caregivers were given a 6-week psychoeducational intervention on healthy sleep habits; sleep journals, actigraphy, and standard questionnaires were used as follow-up measures. Light exercise, sleep hygiene, and light therapy were emphasized, and results indicated improvement in sleep consolidation and delayed institutional placement.²⁰ In a recent meta-analysis of light therapy, Van der Ploeg and colleagues²¹ concluded that there was evidence of improvement in patients with AD who were in a nursing home environment. However, significant methodological issues persist, which limit the generalizability of the data. See Table 1 for suggested nonpharmacological interventions.

Pharmacological interventions

A number of studies have evaluated the efficacy of pharmacological interventions for the treatment of sleep disorders in patients with AD. The findings suggest that patients with AD show diminished levels of the hormone melatonin in the cerebrospinal fluid compared with normal controls.^22,23 Deficiencies in melatonin have been linked to production of free radicals, which can damage neurons in the brain.²⁴ However, the data on the efficacy of melatonin have been limited to small sample sizes.

The use of benzodiazepines in patients with AD is fraught with problems because of the increased risk of sedation, daytime fatigue, confusion, and rebound insomnia. Short-term use for crisis management is suggested. Acetylcholinesterase inhibitors are commonly prescribed for patients with AD. However, donepezil, rivastigmine, and galantamine may increase insomnia and nightmares.^25-28 See Table 2 for pharmacological interventions that might be used for the management of sleep issues in dementia.

CASE VIGNETTE

Mr X, a significantly overweight (BMI = 35) 72-year-old white man, presents at the outpatient clinic with a 1-year history of insidious decline in cognitive functioning. He has been living independently for the past 3 years following the death of his wife. His family checks on him regularly and helps monitor his medications for hypertension and high cholesterol-he is occasionally nonadherent. He has become more withdrawn and dysphoric following the loss of his wife and has relinquished many activities and hobbies.

He reports chronic snoring and daytime fatigue, although he naps frequently during the day. A recent fall led to a severely bruised hip for which he is taking pain medication. He drinks 2 or 3 beers most evenings but will have more on occasion. His family reports some subtle personality changes, including increased irritability, and they have received a number of phone calls in the middle of the night or in the evening from the patient, who seemed confused and disoriented.

This case illustrates the complexities in the assessment and treatment of sleep issues in patients with known or suspected cognitive impairment. The insidious onset of cognitive impairment, apathy, social withdrawal, and evening confusion and irritation is common in early-stage AD. However, some of Mr X’s symptoms could be attributed to depression or chronic bereavement; thus, a thorough psychiatric evaluation is warranted. Medication nonadherence and alcohol use are potential contributing factors and, given the minimal level of supervision, might have led to changes in mentation and recent falls.

With regard to sleep, Mr X has a number of risk factors for apnea, including snoring, daytime fatigue, and obesity; thus, a formal sleep study should be considered. Treatment of obstructive sleep apnea can lead to improvement in sleep and cognition. The evening confusion may represent sundowning; these episodes are among the most frequent reasons for psychiatric consultation and eventual placement in long-term care facilities.

It may be most useful in this case to stagger the interventions so that a formal evaluation of dementia follows appropriate assessment and treatment of mood, sleep, and general health. If AD is diagnosed, long-term treatment planning, including pharmacological interventions such as acetylcholinesterase inhibitors, assisted living, home health support, and behavioral interventions, should be considered. Table 3 provides an example of a treatment plan for Mr X, which can be used for any patient who presents with similar symptoms.

Conclusions

Sleep disorders represent a significant problem in patients with AD due to the potential for exacerbation of symptoms and even a causal relationship to dementia. Clinicians are encouraged to develop deliberate assessment strategies when working with AD patients and their families. A review of current medications and their potential to contribute to sleep problems, identification and treatment of secondary psychiatric issues, and the impact of symptom modification medications should be a regular part of the evaluation process. Formal sleep questionnaires, polysomnography, and sleep diaries may aid in the identification of sleep disorders.

Behavioral strategies that can be consistently implemented in the patient’s environment are effective. Light exercise, social and cognitive stimulation, proper sleep hygiene, and consideration of bright light therapy or melatonin may prove an additive step in treatment.

Disclosures:

Dr Dodzik is Clinical Neuropsychologist and Dr Khan is Pediatric and Adult Neurologist at the Fort Wayne Neurological Center in Fort Wayne, IN. The authors report no conflicts of interest concerning the subject matter of this article.

References:

1. Bliwise DL, Mercaldo MD, Avidan AY, et al. Sleep disturbance in dementia with Lewy bodies and Alzheimer’s disease: a multicenter analysis. Dement Geriatr Cogn Disord. 2011;31:239-246.

2. McCurry SM, Logsdon RG, Teri L, et al. Characteristics of sleep disturbance in community-dwelling Alzheimer’s disease patients. J Geriat Psychiatry Neurol. 1999;12:53-59.

3. Vitiello MV, Borson S. Sleep disturbances in patients with Alzheimer’s disease: epidemiology, pathophysiology and treatment. CNS Drugs. 2001;15:777-796.

4. Rohr JH, Huang Y, Bero AW, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer’s disease pathology. Sci Transl Med. 2012;4:150ra122.

5. Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age, and senile dementia. Brain Res. 1985;342:37-44.

6. Ligouri C, Romigi A, Nuccetelli M, et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer’s disease. JAMA Neurol. 2014;71:1498-1505.

7. Cipriani G, Lucetti C, Danti S, Nuti A. Sleep disturbances and dementia. Psychogeriatrics. 2015;15:65-74.

8. Yaffe K, Laffan AM, Harrison SL, et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011;306:613-619.

9. Sterniczuk SR, Theou O, Rusak B, Rockwood K. Disturbances to the sleep-wake cycle predict future diagnoses of Alzheimer’s disease. New Orleans, LA: Society for Neuroscience; 2012. Program No. 799.11 2012 Neuroscience Meeting Planner.

10. Lim AS, Kowgier M, Yu L, et al. Sleep fragmentation and the risk of incident of Alzheimer’s disease and cognitive decline in older persons. Sleep. 2013;36:1027-1032.

11. Vitiello MV, Bliwise DL, Prinz PN. Sleep in Alzheimer’s disease and the sundown syndrome. Neurology. 1992;42:83-93.

12. Moran M, Lynch CA, Walsh C, et al. Sleep disturbance in mild to moderate Alzheimer’s disease. Sleep Med. 2005;6:347-352.


13. Ancoli-Israel S, Klauber MR, Butters N, et al. Dementia in institutionalized elderly: relation to sleep apnea. J Am Geriat Soc. 1991;39:258-263.

14. Crooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med. 2009;5:305-309.

15. Sinforiani E, Terzaghi E, Pasotti C, et al. Hallucinations and sleep-wake disturbances in Alzheimer’s disease: a questionnaire based study in 218 patient. Neurologic Sci. 2007;28:96-99.

16. Anderson KN, Jamieson S, Graham AJ, Shneerson JM. REM sleep behavior disorder treated with melatonin in a patient with Alzheimer’s disease. Clin Neurol Neurosurg. 2008;110:492-495.

17. Alessi CA, Yoon EJ, Schnelle JF, et al. A randomized trial of a combined physical activity and environmental intervention in nursing home residents: do sleep and agitation improve? J Am Geriatr Soc. 1999;47:784-791.

18. Naylor E, Penev PD, Orbet L, et al. Daily social and physical activity increases slow-wave sleep and daytime neuropsychological performance in the elderly. Sleep. 2000;23:87-95.

19. Ancoli-Israel S, Martin JL, Kripke DF, et al. Effect of light treatment on sleep and circadian rhythms in demented nursing home patients. J Am Geriatr Soc. 2002;50:282-289.

20. McCurry SM, Gibbons LE, Logsdon RG, et al. Nighttime insomnia treatment and education for Alzheimer’s disease: a randomized, controlled trial. J Am Geriatr Soc. 2005;53:793-802.

21. Van der Ploeg ES, O’Conner DW. Methodological challenges in studies of bright light therapy to treat sleep disorders in nursing home residents with dementia. Psychiatry Clin Neurosci. 2014;68:777-784.

22. Skene DJ, Vivien-Roels B, Sparks DL, et al. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer’s disease. Brain Res. 1990;528:170-174.

23. Uchida K, Okamoto N, Ohara K, et al. Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res. 1996;717:154-159.

24. Srinivasan V, Pandi-Perumal SR, Cardinall DP, et al. Melatonin in Alzheimer’s disease and other neurodegenerative disorders. Behav Brain Func. 2006; 2:15.

25. Roger SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Arch Intern Med. 1998;158:1021-1031.

26. Ross JS, Shua-Haim JR. Aricept-induced nightmares in Alzheimer’s disease: 2 case reports. J Am Geriatr Soc. 1998;46:119-120.

27. Rosier M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomized controlled trial. BMJ. 1999;318:633-638.

28. Tariot PN, Solomon PR, Morris JC, et al for the Galantamine USA-10 Study Group. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology. 2000;54:2269-2276.