APPENDIX C
Sleep in the older adult with dementia
Sonia Ancoli-Israel1, Donald L. Bliwise2, PhD, Jennifer L. Martin3, Michael V. Vitiello4,
Kristine Yaffe5, Phyllis C. Zee6
for the Neuropsychiatric Syndromes Professional Interest Area of ISTAART
aDepartments
bDepartment
of Psychiatry and Medicine, University of California, San Diego, La Jolla, California, 92093, USA
of Neurology, Emory University School of Medicine, Wesley Woods Health Center, 1841 Clifton Road, Room 509,
Atlanta, Georgia 30329, USA
cVA
Greater Los Angeles Healthcare Geriatric Research, Education and Clinical Center, Los Angeles, CA 91343 USA and
University of California, Los Angeles and David Geffen School of Medicine, Los Angeles, CA 90095 USA.
dDepartment
of Psychiatry & Behavioral Sciences, University of Washington, Seattle WA 98195-6560 USA
eDepartment
of Psychiatry, University of California, San Francisco, Box VAMC - 181 , San Francisco, CA. 94143, USA
fDepartment
of Neurology, Feinberg School of Medicine, Northwestern University,
710 North Lakeshore Drive, 11th floor, Chicago, Ill 60611 USA
1
Abstract
Many factors contribute to sleep impairment in dementia, including problems with insomnia, obstructive
sleep apnea (OSA), REM behavior disorder (RBD), restless legs syndrome (RLS), circadian rhythm
disorders and being institutionalized. The association between insomnia and dementia is most likely
bidirectional such that each impacts the other. OSA is very common in older adults and even more
common in those with dementia. New research suggests that OSA also puts older adults at greater risk for
developing dementia and treatment of OSA may improve cognitive function. RBD and RLS are also very
common although more difficult to diagnosis as they are based on self-report. Circadian rhythm disorders,
particularly irregular sleep wake rhythm disorder (ISWRD) is characterized by the relative absence of a
circadian pattern in an individual’s sleep-wake cycle and is more commonly seen in institutionalized older
adults with Alzheimer’s disease. There are gaps in knowledge about sleep disturbances in dementia at
every level from mechanisms to effective treatments.
2
among AD patients,(6;7) and treatment of
anxiety may therefore result in improved sleep.
It is also possible that sleep disruptions result
from CNS pathology and damage to the specific
brain structures and pathways related to sleep
regulation and sleep timing. In addition to the
direct impact of AD pathology on sleep, several
comorbidities are relevant. While nighttime
sleep disturbances may be reported frequently,
they are likely to be caused or exacerbated by
other sleep disorders, such as sleep disordered
breathing, restless legs syndrome, and other
medical and psychiatric comorbidities. In
addition, many medications taken to manage
comorbidities can have a negative impact on
sleep, either by increasing alertness at night or
by increasing sleepiness during the day. Finally,
AD patients tend to be more socially isolated
and less physically active than individuals
without dementia, and the lack of sufficient
stimulation during the daytime can contribute to
irregularities in sleep that may present as
insomnia.
Introduction
Many factors contribute to sleep impairment in
dementia, including problems with insomnia,
obstructive sleep apnea, REM behavior disorder,
restless legs syndrome, circadian rhythm
disorders and, in special populations, being
institutionalized. This paper from the
Neuropsychiatric Syndromes Professional
Interest Area (NPS-PIA) Sleep Workgroup will
review the definition, epidemiology, and
treatment of each of these and will include
information on what is known about each in
dementia. A suggested research agenda will
complete the review.
Insomnia
Insomnia is defined as a difficulty initiating or
maintaining sleep, or sleep that is poor in quality
or non-restorative in nature. A diagnosis of
insomnia requires that the sleep difficulty lasts
more than one month, and that it is sufficiently
severe to impact functioning. One caveat of
insomnia research in dementia is that a precise
definition of "sleep complaint" has not been
developed, as many patients with dementia
cannot accurately report how they are sleeping.
Treatment studies of insomnia in dementia have
focused largely on behavioral interventions due
to concerns about adverse effects of
pharmacotherapy for insomnia among AD
patients.(5;8) Such treatments have included
timed exposure to bright light,(9;10) as well as
efforts to structure the sleep schedule and
increase daytime activity.(11)
The association between insomnia and dementia
is most likely bidirectional such that dementia
impacts sleep quality leading to insomnia, and
insomnia then negatively impacts cognitive
functioning. Among patients with dementia,
insomnia may be a symptom of the dementing
illness, generally from neurodegeneration. In
addition, long term sleep quality disturbances
may predispose to cognitive impairment.(1-3)
Finally, insomnia may result from a comorbid
condition. Itt is well known that insomnia is
more common among individuals with any
medical and/or psychiatric comorbidity than
among older adults without comorbidities.
Whatever the direction of the association
between dementia and insomnia, studies focused
on dementia suggest that nearly one third of
caregivers report that patients with AD in their
care suffer from "insomnia."(4)
Future research should focus on developing and
validating methods for evaluation of insomnia in
dementia patients. Studies are also needed to
evaluate the safety and efficacy of
pharmacotherapy for insomnia in dementia
patients, and to adapt and test evidence-based
nonpharmacological interventions for insomnia
among AD patients.
Obstructive sleep apnea
There are two types of sleep apnea, obstructive
and central. Obstructive sleep apnea (OSA) is
common in the general population, but is most
prevalent in older adults. Affected persons
experience repeated events of upper airway
obstruction during sleep that result in reduced
airflow (hypopnea) or complete loss of airway
patency (apnea). OSA is commonly associated
with obesity and the most common presenting
For some patients, cholinesterase inhibitors may
contribute to nighttime sleep disruption
(insomnia).(5) Some studies suggest that
insomnia symptoms are related to anxiety
3
symptoms include loud snoring, gasping
arousals, breathing pauses during sleep and
daytime sleepiness. Although obesity is
associated with OSA across all age groups, it is
important to recognize that this association is
weaker in older adults. In central sleep apnea,
there is a reduction in the effort to breathe which
leads to diminished or absent airflow and is
commonly found in patients with congestive
heart failure or due to respiratory suppressant
medications, such as narcotics. In addition to the
presenting symptoms and physical examination,
polysomnography (PSG) is needed to establish
the diagnosis of sleep apnea.(12)
Rapid Eye Movement Behavior
Disorder (RBD)
It is now widely appreciated that the
synucleinopathies (including Dementia with
Lewy Bodies and broadly defined Parkinsonism)
are associated with a higher likelihood of
disturbed sleep, relative to amyloidopathies such
as AD.(23) Sleep disturbance in AD is likely a
late stage disease manifestation whereas in
Parkinsonism, it may occur much earlier in the
clinical course,(24) or perhaps even be a
prodrome (see below). RBD patients
demonstrate dream enactment behavior during
REM sleep in which they quite literally act out
their dreams.(25) Often the behaviors have a
violent or aggressive quality and involve
punching, fighting or kicking. Occasionally
vocalizations are present as well; these often
have syntactical structure and are germane to the
behaviors demonstrated. Serious injuries to the
patient and/or their bed partners have been
reported (lacerations, fractures). The episodes
are linked temporally to REM sleep and
typically show a pattern of distribution during
the night that mirror the occurrence of REM
(more common later in the night). They may
occur as frequently as multiple times per night to
a far more sporadic presentation (e.g., once a
month or less).(26) Although caregiver
observations alone may be sufficient to make the
diagnosis, overnight polysomnography with
video monitoring provides a deeper
understanding of precisely what time of night
and from what stage of sleep the episodes arise,
and the extent of abnormally elevated
electromyographic activity recorded from
various muscle groups (typically limbs).(27)
PSG also allows for differentiation of RBD from
nocturnal seizure activity and can indicate
whether the episodes occur at the termination of
apneic episodes.(28) On the basis of
observations made in clinical case series, there is
some suggestion that RBD may predicate the
onset of Parkinsonism by as long as two
decades.(29) However, whether RBD suspected
to occur in as much as 1% of the general
population in middle-aged individuals(30)
portends the development of synucleinopathies
remains unknown and represents an important
research topic. Current treatments in non-AD
patients involve clonazepam and melatonin.
The negative impact of untreated OSA on
cardiorespiratory, cerebrovascular, metabolic
and cognitive function has been well
established.(13-15) These adverse health effects
are particularly relevant to older adults, a
population at elevated risk for cardiometabolic
disorders and dementia. Studies estimate the
prevalence of OSA to be approximately 20-25%
in older adults,(16;17) and up to 60% in older
adults with dementia.(18) Cognitive
impairments associated with sleep apnea include
impaired memory for verbal and visuospatial
tasks, reduced psychomotor speed and impaired
executive function. Older women with sleep
disordered breathing were more likely to
develop mild cognitive impairment or
dementia.(15) Thus, sleep apnea may represent a
potentially reversible component of cognitive
impairment in older adults.(19)
Continuous positive airway pressure (CPAP) is
an effective treatment of OSA for most patients,
including older adults and patients with
Alzheimer’s Disease (AD) and patterns of
adherence are similar to that of middle aged
adults.(20) However, younger patients who have
difficulty tolerating CPAP, especially those with
mild to moderate sleep apnea, may benefit from
an oral appliance which opens the airway by
advancing the mandible.(12) Effective treatment
of sleep apnea with CPAP has been shown to
reduce daytime sleepiness and improve
cardiovascular and metabolic function.
Promising recent evidence indicates that
treatment of sleep apnea with CPAP may
improve some aspects of cognitive function in
mild-moderate Alzheimer’s Disease (AD).(21)
as well as slowing the deterioration of cognitive
function in patients with AD.(22)
4
However, large-scale, randomized, double-blind,
placebo-controlled trials with PSG verification
have yet to occur and should be pursued.
must thus remain inferential, but nonetheless
hold important implications for pharmacologic
management. For example, atypical antipsychotics exerting dopamine blockade (e.g.,
risperidone, quetiapine) often increase
wandering, falls and in one study, PLMS,(37)
suggesting that these medications be used
judiciously in dementia patients with a
predisposition for RLS. Additionally wandering
AD patients have been demonstrated to have
reduced dopamine uptake in caudate and
putamen relative to non-wandering AD
patients,(38) findings resembling those seen in
RLS.(39)
Restless Legs Syndrome (RLS)
RLS is a sensory/motor disorder that is
characterized by disagreeable sensations in the
legs that are worse at rest and during periods of
inactivity, are relieved by movement, and are
worse in the evening (and thereby causing
disturbed sleep).(31) The prevalence of the
condition increases with age with prevalence
figures of 15-20% typically noted in older
persons ages 60 and above relative to about 5%
in middle-aged adults.(32) {Aguera-Ortiz, 2011
29759 /id} Associations with deficient iron
storage (low serum ferritin and/or elevated
soluble transferrin receptor) have been reported.
RLS overlaps considerably with NPSG
measurements of periodic leg movements in
sleep (PLMS). Often the patient’s spouse or bed
partner may be aware of the periodic (typically
once every 20-30 seconds) movements, which
may total in the hundreds throughout the night.
Although skepticism exists about the validity of
the syndrome, the independent validation of
single nucleotide polymorphisms by two
separate research groups,(34;35) associated with
RLS and PLMS suggest the condition has a
verifiable genetic basis. Furthermore, the
presence of at risk alleles predisposing for both
RLS and low serum ferritin suggest a plausible
contributing pathophysiologic substrate. In nondemented adults, the first line treatment has
typically involved the FDA approved dopamine
agonists (pramipexole, ropinirole) or GABAergic medications (gabapentin, enacarbil). Other
non-FDA approved medications such as levodopa, opioids, and gabapentin are sometimes
used off-label..
Taken together, the data suggest a diverse
research agenda seeking to a) determine
genotypic risk for wandering and pacing in
dementia patients, and b) conduct intervention
studies that target pharmacologic management
of RLS as potential treatments for wandering
and pacing in AD. This is particularly needed
when those behaviors have been refractory to
treatment by conventionally used medications.
Irregular sleep wake rhythm
disorder
Irregular sleep wake rhythm disorder (ISWRD)
is characterized by the relative absence of a
circadian pattern in an individual’s sleep-wake
cycle. Alterations in the central regulation of
circadian rhythms when combined with
decreased levels of light exposure and
social/physical activity levels likely contribute to
the increased prevalence of ISWRD in older
adults. While the prevalence of ISWRD
increases in later life, age itself is not an
independent risk factor for ISWRD. Rather, the
age associated increase in medical, neurological
and psychiatric disorders have been shown to be
the greatest contributors to the development of
ISWRD.(40) The disorder is more commonly
seen in institutionalized older adults and most
commonly in patients with Alzheimer
disease.(40)
The importance of RLS for sleep in dementia
involves the potential role that the condition may
play in specific syndromes such as wandering
and pacing. The 2003 NIH Workshop,(31)
raised the possibility that late afternoon/early
evening pacing, the time of day when these
behaviors are most likely to occur,(36) could
represent the behavioral component of RLS in
patients whose cognitive status does not allow a
clear verbal expression of their symptoms. Data
on whether the wandering AD patient has RLS
ISWRD is characterized by the lack of a clearly
defined circadian sleep-wake rhythm, such that
sleep and wake periods are distributed
throughout the 24 hours. Daytime is often
composed of multiple naps, whereas nighttime
sleep is severely fragmented and shortened but
5
the total amount of sleep obtained over a 24hour period may be normal for the age of the
patient.(41) Consequently the primary symptoms
of ISWRD are chronic sleep maintenance
insomnia and excessive daytime sleepiness.
pharmacologic agents has not been well studied,
particularly in the elderly with AD. Interventions
aimed at restoring or enhancing exposure to the
various SCN time cues, or “zeitgebers” are
critical. Therefore, a mixed modality behavioral
approach to consolidate nocturnal sleep
(improve sleep hygiene; decrease nocturnal light
and noise levels) and enhance daytime alertness
(increase daytime light exposure; increase social
and physical activity) is recommended as the
mainstay treatment for ISWRD.(9;10) Patients
should be exposed to bright light during the day,
and bright light should be avoided in the evening
and at night.(48;49) Daytime physical and social
activities should also be strongly
encouraged.(50-53) Treatment success can be
highly variable and requires modification to
individual needs and circumstances.
It has been postulated that both dysfunction of
the central processes responsible for the
generation of the circadian rhythm, as well as
decreased exposure to external synchronizing
agents, or “zeitgebers”, such as light and social
activities play a role in the development and
maintenance of irregular sleep-wake rhythms.
The findings of age related loss of neurons and
functional activity within the suprachiasmatic
nucleus (SCN),(42) and a further decrease in the
number of neurons within the SCN in patients
with Alzheimer disease (AD)(43;44) suggest
that neurodegeneration of the SCN may
contribute to the development of ISWRD in
older adults.
While there is currently no direct support for a
genetic basis for ISWRD, several lines of
evidence are emerging that suggest that the
sleep disturbance seen in AD is at least partially
based on genetic factors .(47) Some research
also suggests that having disrupted circadian
rhythms increases the risk of cognitive
impairment.(54) Further research will be needed
to determine if certain mutations or
polymorphisms of circadian clock genes play a
role in the development of ISWR, which may
lead to possible prevention and improved
treatment of this circadian-based disorder.
Further, older adults, especially those with
chronic medical and neurological disorders, are
often exposed to lower levels of daytime light
than their younger counterparts.(45;46) This
reduction may be exacerbated by age-related
visual disorders, such as cataracts which can
further attenuate the effect of ambient light on
the SCN. The impact of diminished exposure to
circadian synchronizing agents, such as light and
activity is most pronounced in patients with AD.
Low light levels and lack of structured social
and physical activities in long term care facilities
may further decrease the amplitude of circadian
rhythms.
Sleep in the Nursing Home
Sleep in nursing home patients is very
fragmented with most patients sleeping on
average only 40 minutes per hour. Many patients
are never asleep for a full hour throughout the
night and are not awake for a full hour
throughout the day.(55;56) In addition, about
half of the residents wake up at least 2-3 times
per hour each night. The primary sleep disorders
discussed above are also very prevalent in the
nursing home population, particularly OSA, yet
these disorders are rarely diagnosed or treated.
Individuals with ISWRD typically present with
the principal symptoms of sleep maintenance
insomnia and excessive daytime sleepiness.
Diagnosis is made by the clinical history of
fragmented sleep and wake periods, usually
along with chronic complaints of sleep
maintenance insomnia and excessive daytime
sleepiness.(47) ISWR should always be
considered in the differential diagnosis of sleep
disturbances in older adults with dementia.
Overall, studies on sleep in dementia patients in
nursing homes suggest that physical activity
needs to be increased during the day, exposure
to light needs to be increased during the day and
decreased at night, and noise levels need to be
decreased at night.(57) Improving the
The primary goals of treatment are to
consolidate sleep during the night and
wakefulness during the day. Studies of the
effectiveness of pharmacologic treatments for
ISWRD have generally yielded negative or
inconsistent results. Furthermore, the safety of
6
environment can have a positive impact on sleep
in this population. However, studies of other
treatments are sorely lacking in this group.
effectiveness of sleep apnea therapy
(positive airway pressure) on
progression of cognitive decline and/or
improvement of cognitive function in
mild to moderate AD.
3. Randomized controlled trials to assess
the comparative long-term efficacy of
specific pharmacological and
nonpharmacological approaches to sleep
management on multiple outcome
measures, including; sleep, daytime
function and behavioral disturbances.
4. Examining the prognostic value of RBD
in the general population as a potential
predictor of future neurodegenerative
disease.
5. Examining whether wandering in
dementia is more likely in individuals
with genetic predisposition for RLS and
whether medications known to be
effective in RLS would be effective in
the treatment of wandering in dementia
patients who carry that genetic risk.
Research Agenda
There are gaps in knowledge about sleep
disturbances in dementia at every level from
mechanisms to effective treatments.
Standardized assessments for sleep disorders in
AD need to be developed. Both behavioral
treatments and pharmacological treatments need
to be tested in patients with dementia to see if
safety and efficacy matches that seen in nondemented older adults.
Specific studies that are needed include:
1. Developing and validating methods for
evaluating insomnia in dementia
patients
2. Given the preliminary finding that
treatment of sleep apnea can potentially
delay the progression of cognitive
impairment, there is need for a
multicenter randomized controlled study
to determine the efficacy and
7
Disclosures
Ancoli-Israel: Consultant to Johnson & Johnson, Merck, Pfizer, Philips/Respironics, Purdue Pharma LP,
sanofi-aventis; Bliwise: Consultant to Ferring; Martin: None; Vitiello: Consultant for sanofi-aventis,
Ferring and Jazz; Yaffe: DSMBs for Pfizer, Medivation, NIA and Takeda and has served as a consultant
for Novartis; Zee: Consultant to sanofi-aventis, Purdue Pharma LP, Merck, Philips/Respironics, Jazz,
UCB.
Acknowledgments
Supported by NIA AG08415 (SAI); NS-050595 (DLB); NIA K23 AG028452, VA RR&D 1RX00013501, VAGLAHS GRECC (JLM); AG031126, AG025515, AG030484, CA116400, NR011400, HP19195
(MVV); R01 AG026720 (KY); P01 AG11412, R01 HL67604, R01 HL069988 (PCZ); R01 AG026720
(KF)
8
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