Curr Psychiatry Rep (2015) 17:97

DOI 10.1007/s11920-015-0631-8

SLEEP DISORDERS (P GEHRMAN, SECTION EDITOR)

Sleep, Cognition and Dementia

Verna R. Porter 1 & William G. Buxton 2 & Alon Y. Avidan 3

# Springer Science+Business Media New York (outside the USA) 2015

Abstract The older patient population is growing rapidly
around the world and in the USA. Almost half of seniors over
age 65 who live at home are dissatisfied with their sleep, and
nearly two-thirds of those residing in nursing home facilities
suffer from sleep disorders. Chronic and pervasive sleep com-
plaints and disturbances are frequently associated with exces-
sive daytime sleepiness and may result in impaired cognition,
diminished intellect, poor memory, confusion, and psychomo-
tor retardation all of which may be misinterpreted as dementia.
The key sleep disorders impacting patients with dementia in-
clude insomnia, hypersomnolence, circadian rhythm mis-
alignment, sleep disordered breathing, motor disturbances of
sleep such as periodic leg movement disorder of sleep and
restless leg syndrome, and parasomnias, mostly in the form
of rapid eye movement (REM) sleep behavior disorder
(RBD). RBD is a pre-clinical marker for a class of
This article is part of the Topical Collection on Sleep Disorders
* Alon Y. Avidan
avidan@mednet.ucla.edu
Verna R. Porter
vporter@mednet.ucla.edu
William G. Buxton
wbuxton@mednet.ucla.edu
1
Department of Neurology, UCLA Mary S. Easton Center for
Alzheimer’s Disease Research, David Geffen School of Medicine at
UCLA, 10911 Weyburn Ave., Suite 200, Los
Angeles, CA 90095-7226, USA
2
Department of Neurology, David Geffen School of Medicine at
UCLA, 300 UCLA Medical Plaza, Suite B200, Los
Angeles, CA 90095-6975, USA
3
Department of Neurology, UCLA Sleep Disorders Center, David
Geffen School of Medicine at UCLA, 710 Westwood Blvd., Room
1-145 RNRC, Los Angeles, CA 90095-1769, USA
neurodegenerative diseases, the Bsynucleinopathies^, and re-
quires formal polysomnographic evaluation. Untreated sleep
disorders may exacerbate cognitive and behavioral symptoms
in patients with dementia and are a source of considerable
stress for bed partners and family members. When left untreat-
ed, sleep disturbances may also increase the risk of injury at
night, compromise health-related quality of life, and precipi-
tate and accelerate social and economic burdens for
caregivers.
Keywords Sleep . Sleep disorders . Dementia .
Neurodegenerative disease . Sun-downing . Aging . REM
sleep behavior disorder . Alpha synucleinopathies .
Alzheimer’s dementia
Introduction
Sleep is a critical function that is necessary for optimal cogni-
tive functioning at all ages, but as age advances, there is an
increased likelihood of sleep disturbances resulting in changes
to the quality and quantity of sleep [1, 2, 3••]. As age in-
creases, a number of changes occur to disrupt sleep that may
result in fatigue, irritability, headaches, depression, excessive
daytime sleepiness, and changes in motor and cognitive func-
tioning among other effects [1]. Sleep disturbances are also
common to many neurodegenerative diseases and may in-
clude difficulty with insomnia, hypersomnia, parasomnias,
excessive and abnormal nocturnal motor activity, disruption
of circadian rhythmicities, and respiratory dysregulation [1, 4,
5]. As the geriatric population continues to increase, so does
the prevalence of dementia. In the year 2000, there were a
reported 34 million Americans over the age of 65 years, and
it is anticipated that by the year 2025, this number will nearly
double to more than 62 million [6]. In 2010, it was estimated
97 Page 2 of 11
that worldwide, 35.6 million people were affected by demen-
tia with an anticipated near-doubling of that number every
20 years to a projected 65.7 million affected in 2030 and
115.4 million affected in 2050 [7]. The medical and economic
impact of dementia is profound, and it was estimated that as of
2010, the worldwide economic impact of dementia had
reached an estimated annual cost of greater than $604 billion
(USD); this is equivalent to 1 % of the world’s gross domestic
product [7, 8]. Effective management of sleep disturbances in
the elderly population with dementia has important social and
clinical implications that may help bridge the gap between
disease modifying therapies and current interventions de-
signed to promote optimal cognitive functioning and delay
progression of dementia [9–11]. The etiology of different neu-
rodegenerative conditions is diverse and complex. Similarly,
the etiologies of different sleep disturbances within these dif-
ferent neurodegenerative conditions also are varied [10]. As
our understanding of the pathophysiology of different neuro-
degenerative conditions improves, so will our understanding
of the effects of these conditions on the sleep-wake cycle of
the aging adult and the varied presentation of sleep distur-
bances in different neurodegenerative conditions.
Sleep and Aging
Sleep is a complex phenomenon with physiological roots in
nervous system regions such as the hypothalamus, brainstem,
and thalamus [6]. At least one chronic sleep complaint has
been reported in more than 50 % of community-dwelling
adults over the age of 65 and in nearly two-thirds of nursing
home residents [6, 12•]. The most common complaints are
inability to initiate and maintain asleep (insomnia), followed
by chronic complaints of excessive daytime sleepiness (EDS)
resulting in frequent naps [1, 6, 11].
The quality and architecture of sleep clearly changes with
healthy aging, and insomnia and excessive daytime sleepiness
are frequently reported in the elderly population. Sleep also
increasingly fragments with age and is characterized by more
nighttime awakenings and an increased desire for daytime
naps [6, 12•]. The homeostatic mechanisms and circadian
rhythms and architecture of sleep also alter with normal aging
[13]. This includes reductions in slow-wave sleep (SWS) per-
cent and spectral power of sleep in the electroencephalogram
(EEG), number and amplitude of sleep spindles, rapid eye
movement (REM) concentration, and amplitude of circadian
rhythms and phase advance (earlier onset) of the brain’s cir-
cadian clock [14].
Of interest, nearly all people over the age of 60 have
disrupted sleep architecture and decreased slow wave sleep
(SWS); and SWS is critical for appropriate consolidation of
long-term memory. Further, aging is associated with regional
brain atrophy in midline frontal lobe regions that is associated
Curr Psychiatry Rep (2015) 17:97
with cognitive decline [15••, 16]. A recent study showed that
these factors may be linked since age-related medial prefrontal
cortex gray matter (mPFC) atrophy is associated with reduced
NREM slow-wave activity (SWA) that further appears to ac-
count statistically for the impairment of overnight sleep-
related memory consolidation. Together, these data support a
model in which age-related mPFC atrophy decreases SWA,
which disrupts long-term memory consolidation. Such find-
ings suggest that sleep disruption in the elderly, accompanied
by structural brain changes, represents a contributing factor to
age-related cognitive decline in older individuals [17]. Sleep is
also thought to serve a variety of physiological functions in-
cluding restoration of tissues and brain-metabolite clearance.
Recently, the Bglymphatic system^ has been proposed in
mouse models to facilitate biomolecule clearance using a con-
vective flow between the cerebrospinal fluid (CSF) and inter-
stitial fluid (ISF) to remove toxic metabolites in the brain
[18••]. There have been reports in mice that this glymphatic
system is strongly activated by sleep and may potentially help
to clear toxic proteins known to contribute to the pathology of
Alzheimer’s disease (AD) such as beta-amyloid (Aβ) [18••,
19••]. Additionally, soluble Aβ 40 and 42 levels have been
shown to be consistently higher during wakefulness and lower
during sleep; with age and with increasing amyloid deposi-
tion, as determined by PiB-PET scans, this sleep-wake varia-
tion decreases [15••, 20•, 21•]. This diurnal Aβ pattern has
also been observed in murine models (e.g., human amyloid
precursor protein (APP) transgenic mice, Tg2576, that devel-
op amyloid deposition) indicating that chronic sleep restric-
tion significantly enhances brain soluble concentrations of Aβ
[22]. APP transgenic mice also have higher concentrations of
Aβ levels during wakefulness, and these levels decrease dur-
ing sleep [22]. The investigators also showed that the use of an
orexin-receptor dual antagonist to induce sleep decreased Aβ
plaque deposition; whereas sleep deprivation increased ISF
concentrations of Aβ and accelerated Aβ deposition into
plaques [22]. Recent human studies have suggested that Aβ
accumulation disrupts human non-REM sleep (NREM) and
associated slow waves (SWA), which may contribute to
hippocampal-dependent cognitive decline [17, 23••]. This
provides for an interesting theoretical model in which Aβ
deposition is associated with diminished NREM sleep and
SWA, with NREM sleep disruption reciprocally promoting
an increased synaptic tone and metabolic activity in the brain
that in turn leads to the accumulation of toxic metabolites
(Aβ) in the CSF, resulting in a subsequent Aβ plaque depo-
sition that further worsens sleep [15••, 22, 23••].
The notable role of sleep in facilitating cognitive function-
ing, memory stabilization, integration, and consolidation has
long been recognized by psychological scientists [3••]. Con-
versely, inadequate sleep has been recognized even in middle-
aged adults to contribute to disruption in attention, executive-
control tasks, working memory, episodic memory, and an
Curr Psychiatry Rep (2015) 17:97
increased frequency of cognitive complaints [3••]. Prolonged
accumulation of sleep debt also impairs physical, mental, and
emotional well-being and may give rise to the emergence of
behavioral and mood disorders [6].
The etiology of sleep disturbances in the elderly may be
divided into internal (patient-related) and external
(environmental) factors. Internal factors consist of primary
sleep disorders such as obstructive sleep apnea [24–26], peri-
odic limb movements of sleep (PLMDS) [27], restless legs
syndrome (Willis Ekbom Disease, WED) [28, 29], and
parasomnias (e.g., rapid eye movement sleep behavior disor-
der, RBD) [30–32]. Sleep disturbances in the elderly may also
arise because of comorbid medical conditions, psychiatric
conditions, polypharmacy, or other psychosocial factors [11].
Conversely, the presence of sleep disorders may also exacer-
bate underlying medical and psychiatric conditions [6]. Large
prospective studies have also suggested that excessive day-
time sleepiness may be independently associated with an in-
creased risk of cognitive decline in the elderly population, thus
suggesting a potential target for early intervention [2, 33–35].
External factors may include increased ambient lighting dur-
ing the night, excessive noise in the sleep environment, or
temperatures that are too warm or too cold. These external
factors are relatively simple to remedy as one formulates a
treatment plan [36].
Sleep Disturbances in Patients With
Neurodegenerative Disease
Dementia (major neurocognitive disorder), as defined by
DSM-V criteria, is characterized by a substantial cognitive
decline from a previous level of performance in one or more
cognitive domains and a decline in neurocognitive perfor-
mance, typically involving a test performance in the range of
two or more standard deviations below appropriate norms
(i.e., below the third percentile) on formal testing or an equiv-
alent clinical evaluation. Further, these cognitive deficits are
sufficient to interfere with independence (i.e., necessitating
assistance with instrumental activities of daily living) [37,
38]. Dementia is currently estimated to affect about 6 % of
individuals over the age of 65 and is strongly correlated with
advancing age [39, 40].
Alzheimer’s disease (AD) is the most common cause of
dementia, accounting for about 70 % of all causes of dementia
and is followed in prevalence by dementia with Lewy bodies
that accounts for about 20 to 25 % of cases [6]. Nocturnal and
daytime sleep disturbances affect as many as 44 % of AD
patients in clinic and community-based samples [39, 41].
However, the highest frequency of sleep disturbances occurs
in individuals with dementia with Lewy bodies (DLB) and
Parkinson’s disease (PD) with nearly 90 % of individuals af-
fected [5, 12•, 43–45]. A recent prospective cohort study
Page 3 of 11 97
observed that insomnia frequency was identical in AD and
frontotemporal dementia (FTD) patients, but about 2.5 and
1.5% more frequent, respectively, in vascular dementia
(VaD) and DLB/PD [9]. Finally, that same study suggested
that patients with AD and mild cognitive impairment (MCI)
had an almost identical frequency of any given sleep distur-
bance which did not allow any prediction concerning the con-
version from MCI to AD [9]. Sleep disordered breathing has
been shown to be more prevalent in VaD, and severe daytime
sleepiness appears to be strongly predictive of vascular de-
mentia, but is not predictive of other non-vascular dementias
[9, 45]. REM behavioral disorder is more frequently present in
DLB and PD [9, 31, 44].
In some cases, use of medications that are designed to
modify various aspects of neurodegenerative conditions
(e.g., benzodiazepines, selective serotonin reuptake inhibitors)
may induce side effects of sleepiness, disrupted sleep archi-
tecture, or even precipitate RBD [32]. For caregivers, disrup-
tive behaviors include being awakened at night and patient
wandering, confusion (e.g., Bsun-downing^), getting out of
bed repeatedly and talking in bed. These comprise some of
the most disruptive behaviors that may lead to earlier nursing
home placement [46].
Alzheimer’s Disease
AD is the most common form of age-related dementia and is
characterized by progressive memory loss and cognitive dete-
rioration. Familial, early-onset (<60 years of age), autosomal-
dominant forms of AD (FAD) have now been shown to asso-
ciate with mutations in the genes encoding for the amyloid
precursor protein (APP), presenilin 1 (PSEN1) and presenilin
2 (PSEN2) [47]. Sporadic AD typically presents at a later
onset (>60 years) and is due to multifactorial genetic and
environmental risk factors [48]. Memory disturbances are
the most common initial presenting symptoms of AD, and in
particular the condition is characterized by difficulty remem-
bering recent events (short-term memory loss). As the disease
progresses, patients present with worsening episodic memory,
executive dysfunction, language compromise (e.g., naming or
semantic problems), loss of visual orientation, behavioral
changes, loss of motivation, and eventually, poor self-care
and behavioral issues. Patients with AD are often affected
by primary circadian dysrhythmia as suggested by the pres-
ence of insomnia, hypersomnia, and a tendency to sleep more
during the day and less at night [6]. As a patient’s condition
progresses and cognition decreases, she or he often withdraws
from family and society. Although the speed of progression
can vary notably, the average life expectancy following diag-
nosis is three to nine years [5, 40, 49]. Pathologically, AD is
characterized by the presence of senile plaques, which are
comprised of extracellular amyloid beta (Aβ) deposits that
97 Page 4 of 11
have historically been felt to be a fundamental pathological
hallmark of AD either by overproduction or some failed clear-
ance mechanism (i.e., amyloid hypothesis); in 2009, this the-
ory was updated, suggesting that an associated amyloid pro-
tein (N-APP) may be a major culprit in the pathophysiology of
the disease [50, 51]. The other pathological hallmark of AD is
neurofibrillary tangles, which are composed of a filamentous
aggregation of hyperphosphorylated tau (p-tau) proteins [47,
48]. Most recently (2015), novel stem cell 3D gel culture
systems have further helped elucidate the sequence of events
in AD pathogenesis, starting with extracellular aggregation
amyloid-β (Aβ) and followed by the accumulation of
hyperphosphorylated tau. The 3D culture generation takes
1–2 days and is associated by aggregation of Aβ observed
after 6 weeks of differentiation, followed by robust tau pathol-
ogy after 10–14 weeks [47]. This has further solidified the
notion that amyloid-β (Aβ) accumulation is the inciting
event, followed by the accumulation of hyperphosphorylated
tau and neurofibrillary tangle formation, with neuronal cell
dysfunction and death likely perpetuated by the inflammatory
milieu that contributes to dysregulation of clearance of toxic
metabolites, other mechanisms that lead to misfolded or dam-
aged neuronal proteins, and to tau-associated disruptions of
axonal transport integrity [47, 48, 52].
Individuals with the apolipoprotein E (APOE- 4) allele are
predisposed to accumulate Aβ and are at an increased risk for
AD [11]. Interestingly, the APOE- 4 allele is the most proin-
flammatory allele and has also been associated with as much
as a two-fold higher risk for the development of obstructive
sleep apnea (OSA), with OSA conferring a higher risk for
subsequent cognitive impairment [11, 53–55]. Conversely,
better sleep consolidation diminishes the effects APOE geno-
type on the incidence of AD and the subsequent development
of neurofibrillary tangle pathology [53]. Chronic systemic in-
flammation may therefore link many AD risk factors (i.e.,
APOE genotype, cardiovascular disease, Type II diabetes
mellitus, poor diet, a sedentary lifestyle, and poor sleep qual-
ity), all of which may contribute to the proinflammatory path-
ophysiology of this condition [11].
Central to the pathophysiological changes of AD is the loss
of cholinergic cells of the nucleus basalis complex and pro-
gressive degeneration of the cortical and subcortical structures
[6]. Interestingly, the use of the cholinesterase inhibitor,
donepezil, improved OSA by improving the apnea-
hypopnea index (AHI) and oxygen saturation after donepezil
treatment [56, 57]. Sleep-wake disturbances such as increased
daytime napping and insomnia at night affect 25 to 40 % of
patients with mild-to-moderate AD [58]. Degeneration of the
cholinergic neurons in the nucleus basalis of Meynert, the
pedunculopontine and laterodorsal tegmental nuclei, and the
noradrenergic neurons of the brainstem may be responsible for
the decreased rapid eye movement sleep (REM) in patients
with AD [1, 6]. Degeneration of neurons of the
Curr Psychiatry Rep (2015) 17:97
suprachiasmatic nucleus (SCN) may be responsible for alter-
ations in circadian rhythmicity, Bsun-downing^ and other
sleep-wake disturbances [1, 6]. Degeneration of the brainstem
respiratory neurons and supramedullary respiratory pathways
may contribute to sleep disordered breathing (SDB) and other
respiratory dysregulation problems affecting sleep in AD [1,
6]. Even in the setting of amnestic mild cognitive impairment,
there are already known clinical (increased insomnia and sleep
disordered breathing) and electroencephalographic (increased
slowing in wakefulness and REM sleep and attenuation of
sleep spindles and slow-wave sleep) abnormalities, many of
which are associated with decreases in sleep-dependent mem-
ory consolidation [9, 14, 59].
Patients with Alzheimer’s disease suffer from a number of
sleep disruptions including insomnia, frequent nighttime
awakenings, decreased total nighttime sleep, increased day-
time sleep, and evening agitation [60]. Patients with AD have
significant sleep architectural disruption including reduced
sleep efficiency, increased non-REM stage N1 sleep, in-
creased arousal and awakening frequency, decreased total
sleep time (TST), and reduced sleep spindles and K com-
plexes [6]. Some of the most disruptive behaviors in patients
with AD include the profound disruption in sleep-wake rhyth-
micity that occurs early in the disease and results in sleep
fragmentation, increased daytime sleepiness, insomnia, noc-
turnal wandering, progressive cognitive decline, increase in
the number of daytime naps, increased time spent in bed (in-
cluding awake time in bed), and increased nocturnal wander-
ing, disorientation, and confusion [1, 5, 12•, 58, 61–63].
Therefore, in patients with AD, support exists that sleep
disruption results in poorer outcomes across multiple do-
mains: (1) poor sleep quality is predictive of cognitive decline
[14, 64, 65••], (2) good sleep quality may help mitigate against
genetic susceptibility factors, e.g., APOE genotype, possibly
by increasing clearance of Aβ from the brain [18••, 66], and
(3) poor sleep quality is proinflammatory and is associated
with a higher risk of metabolic (e.g., diabetes) and cardiovas-
cular disease, which have been suggested to be independent
risk factors for AD [11]. To highlight this, Fig. 1 illustrates the
schematic association between circadian dysregulation and
poor sleep in the context of AD pathogenesis [11]. Production
of soluble Aβ may be relatively increased during the sleep
period by reduced NREM SWA in the context of aging and
associated sleep disturbances (e.g., sleep apnea or insomnia).
These sleep disruptions result in increased time awake during
the relative sleep period, and may link Aβ pathology with
hippocampal-dependent cognitive decline [17, 23••].
During sleep, the default mode network (DMN), which is
active during non-task performance and necessary for episod-
ic memory retrieval, deactivates during sleep and particularly
SWS; it is this domain that is also adversely affected in early
AD. With decreased sleep efficiency and associated decreased
SWS, there is a lack of deactivation of the DMN which results
Curr Psychiatry Rep (2015) 17:97
Fig. 1 AD pathophysiology as a product of circadian dysregulation and
poor sleep: Recent data illustrates that the production of a soluble Aβ may
be relatively accelerated during sleep due to the reduced NREM SWA in
the context of aging and associated sleep disturbances (e.g., sleep apnea
or insomnia). Disturbed sleep results in an increased time awake during
the relative sleep period, and may link Aβ pathology with the
hippocampal-dependent cognitive decline [15••]
in an increase in synaptic and metabolic neuronal activity; this
results in increased soluble Aβ levels in the CSF during the
sleep period, and subsequent increased Aβ aggregation and
deposition into plaques with attenuation in the normal Aβ
diurnal rhythms [15••]. Further, a decrease in SWS is associ-
ated with age-related atrophy of the medial prefrontal cortex
(mPFC) gray matter, which may also give rise to cognitive
deterioration and decline [17, 23••]. Although changes in the
sleep-wake cycle have been associated with markers for AD
pathology (e.g., amyloid deposition), the precise associations
between advancing AD pathology and sleep-wave cycle alter-
ations must still be further investigated [17, 23••].
An alternative explanation is that sleep changes are markers
of AD pathology rather than an initiating event in the cascade
of AD pathogenesis per se. This model suggests that many
changes occur during aging including brain atrophy (regional
atrophy in the mFPC) and changes in sleep parameters (e.g.,
increased wake after sleep onset, decreased sleep efficiency,
decreased SWS and increased incidence of various sleep dis-
orders). These factors interact within an individual with genet-
ic and environmental factors that ultimately determine an in-
dividual’s relative risk of and venerability to developing AD.
In a given individual, depending on the interplay of these other
factors, sleep will play a greater or lesser determinant in
whether that individual develops subsequent AD [15••].
Dementia With Lewy Bodies
Dementia with Lewy bodies (DLB) is an atypical Parkinso-
nian condition characterized as an alpha synucleinopathy with
the cardinal neuropathological finding of the Lewy body, a
neuronal inclusion composed of aggregated α-synuclein
[67]. Lewy bodies are found in the brainstem nuclei (limbic
Page 5 of 11 97
and paralimbic) in both Parkinson’s disease (PD) and DLB;
however, Kosaka et al. have identified Lewy bodies in the
cerebral cortex and subcortical white matter of patients with
DLB, which do not necessarily demonstrate the characteristic
halo but do stain positive for α-synuclein and ubiquitin [67].
Typical clinical features of the condition include fluctuating
alertness, visual hallucinations and predilection to the develop-
ment of RBD and Parkinsonian motor symptoms with a de-
mentia characterized by both cortical and subcortical features.
It is the second most common form of dementia after AD and
accounts for 25 % of all dementias [68]. The prevalence of this
condition is estimated to be 0.7 % of the population over the
age of 65 years with a greater male predominance of the con-
dition, 1.9:1 [69–71]. Risk factors for the development of DLB
include advanced age, hypertension, dyslipidemia, and a car-
rier of one or more APOE 4 alleles [71–73]. As in PD, there is
a higher proportion of the CYP2D6B allele and mutations in
glucocerebrosidase 1 (GBA1), which are significant risk fac-
tors for DLB [74, 75]. In DLB, a greater heterozygous frequen-
cy of GBA1 exists than in PD, 3.5 versus 2.9 %, supporting the
notion that GBA1 mutations likely play an even larger role in
the genetic etiology of DLB than in PD [74, 75].
Sleep disturbances with nighttime sleep disruptions are
common in DLB, and in fact, are more common in DLB than
in AD patients [43]. Patients with DLB suffer more movement
disorders during sleep and more daytime sleepiness [43]. In
patients with DLB, RBD may precede cognitive and motor
impairments by many years [70, 71, 73]. RBD is a REM
parasomnia that is strongly associated with alpha
synucleinopathies. It is demarcated by vivid, often frighten-
ing, quasi dream-enactments associated with motor behaviors
during REM sleep, which may result in injuries to the patient
or his/her bed partners [76]. The polysomnographic features
of RBD include abnormal muscle augmentation during REM
sleep (known as REM sleep without atonia) [76]. Key epide-
miological studies suggest that the majority of patients with
RBD are older men generally in the sixth or seventh decade of
life [59]. More recent longitudinal studies have suggested a
high rate of phenoconversion of patients with idiopathic RBD
(iRBD) to α-synucleinopathies such as PD, DLB, and multi-
system atrophy (MSA) [32, 43, 77–79]. Several markers of
neurodegeneration have been identified in RBD, including
cognitive impairments such as deficits in attention, executive
functions, learning capacities, and visuospatial skills [5, 32,
43, 62, 77–79]. Approximately 50 % of RBD patients also
present with features of mild cognitive impairment (MCI) [9,
62, 64, 77]. RBD has also been highly associated with cogni-
tive decline in PD [32, 77, 78, 80]. A previous study docu-
mented that 38 % of neurologically normal men older than
50 years with RBD subsequently develop a Parkinsonian dis-
order [81].
Of interest, the association of EEG slowing and the pres-
ence of MCI, which is frequently seen in the early stages of
97 Page 6 of 11
DLB, has been an area of active investigation in an effort to
identify objective indicators of those individuals at risk for
conversion to α-synucleinopathies such as PD, DLB, and
MSA [76]. In a recent study (2010), patients with idiopathic
RBD (iRBD) without MCI and healthy controls were follow-
ed for 2.4 years. Patients with RBD who developed MCI had
marked EEG slowing (theta and delta) in central and occipital
regions during wakefulness and REM sleep in baseline studies
as compared to controls and iRBD patients who had not de-
veloped MCI by the time of follow-up. Further, the EEG spec-
tral pattern of RBD+MCI group was similar to that found in
patients with DLB or PD associated with dementia [59]. These
findings suggest that EEG slowing on spectral analysis may
be predictive of the development of MCI within a short period
in patients with an initial diagnosis of iRBD.
In contrast to the dorsal prefrontal pathology seen in AD
and its relationship to sleep, the aberration of REM sleep seen
in RBD has its pathophysiologic correlates in lower brain
structures (i.e., pontine and midbrain nuclei). Since the
pedunculopontine nucleus and the locus coeruleus represent
the largest clusters of cholinergic and noradrenergic neurons
in the brainstem reticular system, and are known to play a role
in arousal and cortical activation, it has been proposed that a
dysfunctional cholinergic system may be contributing to cog-
nitive impairment and EEG slowing in iRBD patients [76].
Further, other studies have shown (by single-photon emission
computer tomography studies) iRBD+MCI patients demon-
strate hypoperfusion in the occipital and temporal regions
compared to iRBC−MCI and controls. Other brain regions
(e.g., left superior temporal lobe, right occipital lobe, both
hippocampi and the left parahippocampal gyrus) have also
been implicated in other imaging studies investigating patients
with iRBD [76]. Taken together, these studies imply that struc-
tural changes in the brain and brainstem are responsible for
EEG slowing and cognitive decline. Therefore, a subset of
patients with EEG slowing and the sleep disturbances associ-
ated with RBD are at increased risk of dementia, and the basis
is quite distinct from the link between slow wave sleep and
Alzheimer’s disease.
Parkinson’s Disease
Parkinson’s disease (PD) is the most common neurodegener-
ative movement disorder with an annual incidence of 13.4 per
100,000 in the US [42]. Sleep disturbances and cognitive im-
pairment are common non-motor manifestations of PD [80].
Various sleep-related conditions that interfere with quality of
life in PD patients include inability to fall asleep and stay
asleep, an urge to move the legs in the evening time (restless
legs syndrome), abnormal and disruptive leg jerks at night
(periodic leg movement disorder) and excessive daytime som-
nolence [42, 82]. A recent study of the associations of health-
Curr Psychiatry Rep (2015) 17:97
related quality of life (HRQOL) measures in PD shows that
essentially all measures of HRQOL in a community-dwelling
sample of PD patients were negatively affected by reports of
significant sleep disturbances, particularly sleep maintenance
insomnia, daytime sleepiness, and inadequate sleep, as well as
awakening short of breath or with a headache [42, 82]. Sleep
spindles and slow waves at baseline have been shown to con-
tribute to brain plasticity and cognitive performance [80]. Re-
sults of recent studies suggest that non-rapid eye movement
sleep irregularities noted on EEG in PD correlate with cogni-
tive decline and risk of developing dementia [83]. Specifical-
ly, sleep spindle activity was notably impaired in PD patients
who subsequently developed dementia, with a more posterior
topographical pattern [80]. This supports the notion that sleep
spindle alterations are associated with subsequent develop-
ment of dementia in patients with PD [80]. Further, a high
percentage of PD patients without frank sleep complaints
may have subclinical or clinical RBD, and RBD may precede
the onset of motor manifestations of Parkinsonism by many
years, particularly in older male patients [1]. Studies have also
shown that cognitive impairment in non-demented patients
with PD is closely correlated with the presence of RBD [79].
Vascular Dementia
Ischemic or hemorrhagic cerebrovascular disease (CVD)
causes injury to brain regions that are important for executive
functions, behavior and memory, leading to decline in cogni-
tive functions and vascular dementia (VaD). The causes of
cerebrovascular disease are diverse (e.g., ischemic, embolic,
thrombotic, and microvascular) and include VaD from hypo-
perfusion of susceptible brain areas. CVD may also worsen
degenerative dementias such as Alzheimer’s disease (AD)
[49, 73]. Currently, the broader diagnostic category for cogni-
tive impairment of vascular origin is vascular cognitive disor-
der (VCD). VCD ranges from vascular cognitive impairment
(VCI) to VaD. The term VCI is used for cases of cognitive
impairment of vascular etiology without frank dementia; VCI
is equivalent to vascular mild cognitive impairment (MCI).
Risk factors for VaD include age, hypertension, diabetes,
smoking, cardiovascular disease (coronary heart disease, con-
gestive heart failure, peripheral vascular disease), atrial fibril-
lation, left ventricular hypertrophy, hyperhomocysteinemia,
orthostatic hypotension, cardiac arrhythmias,
hyperfibrinogenemia, sleep apnea, infection, and high C-
reactive protein [84]. Patients with vascular dementia experi-
ence disruption in sleep-wake cycles and decreased sleep ef-
ficiency [85]. As previously reported in the Caerphilly cohort
of older men, sleep disturbances were predictive of risk of
ischemic stroke (relative odds of up to 1.97; 95 % confidence
limits: 1.26, 3.09), and daytime sleepiness is associated with
an increase in vascular disease events (relative odds: 1.41;
Curr Psychiatry Rep (2015) 17:97
1.04, 1.92) [86]. Research on biomarkers revealed increased
CSF-neurofilament protein levels in VaD, with CSF-tau levels
that were normal. VaD also shows low CSF acetylcholinester-
ase levels; this condition is known to show a response to
acetylcholinesterase inhibitors, confirming the role of cholin-
ergic deficit in its pathogenesis. Evidence strongly suggests
that the control of vascular risk factors, particularly hyperten-
sion, could help prevent VaD [84]. Recent studies further sug-
gest that sleep disturbances, and specifically excessive day-
time sleepiness, appear to be strongly correlated with a higher
predictive power for subsequent VaD, but not for non-vascular
dementias [45].
Frontotemporal Dementia
Frontotemporal dementia refers to a range of neurodegenera-
tive disorders that are characterized by focal atrophy in the
frontal and/or temporal lobes of the brain that often results in
profound behavioral, cognitive, and emotional symptoms
[87]. Two subtypes of FTD are the behavioral variant
(bvFTD) and semantic dementia (SD). Much less is known
about sleep disturbances in FTD, but sleep disruptions that are
characterized by increased nocturnal activity, decreased morn-
ing activity, and excessive daytime sleepiness have all been
reported in patients with FTD [1, 87–89].
Treatments for Sleep Disturbances in Patients With
Dementia
The normal human aging process produces biological changes
in circadian rhythms that produce sleep disorders and disrup-
tions of the sleep-wake cycle. The prevalence of sleep disor-
ders is higher in patients with dementia, and sleep disorders
are often the cause of increased caregiver burden. In treat-
ments of sleep disorders in this cohort, it is important to re-
view sleep disorders carefully with the bed partners or family
members in order to understand the behavioral and psycho-
logical impact of dementia on sleep. In clinical practice, non-
pharmacological therapies, including cognitive-behavioral
and psycho-educational strategies, should be utilized first
and consist of interventions such as combined daytime phys-
ical activity, sleep hygiene, and an enhanced nighttime envi-
ronment. In these enhanced environmental programs, patients
are encouraged to (1) exercise regularly (ideally for 30 min)
during the daytime hours, (2) walk outside in natural light as
often as possible, (3) decrease time spent in bed awake at night
and napping during the daytime, (4) maintain regular bedtimes
and arising times, (5) keep the bedroom reserved for sleep and
a quiet environment with minimal noise/light/TVor light emit-
ting electronics, and (6) minimize use of cholinesterase inhib-
itors and stimulating drugs during the pre-sleep time [90]. In
Page 7 of 11 97
addition, bright-light therapy (BLT) (i.e., using a full-spectrum
light box) for a minimum of half-an-hour daily, usually in the
morning, may enhance sleep in the AD population [90–93].
Most studies have suggested that BLT has positive effects on
normalizing circadian rhythms and improving sleep function
by reducing sleep fragmentation and increasing the duration
of sleep and improving some cognitive and noncognitive
symptoms of dementia [90, 91, 93–95].
Pharmacological therapies may include use of melatonin,
which has been proposed to have cytoprotective, antioxidant,
and perhaps even anti-amyloid effects as well as modest ef-
fects on improving day/nighttime sleep ratios and decreasing
nocturnal activity and sun-downing in patients with AD [10,
60, 93, 96, 97•, 98, 99]. Also, patients with PD have been
shown to have a significantly less increase in nighttime mel-
atonin release compared to controls. Additionally, nighttime
melatonin levels were shown to be significantly lower in the
subset of patients with PD experiencing excessive daytime
sleepiness than in the subset without daytime sleepiness, thus
suggesting the potential utility of supplemental melatonin in
patients with PD [100••].
Other pharmacological treatments that have been utilized
with variable success include antipsychotics (with notable side
effects of sedation, increased fall risk and serious cardiac side
effects with second-generation antipsychotics), hypnotics
(promote sedation at the expense of altering sleep architec-
ture), antidepressants (side effects include somnolence, seda-
tion, anticholinergic effects and dizziness), antihistamines
(side effects include sedation, anticholinergic effects, dizzi-
ness and somnolence), and acetylcholinesterase inhibitors
(may increase REM sleep associated parasomnias, but may
increase REM sleep percentage and density [30, 32, 57,
97•]). Newer agents such as melatonin receptor agonists and
an orexin-receptor antagonist may be more specific in their
mechanism of action [96, 100••, 101]. The appropriate use of a
combination of pharmacological and non-pharmacological
measures to enhance appropriate sleep may successfully in-
crease a patient’s quality of life, improve daytime activity,
increase sleep efficiency, decrease agitated behaviors, reduce
depressive symptoms, and even reduce cognitive compromise
in patients with dementia [10, 90, 94].
Maximizing environmental safety and protecting the
sleeping environment by removing sharp objects from the
bedroom area are cornerstone strategies for patients with both-
ersome dream enactment in the setting of RBD. Suggested
pharmacotherapy for RBD may be in the form of melatonin
(3–12 mg P.O. Q.H.S) or clonazepam (0.25 to 1 mg P.O.
Q.H.S). The former is effective in up to 90 % of patients,
and while there is little evidence of tolerance or abuse with
this pharmacological approach, caution should be exercised
when using it in patients with chronic respiratory diseases or
impaired renal function [102]. The exact mechanism of action
of melatonin in improving RBD is unknown, but it probably
97 Page 8 of 11
exerts its therapeutic effect by restoring REM sleep atonia.
One study reported that melatonin was effective in 87 % of
patients taking 3 to 9 mg at bedtime [103], whereas follow-up
data reported resolution in those taking 6 to 12 mg of melato-
nin at bedtime [104]. The readers should be reminded that
melatonin, a food supplement, is not approved by the Food
and Drug Administration and has poor regulation in terms of
pharmacologic preparation.
Conclusion
Sleep changes profoundly with advancing age. Across both
subjective and objective measures, data confirms an increase
in sleep-wake disturbances, sleep fragmentation, less deep
sleep, and a tendency towards early morning awakening. In
older adults with dementia, the prevalence of sleep-related
breathing disorder, periodic limb movement disorder of sleep
and restless leg syndrome increases and may lead to excessive
daytime sleepiness, insomnia and neurocognitive compromise
that may exacerbate and accelerate the neurodegenerative pro-
cess. Since many of the sleep disorders are potentially revers-
ible, health care providers should incorporate a review of sleep
disturbances into a carefully integrated and diagnostic
decision-making process with the aim to benefit the patient
and their family. Sleep problems of the older adult with early
dementia may contribute significantly to the decision to even-
tually institutionalize the patient, which could magnify the
social and economic burden of chronic nursing home care. It
is now understood that sleep disturbances may lead to Aß
deposition, and therefore fundamentally contribute to the
pathogenesis of conditions such as AD. In patients with alpha
synucleinopathies, the presence of sleep disorders such as
RBD may help predict those with a unique vulnerability to
phenoconversion to a dementia by up to a decade before the
dementia is clinically apparent. In both scenarios, sleep is
central to the notion that (1) disrupted sleep may directly con-
tribute to dementia, and (2) the presence of sleep pathology
can predict, with a high degree of certainty, a patient’s risk of
conversion to clinical dementia. In the first scenario, this ar-
gues strongly for the necessity to treat and manage disrupted
sleep. In the second scenario, the scientific community is en-
couraged to develop neuroprotective agents and interventions
for those patients who present with sleep pathology. Sleep is
pivotal to the health of the population, and its disruption con-
tributes meaningfully to an individual’s relative risk of demen-
tia within the population. A careful assessment of a patient’s
sleep patterns should thus be the new Bvital sign^ for every
clinical visit.
Acknowledgments This material is the result of work supported with
the resources and use of facilities at the UCLA Department of Neurology
in Los Angeles, California, USA.
Curr Psychiatry Rep (2015) 17:97
Compliance with Ethical Standards
Conflict of Interest Verna R. Porter and William G. Buxton declare
that they have no conflict of interest.
Alon Y. Avidan is a consultant for Vanda, Merck, is on the speaker’s
bureau for Merck and Xenoport and received stipends as an author and
lecturer on behalf of the Elsevier, LWW, Best Doctors, AAN, AASM,
ACCP, and CHEST.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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