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Experimental Neurology 243 (2013) 67–73
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Experimental Neurology
journal homepage: www.elsevier.com/locate/yexnr
Review
Sundowning syndrome in aging and dementia: Research in mouse models
Tracy A. Bedrosian ⁎, Randy J. Nelson
Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA
a r t i c l e
i n f o
a b s t r a c t
Article history:
Received 11 January 2012
Revised 30 April 2012
Accepted 8 May 2012
Available online 14 May 2012
Both normal aging and dementia are associated with altered circadian regulation of physiology and behavior.
Elderly individuals and dementia patients commonly experience disrupted sleep–wake cycles, which may
lead to psychomotor agitation, confusion, and wandering. These behaviors are disruptive to both patients
and caregivers. Sundowning syndrome, which encompasses many of these behaviors, is characterized by a
temporal pattern in the severity of symptoms, usually expressed as worse during the late afternoon or evening.
Other than antipsychotic medications, off-label medications, and restraint, few treatment options are available.
The aim of this paper is to review mouse studies of circadian behavioral disturbances relevant to sundowning,
in order to determine potential models for studying the mechanisms of sundowning syndrome. The emergence
of a useful mouse model should facilitate the development of novel therapeutic approaches.
© 2012 Elsevier Inc. All rights reserved.
Keywords:
Aging
Alzheimer disease
Agitation
Circadian
Contents
Introduction . . . . . . . . . .
What is sundowning? . . . . .
Clinical research . . . . . . . .
Pre-clinical research . . . . . .
Potential mechanisms underlying
Future directions . . . . . . . .
Acknowledgments . . . . . . .
References . . . . . . . . . . .
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sundowning
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Introduction
Increasingly, evidence suggests a role for the circadian system in
mood and emotion (Benca et al., 2009). Circadian disturbances are
particularly common during the aging process, which may contribute
to psychological or behavioral disturbances. Much of this circadian
dysregulation is exacerbated in cases of underlying dementia pathology,
leading to even more behavioral problems among this population. Traditionally, greater importance has been given to cognitive symptoms of
aging and dementia, though non-cognitive symptoms represent a major
cause of hospitalization, institutionalization, and distress for these individuals (Finkel, 2000).
One prominent age-related change in circadian organization is
dysregulation of physiological rhythms. For example, aging is often
⁎ Corresponding author at: Department of Neuroscience, 636 Biomedical Research
Tower, Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.
E-mail address: [email protected] (T.A. Bedrosian).
0014-4886/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.expneurol.2012.05.005
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associated with reduced amplitude of 24-h patterns in arousal, body
temperature, and hormone fluctuations (for review: Van Someren,
2000). Altered period, amplitude, and responsiveness to zeitgebers
(i.e., entraining cues) may also occur for certain rhythms among
aged individuals. In Alzheimer patients, phase delays in core body
temperature may be related to the severity of disease pathology
(Hatfield et al., 2004). Mouse studies have similarly shown a decrease
in circadian output with age, originating in the brain's master clock
(Nakamura et al., 2011), and behavioral changes in locomotor activity
and anxiety (Scheuermaier et al., 2010). Some of this circadian dysregulation, particularly altered activity and arousal rhythms, may
facilitate circadian behavioral disturbances such as sundowning.
Sundowning syndrome, which includes agitation and delirium, is
characterized by a temporal pattern in the severity of symptoms,
usually expressed as more severe during the late afternoon or evening (Bachman and Rabins, 2006).
Elderly individuals and dementia patients commonly experience
disrupted sleep–wake cycles and poor sleep quality, which may lead
to psychomotor agitation, confusion, and wandering (Vitiello and
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T.A. Bedrosian, R.J. Nelson / Experimental Neurology 243 (2013) 67–73
Borson, 2001). These behaviors are disruptive to both the patient and
caregivers (Donaldson et al., 1998; Pollak and Perlick, 1991). Interestingly, degree of sleep disturbance is associated with disease severity
in Alzheimer patients (Bliwise et al., 2011). In mice, sleep deprivation
may be anxiogenic in animals exposed to assessments of anxiety-like
responses (e.g., performance in an elevated plus maze) (Silva et al.,
2004). Sundowning symptoms may or may not simply reflect sleep
deprivation; alternatively, sundowning symptoms may be exacerbated
by sleep deprivation or relatively independent of sleep.
Taken together, circadian disturbances represent a serious detriment to individuals' quality of life. The majority of the elderly population experiences chronic sleep disturbances, which worsen with
age (Van Someren, 2000). Other than antipsychotic medications,
off-label medications, and restraint, few treatment options are available. Novel therapies require an understanding of the underlying
mechanisms of sundowning and development of new therapeutic
approaches. Research using mouse models is integral to expanding
research on circadian aging from observation of outward rhythms to
mechanistic studies.
Mouse models represent a useful tool in understanding the mechanisms of circadian behavioral disorders in aging humans. Clinical
studies are useful in their direct application; however, these studies
are limited to establishing correlations between biological metrics
and behavior, whereas animal research makes it possible to determine causative mechanisms of behavior. Most clinical studies are
observational or retrospective (e.g., assaying post-mortem brain
gene expression), but animal research allows studies of changes in
hormones or neurotransmitters during the behavior itself. Research
in mouse models furthermore provides opportunity to directly manipulate variables such as genes or environmental conditions.
There are, however, limitations to using mouse models to study
psychiatric disorders. Certain components of these disorders are impossible or very difficult to model in mice. For example, hallucinations or
nighttime wandering are not easily evaluated in mice. And furthermore,
some behaviors that we can demonstrate in a mouse model may not
exactly replicate the human behavior. For these reasons, it is difficult
for a single mouse model to completely replicate a complex psychiatric
disorder. Nevertheless, it is useful to model specific symptoms using
different mouse models, in order to dissect out the mechanisms of
each behavior (Workman and Nelson, 2010).
Establishing a useful mouse model requires satisfaction of three
criteria of validity: face, construct, and predictive validity. Face validity
is satisfied when the mouse model phenotype closely resembles the
symptoms of the human disorder. Construct validity refers to similarities in the mouse model to the underlying mechanisms of the human
disorder, for example certain genes are implicated in both the behavior
of the model and the human disorder. Predictive validity requires that
therapeutic treatments administered in the mouse model elicit a similar
response as observed in human patients. An ideal mouse model satisfies
each of these criteria, but a model can still be useful and offer insights
into mechanisms if it only satisfies one or two of these criteria.
The aim of this paper is to review mouse studies of circadian behavioral disturbances relevant to sundowning, in order to determine
potential models for studying the mechanisms of sundowning syndrome. The emergence of a useful mouse model should facilitate the
development of novel therapeutic approaches.
What is sundowning?
Sundowning syndrome, also referred to as “nocturnal delirium”, is
characterized by a temporally specific pattern of recurring disruptive
behaviors that can have many contributing causes (Fig. 1). Patients
may become highly agitated, aggressive, restless, vocal, or delirious.
These behaviors worsen specifically during the late afternoon or early
evening, whereas symptoms improve or disappear during the day.
Dementia patients are more often afflicted than any other group; however, cognitively-intact elderly individuals have also been reported to
exhibit sundowning symptoms during hospitalization (Evans, 1987;
Kim et al., 2005).
Estimates of the prevalence of sundowning vary depending on disease state and living conditions. Reported rates among institutionalized patients range from 10 to 25% (Evans, 1987; Martin et al.,
2000), whereas numbers are much higher, approximately 66%, for
dementia patients living at home (Gallagher-Thompson et al., 1992).
The greatest prevalence is observed among patients with severe dementia, in particular those living at home, rather than in a nursing
home or other institution. It is unknown whether sundowning varies
in prevalence by subtype of dementia and rates among cognitively
intact individuals are difficult to obtain.
The costs of sundowning syndrome are tremendous, both in terms
of the financial burden placed on caretakers, the emotional distress
caused to families, and the cost in quality of life for the patient.
Sundowning symptoms are often cited as a main reason for families
to move the patient from home into a skilled nursing facility (Coen
et al., 1997; Pollak et al., 1990). In 2006, costs of care for each dementia patient were almost $1300 per month in the United States, with
the severity of behavioral disturbances directly affecting the costs
(Herrmann et al., 2006). Sundowning symptoms also cause emotional
distress for family members. Caretakers are under high stress and at
elevated risk for anxiety and depression (Gallagher-Thompson et al.,
Fig. 1. Possible contributors to sundowning symptoms. AVP: arginine vasopressin; VIP: vasoactive intestinal peptide.
T.A. Bedrosian, R.J. Nelson / Experimental Neurology 243 (2013) 67–73
1992; Mahoney et al., 2005). Some symptoms of sundowning, such as
physical aggression and agitation, may put professional caregivers
(i.e., nurses, attendants, doctors) at a safety risk. Finally, sundowning
syndrome is detrimental to the quality of life of the afflicted individual,
especially because some behaviors such as wandering and physical aggression may compromise safety of the patient or lead to uncomfortable
treatments like physical restraint.
At present, treatment options for sundowning are limited, primarily
because of our limited knowledge of the etiology and pathophysiology
of this disorder. Clinical literature describes four main strategies to
control sundowning symptoms, each with limited efficacy. First, light
therapy may be somewhat useful in ameliorating the sleep–wake disturbance associated with sundowning. Reduced sensitivity to zeitgebers
and degenerative pathology in the SCN occur in aging and dementia,
thus stimulation with light therapy may help counteract these changes.
One study administered bright light pulses to hospitalized Alzheimer
disease patients experiencing sundowning and sleep disturbances
(Satlin et al., 1992). The light therapy occurred between 19:00 and
21:00 for one week. Ratings of sundowning symptoms by trained
nurses improved during and after the week of therapy in eight of ten
subjects. Interestingly, the most severe sundowners displayed the
most improvement after treatment. In contrast, a review of 8 trials
using light therapy for managing cognitive and behavioral symptoms
in dementia found insufficient evidence to support the value of light
therapy (Forbes et al., 2009).
Melatonin treatment has been used in several clinical studies to
improve sundowning symptoms, in response to the hypothesis that
it may help regulate sleep and synchronize rhythms. Open label
pilot studies demonstrate improved daytime sleepiness and reduced
evening agitation both by nursing staff reports and wrist actigraphy
in samples of dementia patients residing in nursing homes (CohenMansfield et al., 2000; Mahlberg et al., 2004). Meta-analyses of the literature have revealed similar conclusions that melatonin treatment
improves sundowning symptoms and disrupted sleep–wake cycles
in dementia patients (Cardinali et al., 2010; de Jonghe et al., 2010).
These studies mainly involve small pilot study samples or case reports, thus more extensive trials are necessary before making clinical
recommendations.
Atypical neuroleptics are an appealing choice to mollify a patient
displaying extremely disruptive or aggressive behaviors. They are reportedly the most-prescribed pharmacotherapeutic in treating sundowning
syndrome, despite little empirical evidence to support their use (Greve
and O'Connor, 2005) and possible risks (Schneider et al., 2005). Given
the reduced strength of the sleep–wake rhythm in aging and dementia,
neuroleptics, which further weaken these rhythms, may ultimately be
a poor choice of therapy. These drugs tend to enhance symptoms of confusion, impaired cognition, and excessive sedation (Ancoli-Israel and
Kripke, 1989; Stoppe et al., 1999), and also may increase the duration
of hospitalization (Yuen et al., 1997). More evidence toward the efficacy
and biological mechanism of these drugs in sundowning is necessary to
fully justify their use.
Some evidence suggests donepezil, an acetylcholinesterase inhibitor, may be effective in improving sundowning symptoms. A case
study report of a 71-year old man diagnosed with dementia with
Lewy bodies demonstrated improved behavioral symptoms after
treatment with donepezil (Skjerve and Nygaard, 2000). The patient
exhibited sundowning symptoms as assessed by trained nurses and
wrist activity measures. After 10 days of treatment with donepezil,
behavioral symptoms improved and evening activity levels markedly
decreased. Meta-analysis of the efficacy of cholinesterase inhibitors in
treating neuropsychiatric symptoms in Alzheimer disease also found
a beneficial impact of this treatment (Trinh et al., 2003). Though
more extensive studies must be completed, it is possible that reduced
cholinergic activity in aging and dementia may provoke circadian
rhythm disturbances, such as sundowning, and that augmenting cholinergic function may counteract these changes.
69
Clinical research
Sundowning was first reported in the clinical literature more than
70 years ago (Cameron, 1941), and since then many clinical studies
and case reports have characterized the disorder. Most physicians
and nursing staff recognize the phenomenon of sundowning as a
legitimate syndrome; however, there has been some argument in the
field (Khachiyants et al., 2011). Some researchers have questioned
whether sundowning symptoms are only perceived worse near sundown by fatigued caregivers. This difference of opinions may reflect discrepancies between studies arising from varying settings or methods.
Sundowning symptoms can be characterized by many different techniques, including caregiver questionnaires, retrospective chart review,
and wrist actigraphy. In the current Diagnostic and Statistical Manual
of Mental Disorders (DSM), sundowning remains a descriptor, rather
than an independent psychiatric diagnosis, although its independent
addition has been proposed.
Evidence against sundowning as a legitimate syndrome comes
from the notion that caregivers and nursing staff are particularly fatigued near the end of the day. Shift changes routinely occur around
this time as well, giving rise to the possibility that disruptive behavior
is only perceived worse at sundown due to fatigue and understaffing,
and that there is no real temporal pattern to the behavior. One study
investigated patterns of agitation by hour and season in dementia patients residing in nursing home facilities (Bliwise et al., 1993). Patients
exhibited a consistent peak in agitation around 16:00, irrespective of
the season. This suggested agitation was not tied to sundown because
the peak occurred at the same clock time regardless of day length. The
16:00 peak corresponds to the time of nursing staff shift change, though
the increase in agitation was a gradual slope, rather than a sharp peak.
This was interpreted as reflective of the gradual tiring of nursing staff,
leading up to the major disruption of shift change, though this pattern
was only observed for the end of the day shift, not the evening shift.
Alternatively, this increase in agitation could reflect a disconnect between the internal biological clock of elderly residents and external
zeitgebers so that internal clock time did not entrain appropriately to
the changing times of dusk.
In contrast, many clinical studies support the notion of a legitimate
sundowning syndrome. One study observed a peak in disruptive vocalizations, compulsive picking, and aggression among nursing home
residents between 16:30 and 23:00 (Cohen-Mansfield, 2007). Interestingly, individualized patterns were observed among patients, despite
the constant daily routine experienced by all, which suggests that
there is a biological basis for the peak in symptoms. Other studies
have also confirmed an afternoon or evening peak in behavioral symptoms using observation, retrospective chart review, accelerometry, and
computer-assisted measurements (Burgio et al., 1994, 2001; Godfrey
et al., 2010; Lebert et al., 1996; Martin et al., 2000; Nowak and Davis,
2007). Variability in the diagnostic criteria for sundowning syndrome
may contribute to some of the discrepancy in opinion about its existence. A unified addition in the DSM would be useful in this regard.
Pre-clinical research
Pre-clinical studies investigating the biological basis of sundowning
syndrome are lacking, despite the marked need for basic animal research to elucidate the mechanisms of this disorder. One likely explanation for the paucity of work in this field is the lack of an appropriate
animal model. It has been difficult to model both the circadian and
affective components of sundowning syndrome in mice. Also, as a nocturnal species, the timing of sundowning symptoms is reversed in mice
relative to humans, meaning that sundowning would occur toward
the end of the night (i.e., during the onset of the inactive phase) in
mice versus the end of the day (i.e., onset of the inactive period) in
humans. Thus far, only a few studies have successfully captured aspects
of sundowning in mice. In particular, mouse models of Alzheimer
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T.A. Bedrosian, R.J. Nelson / Experimental Neurology 243 (2013) 67–73
disease and of anxiety have been investigated as possible models for
sundowning symptoms.
Transgenic APP23 mice express a Thy-1 promoter to drive human
APP751 cDNA encoding the Swedish double mutation K670N/M671L,
implicated in familial AD (Sturchler-Pierrat et al., 1997). These mice
develop hyperactivity relative to wild-type mice at the end of the
active period in an age-dependent manner. Altered activity patterns
begin to develop around 6 months of age and are quite prominent
at 12 months (Vloeberghs et al., 2004). In comparison to human
actigraphy data from probable AD patients exhibiting sundowning
symptoms, the activity pattern is quite similar, making transgenic
APP23 mice a potential model for sundowning activity disturbances,
though the model lacks the affective component of the syndrome.
Transgenic PDAPP mice express a platelet-derived growth factor
promoter driving hβAPP minigene encoding for the 717v→F mutation
implicated in familial AD (Sasahara et al., 1991). Sleep and wakefulness
were measured in these mice using telemetry to evaluate electroencephalogram (EEG) and electromyographic (EMG) activity (HuitronResendiz et al., 2002). Data were shown in 3 h intervals across 24 h.
At a young age of 5–6 months, preceding the development of amyloid
plaques, PDAPP mice behaved similarly to non-transgenic mice in
terms of time spent awake versus engaged in slow wave sleep. Aged
PDAPP mice (20–26 months), however, spent more time awake and
less time in slow wave sleep during the last part of the dark phase compared to age-matched non-transgenic mice. During the light phase,
aged PDAPP were generally more wakeful, perhaps indicating fragmented sleep such as that seen in AD patients. Although the authors do not
allude to the concept of sundowning in this study, it is interesting that
the pattern of wakefulness observed among aged PDAPP mice might
be interpreted as similar to that of the sundowning patient. Aged
PDAPP mice and non-transgenic mice differed only during the very
last part of the active period, not during earlier hours within the dark
phase. This may be reminiscent of the increases in activity observed
among sundowning patients, whereas a typical individual is “gearing
down” during this time period.
Alterations in cholinergic neurotransmission have been implicated
in anxiety induction; muscarinic acetylcholine receptor antagonists
are anxiogenic in rodents (Rodgers and Cole, 1995; Smythe et al.,
1996), whereas nicotinic receptor agonists decrease anxiety (Brioni
et al., 1993; Irvine et al., 1999; Szyndler et al., 2001) and acetylcholinesterase inhibitors reduce neophobia (Sienkiewicz-Jarosz et al., 2000).
Scopolamine, a muscarinic receptor antagonist, administered to rodents
provokes certain symptoms reminiscent of sundowning, though without the circadian component. For example, scopolamine-treated rats
have been proposed as a delirium model (Nakamura et al., 2008); however, scopolamine also induces other symptoms more similar to schizophrenia or psychosis as well (Barak and Weiner, 2007). This model
captures the delirium that sometimes manifests during an episode of
sundowning, and may be useful in understanding the mechanism of
that particular symptom.
Interestingly, sundowning behavior may be related to the notion
that dementia patients are more susceptible to psychosocial stress, leading to increased fear and anxiety. A triple-transgenic mouse model of
AD (3×TgAD mice) was administered a chronic psychosocial stress regimen for 6 weeks, consisting of random changes in cage composition of
group-housed mice (Rothman et al., 2012). Stress increased open-field
anxiety-like behaviors in 3×TgAD mice and prolonged the corticosterone response to acute stress, but these responses were not observed
in wild-type mice. These data suggest that AD patients may have heightened sensitivity to stressors, perhaps provoking anxiety and agitation.
An interesting follow-up study would be to evaluate anxiety-like behaviors after acute psychosocial stress administered at different times
throughout the day, in order to determine the effect of acute stress
and whether time of day interacts with the anxiety response.
A phenomenon of generalized CNS arousal has been proposed, in
which more arousal corresponds to greater responsiveness to sensory
stimuli, more motor activity, and greater emotional reactivity. Fluctuations of generalized arousal are the most obvious effects of circadian
rhythms and sleep–wake cycles, in turn activating other behavioral
responses which may lead to behavioral disorders in a pathological
situation. Mice rendered brain-damaged using anoxia treatment
and tested in a generalized arousal assay reduced fear behavior and
reduced horizontal activity across the day, except for the end of the
active phase, during which the mice were hyperactive (Arrieta-Cruz
and Pfaff, 2009). This diurnal fluctuation in generalized arousal seen
in post-anoxia mice, but not in control mice, is interpreted as reminiscent of sundowning syndrome in elderly adults.
Wild-type C57BL6 mice aged 29-months and housed in static
long-day lengths (14:10 L:D) increased homecage locomotor activity
relative to middle-aged (9-month) control mice at the end of the
active phase (Bedrosian et al., 2011b). Interestingly, when these
mice are tested for anxiety-like behavior on an elevated plus maze
at different times of the night, those aged mice tested late in the
active phase display an exaggerated anxiety-like response compared
to middle-aged mice tested at the same timepoint (Figs. 2C–E). In
contrast, testing either age group at an earlier timepoint in the active
phase reveals no differences in anxiety response, showing some temporal component to anxiety-response exists among aged mice. A
similar pattern of behavior in the elevated plus maze is observed in
APPSWE (Taconic) mice at 9 months of age, the same age at which
amyloid plaques begin to accumulate in the brains of these mice
(Hsiao et al., 1996).
Potential mechanisms underlying sundowning
At present, the neurobiological mechanisms underlying sundowning
syndrome remain unspecified, but likely include several contributors.
Sleep disruption may be one very important contributor (Staedt and
Stoppe, 2005). Aging and dementia can lead to reduced consolidation
of NREM sleep, decreased sleep efficiency, increased sleep disruptions,
and episodes of nocturnal wandering, as well as elevated daytime
napping (Klaffke and Staedt, 2006). These sleep-related disturbances
are common with aging and often exacerbated by the presence of dementia. Over 38% of individuals aged 65 years and older report sleep disturbances (Foley et al., 1995) and this number is higher for those
diagnosed with dementia (Tractenberg et al., 2003). Furthermore, cognition, affect, and sleep are closely related. In dementia patients, the disruption of normal sleep is correlated with the severity of dementia
(Bliwise et al., 1995). Mood is also modulated by quality of sleep
(Vandekerckhove and Cluydts, 2010). For example, mild sleep deprivation increases negative affect, including depression, anxiety, paranoia,
and somatic complaints (Kahn-Greene et al., 2007). It also enhances negative emotional reactivity and subdues positive reactions to positive
events (Zohar et al., 2005).
Reduced zeitgebers contribute to sleep disturbances and impaired
synchronization in a variety of daily rhythms. For example, many
aged individuals, particularly dementia patients, are bound to their
homes and experience relatively constant dim light exposure. Because of the lack of exposure to bright light outdoors and chronic
exposure to dim indoor illumination, elderly individuals frequently
lack sufficient lighting to entrain and reset the circadian system.
Level of light exposure has been positively associated with stability
of the sleep–wake rhythm in dementia patients, pointing to the importance of light as a zeitgeber in this population (Ancoli-Israel
et al., 2003). Nevertheless, in some nursing homes, median light intensity reaches only 54 lx, in comparison to 300–500 lx measured in
workplaces or 3000–4000 lx outdoors in the winter (Shochat et al.,
2000; Staedt and Stoppe, 2005). Intensities of ~ 180 lx are required
to significantly phase shift the human circadian clock (Boivin et al.,
1996). At least one study, however, has reported that healthy elderly
individuals are actually exposed to higher levels of light than healthy
young adults; but this group also experienced greater light at night
T.A. Bedrosian, R.J. Nelson / Experimental Neurology 243 (2013) 67–73
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Fig. 2. Sundowning-like behaviors in aged mice. Aged mice (29 months) are more active than middle-aged adults (7 months) during the last part of the dark (active) phase, between
23:00 and 01:00 (A–B). Arrows in A indicate the times at which anxiety testing was performed. Aged mice tested at the end of active phase exhibit more anxiety-like behaviors in the
elevated plus maze than aged mice tested early in the dark phase or middle-aged adult mice tested at either time, in terms of duration spent in the open arms (C), number of open arm
entries (D), and latency to first enter the open arms (E). Activity graph (A) depicts mean ± SD and bar graphs depict mean ± SEM. *p b 0.05; † p b 0.05 Aged Late vs. All other groups;
††p b 0.01 Aged Late vs. All other groups. For activity, N = 10–13 mice per group. For anxiety, N = 3–7 mice per group.
Adapted from Bedrosian et al. (2011b).
exposure (Scheuermaier et al., 2010). Disruptive lighting during the
night, especially in nursing homes, can also impair sleep and disrupt
circadian timing. There is evidence for negative effects of light at
night on mood in rodent models as well (Bedrosian et al., 2011a).
Complicating matters, reductions in melatonin production and melatonin receptor sensitivity have been reported in aging individuals,
which may further disrupt regulation of sleep and wake (Skene and
Swaab, 2003; Wu and Swaab, 2005). Also, age-related changes in
lens opacity decrease transmission of short-wavelength light to the
retina (Charman, 2003). Short-wavelength (i.e., blue light) most
potently entrains the circadian system (Hattar et al., 2003), so reductions in these wavelengths may have detrimental effects for circadian
timekeeping. Furthermore, napping, reduced physical activity, and
lack of daily routine can all contribute to a disrupted sleep–wake
cycle.
The suprachiasmatic nuclei (SCN), comprising the body's master
circadian clock, undergo age-related degenerative changes which
further contribute to overall circadian dysregulation. Reduced cholinergic input to the SCN from the nucleus basalis of Meynert (NBM) impairs neuropeptide synthesis and expression (Madeira et al., 2004).
This impaired activity of the SCN, along with reduced external zeitgebers, disrupts a variety of biological rhythms. For this reason, bright
light therapy has been suggested as a possible therapy for age-related
circadian disorders and sundowning, as was described above. Interestingly, there is some evidence to relate decreased SCN output to
sundowning syndrome. Break-down of the circadian rhythm in body
temperature, especially reduced amplitude and phase delays, correlates
with worsening of sundowning symptoms (Volicer et al., 2001).
Neuropathology within the NBM may also affect sleep and
sundowning behavior in dementia patients. The NBM is part of the
ascending reticular activating system and sends cholinergic projections to the prefrontal cortex (Wenk, 1997) to modulate arousal. It
undergoes major degenerative changes and loss of cholinergic activity in Alzheimer disease (McGeer et al., 1984). Thus, one theory is
that disrupted rest–activity rhythms in conjunction with disrupted
arousal and attentional processes may combine at the end of the
day to contribute to agitation and sundowning symptoms (Staedt
and Stoppe, 2005).
Klaffke and Staedt (2006) have proposed an interesting theory on
the pathophysiology of sundowning syndrome based on the circadian
disturbances mentioned above. They suggest that sundowning in
Alzheimer disease is precipitated by a desynchronization of arousal
processes and the rest–activity rhythm. Arousal, such as anxiety produced by the environment, may rise at the end of the day due to nursing staff shift changes, impaired visual orientation due to decreased
lighting, or a variety of other disruptions. At the same time, the neocortex is “turned off” in preparation for sleep, an effect of poorly
entrained sleep–wake cycles and decreased cholinergic input to the
cortex by the NBM. The patient thus lacks the attentional capacity
to process the arousal and anxiety, which further augments the agitation symptoms. Aged mice exhibiting sundowning-like symptoms
have increased expression of acetylcholinesterase in the NBM (Fig. 3),
which temporally coincides with the behavior, as well as overall reductions in NBM choline acetyltransferase expression, lending some support to this theory (Bedrosian et al., 2011b).
Future directions
Sundowning syndrome is a complex behavioral disorder affecting
elderly individuals, with tremendous costs for families, caretakers,
and patients themselves. Without a strong mouse model to use in
investigating the pathophysiology of this disorder, it will be difficult
to develop new therapeutic options, which are greatly needed. An
ideal mouse model must display both the circadian and affective components of sundowning. Several models presented in this review
exhibited either circadian locomotor activity changes, without measurement of any affective behaviors, or exhibited affective changes
without a circadian component. The combination of both factors
is at the core of sundowning syndrome and should be represented
in a strong mouse model. Furthermore, ideally the symptoms of
sundowning should be modeled in a transgenic mouse expressing
dementia-like brain pathology, as dementia patients are the most
72
T.A. Bedrosian, R.J. Nelson / Experimental Neurology 243 (2013) 67–73
Fig. 3. Acetylcholinesterase staining in nucleus basalis of Meynert (NBM) of aged mice. Relative optical density was quantified in sections containing the NBM (A). Aged mice had
greater AchE expression late in the dark phase compared to other groups (B), coinciding with the sundowning-like behavioral changes observed (see Fig. 2). Images captured at
10 ×. Scale bar = 100 μm. Graph depicts mean relative optical density ± SEM. *p b 0.05. NBM: nucleus basalis of Meynert; opt: optic tract; f: fornix. N = 3–6 mice per group.
Adapted from Bedrosian et al. (2011b).
commonly afflicted group. Such a model would provide the opportunity to gain insight into the mechanisms of this complex circadian
disorder.
Acknowledgments
We thank Dr. Zachary M. Weil for comments on this manuscript. TAB
was supported by a National Defense Science and Engineering Graduate
fellowship and RJN was supported by NIH grant RO1MH057535 and
NSF grant IOS-08-38098 during the preparation of this review.
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