Neurobiology of Disease 145 (2020) 105075
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Neurobiology of Disease
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Editorial
Sleep and circadian rhythms in the treatment, trajectory, and prevention of neurodegenerative
disease
1. Significance of sleep and circadian rhythms in
neurodegenerative disease
Neurodegenerative disorders account for a growing burden of dis­
ease globally, and this will only increase as the population ages (Feigin
et al., 2019). Fortunately, there have been measurable strides in miti­
gating the impact of these devastating diseases. Several modifiable risk
factors for neurodegeneration have been identified (Livingston et al.,
2017), with sleep and circadian rhythms being considered promising
targets for identifying individuals most at risk and for targeted inter­
ventions (Wulff et al., 2010).
This special issue reviews the current state of the field of sleep and
circadian rhythms and neurodegenerative diseases in aging popula­
tions. It focuses on abnormalities that precede and co-occur with neu­
rodegenerative diseases and the neurobiological mechanisms that drive
associations between sleep and neurodegeneration. Neurodegenerative
diseases covered in this issue include Alzheimer's disease and other
dementias, Parkinson's disease, Multiple System Atrophy, and
Huntington's disease. Toward translation of this knowledge to patient
care, the clinical utility of targeting sleep and circadian rhythms to
reduce risk for, and delay the progression of, neurodegeneration is
emphasized.
2. Sleep and circadian rhythms as early markers of
neurodegeneration
Changes in sleep and circadian rhythms may be the first manifes­
tation of neurodegeneration (Musiek and Holtzman, 2016). Exponential
progress has been made in identifying individuals in the prodromal
phases of neurodegenerative disease, who will serve as prime candi­
dates for targeted neuroprotective and/or disease-modifying therapies
(Dubois et al., 2014; Heinzel et al., 2019; McKeith et al., 2020; Paulsen
et al., 2014; Postuma et al., 2015). The quintessential example of this is
rapid eye movement (REM) sleep behavior disorder (RBD). RBD heralds
α-synucleinopathies, which include two of the most common neuro­
degenerative disorders, Parkinson's disease and Dementia with Lewy
Bodies (Postuma et al., 2012b). RBD is seen as a candidate target for
application of preventative neuroprotective therapies (Postuma et al.,
2012a; Postuma et al., 2015), as pharmacological treatments have
failed when tested after neurodegeneration has developed. In this issue,
Hu (2020) reviews RBD and the extent to which it provides a window to
study prodromal Parkinson's disease, Dementia with Lewy Bodies, and
Multiple System Atrophy. Hu points out the high conversion rates
among RBD patients to α-synucleinopathy-mediated neurodegenerative
diseases and describes the breakdown of cortical circuitry involved in
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Available online 02 September 2020
0969-9961/ © 2020 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
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T
REM sleep in patients with RBD. Hu discusses important data that in­
dicate that Parkinson's disease patients with RBD have greater patho­
logical burden, cognitive impairment and other neuropsychiatric
symptoms.
Neurodegenerative diseases may lead to other sleep and circadian
disorders such as insomnia, dampened circadian rhythms, and changes
in sleep architecture including decreases in slow-wave sleep (Lim et al.,
2013; Musiek et al., 2018) as described here by Lucey (2020). In this
issue, Fifel and Videnovic (2020) discuss circadian alterations in Alz­
heimer's disease, Parkinson's disease, and Huntington's disease. They
describe the pathologic involvement of neural circuits that generate
circadian rhythms and describe prodromal changes such as retinal al­
terations that may be used as biomarkers to screen for early Alzheimer's
disease.
Sleep and circadian disorders are highly debilitating for patients and
their families (Bhatt et al., 2005). For this reason, interventions that
improve sleep and circadian rhythms tailored for patients with neuro­
degenerative disease can substantially improve quality of life in pa­
tients and are critically needed (Iranzo and Santamaria, 2015). In this
issue, Memon et al. (2020) discuss the extent to which the sleep dis­
ruptions seen in various neurodegenerative diseases can be improved
with exercise. Memon et al. (2020) suggest, based on a small set of
randomized control trials, that exercise may improve subjective sleep
quality, increase sleep duration, and reduce sleep fragmentation in
Alzheimer's and Parkinson's disease.
3. Mechanistic role of sleep and circadian rhythms in the
progression of neurodegenerative disease
Growing evidence suggests that sleep and circadian changes may
also be directly involved in the pathways contributing to neurodegen­
eration. These include, but are not limited to, accumulation of ab­
normal proteins such as beta-amyloid (Aβ) and tau in Alzheimer's dis­
ease (Jack et al., 2010) and α-synuclein in Parkinson's disease and
Dementia with Lewy Bodies (Goedert, 2001), as well as activation of
astrocytes and microglia (Sadick and Liddelow, 2019).
Several articles in this issue highlight the potential for sleep dis­
orders to increase vulnerability to Alzheimer's disease. Lucey (2020)
discusses the bidirectional connection between sleep and neurodegen­
eration, focusing on the role of sleep in production, release, and
clearance of pathogenic proteins involved in Alzheimer's disease. Lucey
(2020) describes the consequences of sleep deprivation on cere­
brospinal fluid (CSF) proteins, including diurnal fluctuations in CSF Aβ
and tau. These changes may, over time, influence clearance of these
proteins, and in turn deposition of conformationally and/or chemically
Editorial
abnormal forms in the central nervous system. Owen and Veasey (2020)
discuss the long-term negative impact of short sleep and sleep disrup­
tion on neurogenesis, neuronal injury, and astrocyte and microglia
activation, as well as accumulation of abnormal Aβ, tau, and α-synu­
clein. Focusing on animal models of Alzheimer's disease, Owen and
Veasey (2020) describe the role of astrocytes and microglia in in­
flammation, and the extent to which sleep loss influences pro-in­
flammatory and anti-inflammatory markers. Critically, Owen and
Veasey (2020) highlight studies showing that recovery sleep does not
reverse neural injury, suggesting that effects of poor sleep can be long-
lasting. Lananna and Musiek (2020) review the potential role of cir­
cadian rhythm abnormalities in neurodegeneration. They propose that,
while circadian disorders result from neurodegeneration, age-related
circadian alterations can exacerbate pathogenic processes such as in­
flammation and oxidative stress - the imbalance between reactive
oxygen species and antioxidants (Betteridge, 2000). These pathogenic
processes are proposed to prime the brain for neurodegeneration.
Mullins et al. (2020) review cross-sectional and longitudinal studies of
obstructive sleep apnea in humans with assessments of Aβ and tau using
positron emission tomography (PET) or in cerebrospinal fluid (CSF).
They discuss a variety of pathways through which obstructive sleep
apnea may influence neurodegeneration, such as microglia activation,
CSF pulsations, and blood-brain-barrier breakdown.
4. Clinical implications for the role of sleep and circadian rhythms
in progression of neurodegenerative disease
The links between sleep and circadian rhythms with neurogenera­
tive diseases provide opportunities for low-cost, early interventions to
delay the progression of neurodegeneration. In reviewing the literature
on RBD as a prodromal manifestation of Parkinson's disease and other
neurodegenerative disorders, Hu points out that the prodromal phase
for Parkinson's disease can be 20 years and that this time frame is an
opportunity to slow neurodegeneration and prevent morbidity from
Parkinson's disease. Thus, Hu points to the need for studies targeting
patients with RBD to delay onset of Parkinson's disease and related
disorders.
Sleep and circadian disorders may serve as key targets to reduce
neurodegeneration. Behavioral interventions to improve insomnia, po­
sitive airway pressure to treat sleep-disordered breathing, and en­
hancement of slow-wave sleep and other electrophysiologic targets are
all promising approaches. However, evidence to support the direct
benefits of these treatment approaches on underlying neuropathology
and clinical measures such as cognition is limited. For instance, in this
issue Mullins et al. (2020) review the effects of obstructive sleep apnea
treatment, such as continuous positive airway pressure (CPAP) on
biomarkers of Alzheimer's disease. They point out the very limited
number of studies and conflicting findings regarding the effects of CPAP
on Alzheimer's disease biomarkers. They suggest that effects of CPAP on
cognition and Alzheimer's disease pathology may be most robust in
those with moderate or severe obstructive sleep apnea. Lananna and
Musiek (2020) point to the circadian clock as a promising target for
improving neurodegeneration through pathways such as neuroimmune
regulation. Grimaldi et al. (2020) discuss the extent to which sleep
enhancement methods can improve cognition, particularly memory
consolidation. They describe promising techniques such as transcranial
electrical stimulation, transcranial magnetic stimulation, and acoustic
stimulation that have been shown to enhance slow-wave activity during
sleep. While these techniques enhance slow-wave activity, their effects
on cognition are not well understood.
5. Conclusions and future directions
This issue reinforces the state of the field that bidirectional links
between sleep and circadian rhythms and prevalent forms of neurode­
generation are likely. While adequate sleep and circadian health are
2
Neurobiology of Disease 145 (2020) 105075
critical for optimal brain function, moving toward experimental ap­
proaches is necessary to fully characterize the putative bidirectional
relationship between sleep and circadian circuits and neurodegenera­
tion. This will allow the field to expand use of sleep and circadian
rhythms as markers for early treatment of prodromal neurodegenera­
tive disease and will inform interventions that are most beneficial for
improving sleep and circadian rhythms to most directly mitigate neu­
rodegeneration.
There are important future directions raised in this Special Issue. In
light of the robust data indicating that RBD is the earliest presentation
of α-synucleinopathy, Hu highlights the need for interventional studies
of neuroprotective and disease-modifying therapies in the RBD popu­
lation. This will help to reduce disease progression and prevent dis­
ability from Parkinson's disease, Dementia with Lewy Bodies, and re­
lated disorders.
Owen and Veasey (2020) point out that data are lacking on when,
during the lifespan, poor sleep is most likely to impart neuronal injury.
Clinical research studies of this kind in humans require decades of re­
search- and sleep has only recently been prioritized in clinical studies of
neurodegenerative disease. Indeed, from the standpoint of under­
standing the causal effects of poor sleep and circadian rhythms on
neurodegenerative disease progression via interventional studies, there
is currently a dearth of data. Mullins et al. (2020) point to the need for
additional longitudinal studies on the relationship between obstructive
sleep apnea and incident Alzheimer's disease pathology. They make
intriguing suggestions for study designs to more directly assess effects
of treatment of OSA, including expanding tests of cognitive function to
include not only the typical daytime functions but also measures of
overnight memory retention. Grimaldi et al. (2020) discuss the nascent
field examining whether cognition can be improved through slow-wave
sleep enhancement. Grimaldi et al. (2020) emphasize the pressing need
for more data on the effects of sleep enhancement on cognition and
other functions affected by neurodegeneration. There is also a need to
understand the optimal timing for introduction of sleep enhancement
interventions: whether measurable, clinically significant effects can be
demonstrated in populations with advanced pathology and neurode­
generation or if they are most effective before significant neurodegen­
eration has occurred.
While there has been a recent surge in studies of sleep in the context
of neurodegeneration, several important gaps remain in the literature.
There is a need for studies specifically designed to test the connection
between sleep and neurodegenerative diseases and a need for studies
with gold-standard objective and subjective measures of sleep collected
longitudinally. Creating cohort studies focused on sleep will be bene­
ficial in determining the sleep features and behaviors that increase risk
for specific neurodegenerative disease. Critically, samples re­
presentative of the racial and ethnic diversity of the greater population
will be essential and will ensure that populations with a high pre­
valence of sleep disorders and Alzheimer's disease are represented in
the scientific literature (Babulal et al., 2019).
As highlighted throughout this issue (Fifel and Videnovic, 2020;
Grimaldi et al., 2020; Hu, 2020; Lananna and Musiek, 2020; Lucey,
2020; Mullins et al., 2020; Owen and Veasey, 2020), accumulating
evidence indicates a relationship between sleep, CSF dynamics, and
clearance of potentially neurotoxic proteins (Ovod et al., 2017). In­
novative, non-invasive techniques to study CSF would greatly facilitate
investigation in this area. For instance, imaging of CSF flow, as recently
performed in the context of sleep (Fultz et al., 2019), is a promising
technique for studying the link between sleep and circadian rhythms
and clearance of proteins involved in neurodegenerative disease.
As this special issue illustrates, sleep and circadian rhythm disorders
are part and parcel of the study of neurodegeneration, its risk factors,
and manifestations. As the population ages globally, it is becoming
increasingly crucial to understand how these factors influence one an­
other and may be targeted experimentally, and ultimately translated to
clinical care. Treating sleep and circadian disorders has the potential to
Editorial
reduce risk of neurodegeneration and its manifestations and can im­
prove quality of life and symptoms in those with neurodegenerative
disorders.
Funding
K.A.W. is supported by a Career Development Award from the
National Institutes of Health NIH: K01 AG049879
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Kristine A. Wilckensa, Lana M. Chahineb,
⁎
a
University of Pittsburgh, School of Medicine, Department of Psychiatry,
Pittsburgh, PA, USA
b
University of Pittsburgh, School of Medicine, Department of Neurology,
Pittsburgh, PA, USA
E-mail address: lchahine2018@gmail.com (L.M. Chahine).