Keywords
neurodegeneration - stroke - sleep deprivation - circadian rhythm - glymphatic system
- memory
Sleep health and circadian rhythm regulation are fundamental to human health, playing
a critical role in optimizing brain function, mental well-being, immune resilience,
and cardiometabolic health. Sleep is an active process facilitating several functions
essential for brain health, including memory consolidation,[1] synaptic plasticity,[2] and the clearance of neurotoxic waste products through the glymphatic system.[3] Despite its vital role, over half of the world's adult population falls short of
the recommended 7 to 9 hours of nightly sleep—with profound consequences for brain
health[4]
[5]
[6] ([Fig. 1]).
Fig. 1
Healthy sleep. Schematic overview highlighting the essential role of sleep in maintaining healthy
brain function. The circular element at the top illustrates a 24-hour cycle, with
the pink segment representing wakefulness and the black segment representing sleep.
Inside the circle, a stylized brain indicates key structures involved in sleep regulation
(mainly in the hypothalamus and brainstem). Below, three panels depict critical processes
that occur, or are enhanced, during sleep: (1) clearance through the glymphatic system,
(2) memory consolidation, and (3) synaptic plasticity. Ach, Acetylcholine; LC, Locus
Ceruleus; LH, Lateral Hypothalamus; SLD, Sublaterodorsal Nucleus; TMN, Tuberomammillary
Nucleus; LDT, Laterodorsal tegmental Nucleus; VLPO, Ventrolateral preoptic nucleus.
Sleep serves as a cornerstone for preventing and better managing various neurological
disorders ([Fig. 2]). Sleep–wake disturbances are closely associated with major neurodegenerative diseases
(NDDs), with sleep disorders, alterations in sleep architecture, and circadian rhythm
disruptions often preceding their clinical onset.[7] Similarly, sleep disturbances are highly prevalent among post-stroke patients.[8] Notably, even during the developmental stages, sleep loss reduces brain size and
produces long-lasting behavioral, morphological, and biochemical abnormalities in
later life.[9] Therefore, not only is sleep research paramount in neuroscience, but clinicians
also have a unique opportunity to transform patient outcomes and enhance quality of
life by making sleep assessment a core component of their practice.
Fig. 2
Disturbed sleep and its consequences on brain health. Schematic representation of how sleep disorders, circadian rhythm disturbances, and
sleep architecture changes can negatively affect brain health. These have a bidirectional
relationship and converge to impair several key processes in the brain, including
synaptic damage, oxidative stress, glymphatic dysfunction, and increased protein misfolding.
The downstream consequence of these disturbances is an elevated risk for neurological
disorders (e.g., dementia, Parkinson's disease, and stroke), illustrated at the bottom.
Sleep Physiology and Brain Health: Mechanisms, Homeostasis, and Implications
Sleep Physiology and Brain Health: Mechanisms, Homeostasis, and Implications
Two-Process Model and Neuronal Circuits Regulating Sleep
The two-process model proposed by Borbély more than four decades ago still offers
an important conceptual framework for understanding sleep–wake regulation.[10] The model proposes that sleep regulation is governed by the interaction of a homeostatic
process, which builds up during wakefulness and decreases during sleep (Process S),
and a circadian process driven by the body's circadian pacemaker, aligning sleep and
wakefulness with the 24-hour light–dark cycle (Process C).[11] Brain nuclei involved in sleep–wake regulation are located within the brainstem
and the hypothalamus.
The accumulation of endogenous sleep-promoting substances during the day, such as
adenosine, activates the ventrolateral preoptic area (VLPO), which is well described
in rodents, and the median preoptic nucleus (MnPO).[12] The rodent VLPO and MnPO, which mainly produce gamma-aminobutyric acid (GABA), act
on different neurotransmitters and circuits, inhibiting wake-promoting regions ([Fig. 1]).[12] Other neuronal circuits promoting non-rapid eye movement (NREM) sleep include the
parafacial zone in the brainstem (GABA/glycine) and the nNOS neurons in the cortex
(nitric oxide),[13] whereas neurons involved in regulating rapid eye movement (REM) sleep are mainly
located in the pons.[12]
[14] Additionally, at night, the absence of light reduces suprachiasmatic nucleus (SCN)
activity, lifting the inhibition on melatonin production that the SCN imposes during
the day, allowing melatonin synthesis to occur.[15] Melatonin, in turn, enhances the activity of the VLPO and reduces the activity of
arousal-promoting brain regions, which promotes sleep.
Circadian Rhythms and Brain Health
Circadian Rhythms and Brain Health
Circadian rhythms, the intrinsic 24-hour cycles that regulate various physiological
processes, play a crucial role in maintaining brain health and function. These rhythms
are orchestrated by the SCN in the hypothalamus, which serves as the master clock,
synchronizing circadian rhythms throughout the body, including those in the brain.
The circadian rhythms are self-sustained, meaning that they exist in the absence of
any exogenous signals. However, they can be entrained by environmental factors and
are influenced by genetics.[16] Light is the primary stimulus (Zeitgeber) for entraining the SCN rhythm period,
along with other environmental factors such as physical activity and temperature.
Additionally, light suppresses the secretion of melatonin, a hormone that facilitates
the transition to sleep, synthesized in the pineal gland with its receptors located
in the SCN, as mentioned earlier.[15] The collective work of Jeffrey Hall, Michael Rosbash, and Michael Young demonstrated
that individual cells also have a circadian molecular rhythm, which is regulated via
a transcriptional–translational feedback loop. Transcription factors such as circadian
locomotor output cycles kaput (CLOCK) or brain and muscle ARNT-like protein 1 (BMALI1)
regulate the expression of genes such as the encoding period (PER) and the cryptochrome
(CRY) that, once translated, inhibit their own transcription.[17] Furthermore, circadian rhythms also experience changes with aging; the timing of
sleep onset is relatively earlier in childhood compared with adulthood and shifts
later during adolescence, returning to being earlier again in older adults.[17] These changes are also observed at a molecular level.[18] Aging is also associated with a decrease in sensitivity to environmental cues (e.g.,
reduced response to light due to increased prevalence of ophthalmological conditions[19]), aligning the circadian rhythms to the natural day/night cycle. Disruptions in
circadian rhythms have been linked to neurological disorders, highlighting their significance
in brain health, as we discuss in the following sections. Perhaps the most directly
affected group is shift workers, as 10% suffer from shift work sleep disorder and
are at risk of significant health consequences.[20] Furthermore, a recent meta-analysis showed that shift work was associated with an
increased incidence of dementia.[21] Of note, the implications of circadian rhythms disturbances extend beyond cognitive
decline; they also encompass metabolic and immune dysregulation, which can further
compromise brain health. For example, the interplay between circadian rhythms and
the gut microbiome has been identified as a critical factor influencing overall health,
including mental well-being.[22]
Melatonin, beyond its role in regulating circadian rhythms, has been suggested to
have neuroprotective properties, particularly through its interactions with mitochondrial
dynamics and cytoprotection.[23] It acts as an antioxidant, scavenging reactive oxygen species (ROS) and enhancing
the activity of antioxidant enzymes. Melatonin and its metabolites reduce oxidative
damage in particular in the mitochondria, reducing also mitochondria-related apoptosis,
contrasting aging-related mitochondrial dysfunction.[24] In line with that, age-related declines in melatonin levels are associated not only
with mitochondrial dysfunction but also with increased neuroinflammation, contributing
to the pathophysiology of neurodegenerative diseases.[23] This makes melatonin a potential therapeutic candidate for age-related brain disorders.
Sleep Architecture Across the Lifespan
Sleep Architecture Across the Lifespan
The structure of sleep is broadly categorized into two primary states: non-rapid eye
movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is further subdivided
into three distinct stages: N1, N2, and N3, with N3 being characterized as slow-wave
sleep. Each stage of sleep exhibits unique electroencephalographic (EEG) patterns,
eye movement characteristics, and variations in muscle tone. The progression between
NREM and REM sleep occurs in a cyclical manner throughout the sleep period.[25] The time course of process S is characterized by an exponential decline in slow-wave
activity during both baseline sleep and recovery sleep following sleep deprivation.
REM sleep, on the other hand, is mainly regulated by the circadian pacemaker.[11]
Sleep architecture changes across the lifespan; for example, REM sleep is predominant
in infants and subtly decreases with age, while the percentage of N3 sleep decreases
linearly by approximately 2% per decade of life, plateauing after the age of 60. Consequently,
there is an increase in N1 and N2 sleep and wake after sleep onset.[26] Furthermore, sex differences exist, as the decline in N3 sleep is slower in women
compared with men.[27] These changes in sleep architecture are accompanied by hormonal changes, as the
decline of N3 sleep from early adulthood to midlife is paralleled by a major decline
in growth hormone secretion, and increased sleep fragmentation related to aging is
associated with higher cortisol levels.[28]
Adenosine: A Key Regulator of Sleep and Cognitive Health
Adenosine plays a crucial role in the regulation of sleep, acting as a homeostatic
sleep factor that accumulates during wakefulness (thereby contributing to factor S)
and promotes sleep through its interaction with specific adenosine receptors, primarily
A1 and A2A receptors.[29] Adenosine mediates a glial–neuronal circuit linking glial metabolic state (modulated
by adenosine kinase in astrocytes) to neural-expressed sleep homeostasis.[30] The extracellular accumulation of adenosine in the basal forebrain and preoptic
areas during prolonged wakefulness enhances sleep pressure, leading to increased sleep
propensity. The sleep-promoting effects of adenosine are further evidenced by the
observation that its receptor agonists can increase NREM sleep in rats[31] and cats.[32] The stimulation of A1 adenosine receptors induces EEG changes that are similar to EEG profiles observed
after sleep deprivation.[33] On the other hand, antagonists like caffeine, the most consumed stimulant, counteract
these effects by blocking adenosine receptors (non-selectively), thereby increasing
alertness and reducing the drive for sleep.[34] The mean half-life of caffeine is about 5 hours,[35] and when humans consume approximately 200 mg of caffeine in the early evening, the
endogenous melatonin rhythm is delayed by around 40 minutes. Additionally, one study
indicated that caffeine lengthens the circadian rhythms and causes a phase delay ex
vivo.[36] Therefore, antagonizing the effect of adenosine could also affect sleep through
changes in circadian rhythms (Process C). Furthermore, adenosine plays a role in memory
performance. For example, the short-term memory impairment induced by scopolamine
could be prevented by A1 and A2A antagonists, while the activation of A2A receptors is sufficient to trigger memory impairment in mice.[37] Additionally, one study showed that administration of caffeine enhanced memory consolidation
but not retrieval for up to 24 hours according to an inverted U-shaped dose–response
curve.[38] Moreover, chronic caffeine consumption was associated with a reduced risk of dementia
progression in patients with mild cognitive impairment (MCI), and epidemiological
studies found an association between coffee consumption and a lower incidence of Alzheimer's
disease (AD).[39]
[40] These effects are primarily attributed to the antagonism of adenosine receptors.[41] In line with these findings, a recent study showed that blockade of A2A receptors could reverse early spatial memory defects in transgenic mouse AD models
by promoting synaptic plasticity.[42] Although the precise mechanism by which adenosine receptor antagonism might prevent
dementia progression remains unclear, a recent study has shown that A2A receptors are upregulated in brain samples from patients with various tauopathies
(including frontotemporal dementia, corticobasal degeneration, and Pick's disease),
potentially accelerating neurodegeneration.[43] This observation suggests that caffeine, through its antagonistic action on these
receptors, may help counteract such effects and slow the neurodegenerative processes.
However, current evidence on the relationship between caffeine and brain health is
inconsistent across various studies due to factors such as gender, age, genetic predisposition,
and caffeine dosage. In patients with severe hypertension, drinking more than two
cups of coffee a day was associated with an increased risk of cardiovascular mortality.[44] Additionally, coffee consumption in higher dosages (≥300 mg) is associated with
an increased risk of neuropsychiatric symptoms in individuals with mental disorders
or dementia.[45]
[46] Daytime caffeine consumption was associated with reduced apathy and aberrant motor
behavior but more frequent nighttime awakenings in elderly dementia patients, with
caffeine intake after 6 pm significantly contributing to sleep disturbances[47] and reported improved sleep after eliminating caffeine.[48] A study on habitual caffeine consumers found that 10 days of caffeine intake led
to reduced gray matter (GM) volume in the medial temporal lobe, independent of sleep
depth, suggesting that daily caffeine consumption may induce neural plasticity in
this region.[49] Similarly, another study on 36 healthy adults found that 5 days of sleep restriction
led to increased gray matter in several brain regions, while caffeine consumption
during this period resulted in GM reductions, particularly in the thalamus and prefrontal
cortex. The findings suggest that sleep restriction alone may trigger adaptive GM
changes, whereas caffeine interferes with this process, potentially through mechanisms
independent of A1 adenosine receptor availability.[50]
In summary, adenosine regulates sleep, circadian rhythms, and cognition, while caffeine,
as its antagonist, enhances alertness but can also disrupt sleep and alter brain structure,
with still unclear effects on neurodegenerative processes.
Memory Consolidation and Synaptic Homeostasis During Sleep
Memory Consolidation and Synaptic Homeostasis During Sleep
Several studies showed that memory performance improves significantly after a whole
8-hour sleep at night[51]
[52]
[53]; moreover, 1- to 2-hour naps[54]
[55] or even 6-minute naps were shown to provide memory benefits,[56] with longer durations yielding more benefits.[57] Interestingly, for the largest benefits, sleep should happen relatively close to
the learning process, as better results on declarative memories have been reported
if sleep happens 3 hours compared with 10 hours after learning.[58]
[59] Not only the duration of sleep but also the different sleep stages play a role in
memory consolidation, with different sleep stages affecting different types of memory.
NREM sleep is thought to facilitate declarative, hippocampus-dependent memories (e.g.,
learning facts), whereas REM sleep is thought to facilitate consolidation of memories
that are non-declarative (procedural and emotional aspects, e.g., driving a bike).[60] Notably, some studies showed that declarative and non-declarative memory consolidation
can occur at any sleep stage.[61]
[62]
Mechanisms involved in memory reinforcement during sleep include memory reactivation
and synaptic consolidation.[57] Compelling evidence of the former emerged from a study where participants learned
spatial locations paired with an odor. When the odor was reintroduced during N3 but
not during REM sleep, it led to a notable enhancement of spatial memory.[63] Moreover, in rats, it was shown that spatial–temporal patterns of neuronal firing
occurring during learning are reactivated in the same order during subsequent slow-wave
sleep.[64] Slow-wave sleep and sleep spindles are thought to initialize long-term potentiation
(LTP)[65] and aid in synaptic consolidation during subsequent REM sleep. Some studies showed
a positive correlation between spindle density and post-sleep memory improvement.[66]
Moreover, specific neurotransmitters are essential for memory processes during sleep.
For instance, acetylcholine has been shown to facilitate memory consolidation during
NREM sleep by stabilizing neural network dynamics and enhancing synaptic plasticity.[67] Additionally, the expression of clock genes, such as Per1, has been implicated in
regulating memory consolidation during the day, suggesting that the timing of sleep
relative to the circadian cycle can influence memory outcomes.[68] Thus, NREM and REM sleep seem to play complementary roles, interacting with circadian
cycles, which ultimately optimize memory consolidation.
Sleep and Waste Clearance
Sleep and Waste Clearance
The glymphatic system is a recently discovered waste clearance pathway in the brain,
primarily active during sleep.[69] It is a functional system analogous to the lymphatic system but unique to the central
nervous system, as the brain lacks conventional lymphatic vessels. This system operates
through a network of perivascular spaces that allow cerebrospinal fluid (CSF) to flow
through the brain, effectively flushing out waste products that accumulate during
wakefulness. The glymphatic system's perivascular tunnels connect directly to the
brain's subarachnoid spaces, where cardiac rhythm–driven arterial pulsations propel
CFS flow.[70] The organizational units of this system are astrocytes and the water channel Aquaporin
4 (AQP4), which face the vessel wall. The observation that sleep and the glymphatic
system are related came initially from animal models, whereby sleep was associated
with a 60% increase in the interstitial space, resulting in a significant increase
in the convective exchange of CSF with interstitial fluid.[71] Indeed, CSF tracer influx was found to be correlated with EEG slow-wave activity,
which means that the glymphatic clearance is most active during N3 sleep (which physiologically
corresponds to the first hours of sleep).[72] Moreover, glymphatic flow was shown to be regulated by circadian rhythmicity.[73] In humans, it was found that even a single night's sleep deprivation significantly
impairs cerebral clearance.[74] The implications of glymphatic dysfunction are particularly interesting in the context
of neurodegenerative diseases. By analyzing multimodal data from the AD Neuroimaging
Initiative project, it was shown that coupling between the global functional magnetic
resonance image (fMRI) signal and CSF influx is correlated with AD-related pathology.[75] Furthermore, interstitial fluid's convective fluxes increase the amyloid-β clearance
rate during sleep.[71] However, one recent study has reported findings that challenge the notion of consistently
enhanced glymphatic flow during sleep. This study showed that in mice, brain clearance
is markedly reduced, not increased, during sleep and anesthesia.[76] This might, however, be related to methodological aspects, e.g., the dye injection
technique used, which can affect brain clearance, impacting the findings and methods
applied to measure brain clearance. Therefore, although the concept of the glymphatic
system is very promising to improve the understanding of neurodegeneration pathophysiology,
no methodology has been established to clearly and directly assess its function, and
more research is needed in this area.
Consequences of Sleep Deprivation on Brain Health
Consequences of Sleep Deprivation on Brain Health
The optimal sleep amount recommended by the American Academy of Sleep Medicine is
7 to 9 hours per night.[5] There is an inverted U-shaped relationship between health outcomes and sleep durations,
with sleep duration of less than 6 hours or more than 9 hours being associated with
all-cause mortality, older phenotypic age, and increased likelihood of depression.[77]
[78]
[79] Sleep deprivation, broadly defined as an insufficient amount of sleep, can manifest
in two main forms: acute and chronic. Acute sleep deprivation involves a short-term
period—usually 24 to 48 hours—of severely restricted or entirely missed sleep, such
as pulling an “all-nighter” to meet a deadline. By contrast, chronic sleep deprivation
arises from a longer-term pattern of consistently limited sleep over weeks or months.
Both forms can yield profound negative consequences on brain health. Numerous studies
showed a decrease in attention and working memory after acute sleep deprivation; these
include findings such as slower reaction time, reduced vigilance, and lower performance
in serial addition/subtraction tasks.[80]
[81] Sleep deprivation increases adenosine levels in the basal forebrain, thereby inhibiting
the cholinergic system, which plays a role in memory modulation, as mentioned earlier.[82]
[83] Regarding clearance of brain waste products, one study showed that sleep deprivation
increased overnight amyloid-β38, amyloid-β40, and amyloid-β42 levels by 25 to 30%
as measured in the CSF.[81] Using positron emission tomography (PET), another study showed that sleep deprivation
increases amyloid-β in the hippocampus and thalamus, an increase which was associated
with mood worsening; moreover, the study found an inverse association between amyloid-β
burden in subcortical areas and reported night sleep hours.[84] Beyond the acute effect of sleep deprivation, a recent study showed that persistent
short sleep duration at ages 50, 60, and 70 compared with persistent normal sleep
duration was associated with a 30% increased dementia risk.[85] Moreover, reduced sleep efficiency (defined as the percentage of the time in bed
spent sleeping) was associated with incident risk of all neurodegenerative diseases.[86] Another recent study showed that sleep regularity seems to be a stronger predictor
of mortality than sleep duration.[87] Although more data are needed to disentangle the complex relationship between sleep
duration and brain health, these studies highlight the critical role of healthy sleep
in maintaining optimal brain health.
Sleep in Neurodegenerative and Neurovascular Diseases
Sleep in Neurodegenerative and Neurovascular Diseases
Sleep Disorders and Neurodegenerative Diseases
As mentioned earlier, since sleep and circadian rhythms rely on coordinated functions
across multiple regions, nuclei, and neurotransmitters in the central nervous system,
it follows that neurodegenerative conditions can easily disrupt these interconnected
pathways, thereby contributing to sleep disturbances. In AD, for instance, a reduction
in the number of neurons within the SCN,[88] combined with diminished synchrony among various circadian oscillators in the brain,[89] is frequently linked to daytime sleepiness, sleep apnea, insomnia, and fragmented
sleep patterns.[90] Likewise, very early in the course of Parkinson's disease (PD) the centers responsible
for sleep–wake regulation, as well as the expression of clock genes, are impacted,
leading to sleep disturbances in nearly all patients.[91] The most common disorders include rapid eye movement sleep behavior disorder (RBD),
insomnia, restless legs syndrome (RLS), and sleep-related breathing disorders. Moreover,
excessive daytime sleepiness is common in patients with PD.[91] Sleep problems are not confined to these two prevalent neurodegenerative disorders
but also affect patients suffering from other neurodegenerative diseases, such as
dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis,
progressive supranuclear palsy, Huntington's disease, and spinocerebellar ataxias.[7]
Importantly, sleep disturbances are among the critical early markers indicating the
onset of neurodegeneration. The best example is RBD, which is characterized by abnormal
behaviors, jerks, and/or vocalizations during REM sleep, and the absence of physiological
muscle atonia during REM sleep. Longitudinal studies have reported that the vast majority
of patients with isolated RBD (i.e., RBD not secondary to a manifest NDD, other neurological
diseaser or other sleep disorders such as narcolepsy) eventually develop an α-synuclein-related
neurodegenerative disorder (i.e., PD, dementia with Lewy body and multiple system
atrophy), whereby the risk for developing neurodegenerative diseases was 33.5% at
5 years follow-up, 82.4% at 10.5 years, and 96.6% at 14 years.[92] Additionally, in patients with isolated RBD, there is a frequent occurrence of subtle
prodromal neurodegenerative abnormalities such as hyposmia, subtle motor deficits,
constipation, and orthostatic hypotension, along with abnormalities detected on various
neurophysiological and autonomic tests as well as on neuroimaging and biofluids (including
the presence of pathological α-synuclein aggregates).[93]
[94]
Another well-investigated example of the link between sleep and neurodegeneration
is sleep-disordered breathing (SDB), characterized by recurrent apneas and hypopneas
frequently leading to recurrent arousals from sleep, which has been associated with
dementia. The earliest longitudinal evidence came from a community study, where women
with SDB were more likely to develop MCI (adjusted HR 1.85; 95% confidence interval
(CI) 1.11–3.08) after 5 years follow-up.[95] Similarly, in community-dwelling men participating in the Osteoporotic Fractures
in Men Study (MrOS), nocturnal hypoxemia was associated with global cognitive decline
both cross-sectionally and after 3.4 years.[96]
[97] In the AD Neuroimaging Initiative cohort, patients with SDB were younger at MCI
onset (72–77 versus 82–89 years), or AD dementia onset (83 versus 88 years) after
3 years follow-up, compared with participants without SDB. Moreover, continuous positive
airway pressure (CPAP) use was associated with older age at MCI onset.[98] In the Atherosclerosis Risk in Communities Study, initially no association was found
between SDB and incident risk of dementia after 15 years. However, a later study from
the same cohort, including more participants, indicated that the relationship might
not be linear as severe OSA (≥30 apnea–hypopnea events/hour) versus no OSA (<5 apnea–hypopnea
events/hour) was associated with a higher risk of all-cause dementia (risk ratio 2.35).[99] A meta-analysis covering 4.3 million individuals indicated that those with SDB were
26% (risk ratio, 1.26; 95% CI, 1.05–1.50) more likely to develop cognitive impairment.[100] In a sample of 53,000 Medicare beneficiaries with SDB, PAP treatment and adherence
were associated with lower odds of incident diagnosis of AD (odds ratio [OR] 0.78,
95% CI, 0.69–0.8).[101] Furthermore, imaging studies in cognitively asymptomatic individuals with SDB showed
medial temporal lobe atrophy, which may increase the risk of developing memory impairment.[102] Recently, metrics other than the classical apnea–hypopnea index, such as hypoxic
burden, were shown to predict cognitive dysfunction in sleep apnea patients.[103]
Besides SDB, other sleep disorders and disturbances, such as insomnia, excessive daytime
sleepiness, and sleep fragmentation, predate the diagnosis of NDDs.[104]
[105]
[106] Furthermore, beyond manifest sleep disturbances, we found that early sleep architecture
changes, as measured by polysomnography, are present up to 12 years before the diagnosis
of NDDs. These include reduced REM sleep, N3 sleep, sleep efficiency, as well as increased
wake in sleep period time.[86] Similarly, in a subset of the Framingham Heart Study (FHS), lower REM sleep percentage
and longer REM sleep latency were both associated with a higher risk of incident dementia
after 12 years.[107] Additionally, in the MrOS study lower REM sleep percentage and lower α/theta ratio
in sleep EEG were associated with incident PD after a median follow-up of 9.8 years.[108]
Circadian disturbances are also prevalent in NDDs and are associated with their incidence.
For example, these patients may exhibit increased nighttime activity and reduced daytime
activity, and in some cases even experience a complete reversal or disruption of their
normal 24-hour rest–activity cycle. AD patients also experience increased neuropsychiatric
symptoms around sunset, referred to as “sundowning,” which is partly attributed to
circadian misalignment.[109] To understand circadian changes in patients with NDD, it is important to distinguish
circadian phase from circadian amplitude. The former refers to the timing of specific
points within the roughly 24-hour cycle—such as when melatonin levels begin to rise
or when core body temperature reaches its lowest point.[110] Circadian amplitude, on the other hand, reflects the intensity of the rhythmic variation—often
quantified as the difference between the maximum and minimum levels of a measured
circadian parameter (like melatonin concentration or body temperature).[110] PD is characterized by a reduction in the circadian amplitude without shifts in
circadian phases.[111] In AD, rest–activity rhythm fragmentation[112] and circadian shifts prevail. Regarding the latter, literature findings are mixed,
with one study showing phase delay among AD patients[79] and others finding phase advance.[113] Of note, it is still unclear whether neurodegeneration is a consequence or a cause
of circadian disturbances, or both. Using data from the UK Biobank and MrOS, variables
reflecting circadian rhythm disruption were derived from the accelerometry data and
showed that disturbed circadian rhythm is associated with all-cause dementia, PD,
and anxiety disorders 6 to 11 years before their clinical onset.[114]
[115] Another study found that preclinical AD was associated with rest–activity rhythm
fragmentation, and that aging was associated with circadian dysfunction independently
of preclinical AD pathology (assessed with PET imaging and amyloid-β pathology).[116] Additionally, a randomized controlled double-blinded study showed that long-term
application of bright light treatment (+/− 10,000 lux) reduced cognitive decline by
a modest 5% and improved depressive symptoms, while the combination of bright light
treatment with melatonin improved sleep efficiency and reduced nocturnal restlessness.[117] In PD patients, bright light exposure (10,000 lux) improved daily activity and reduced
daytime sleepiness.[118] Blue light exposure early in the day not only suppresses daytime melatonin but also
enhances serotonin levels via the retino-raphe pathway, where photoreceptor signals
from the retina stimulate the dorsal raphe nucleus. This process enhances tryptophan
metabolism, leading to increased serotonin availability, which is later converted
into melatonin in the pineal gland.[119] As a result, natural sunlight exposure during the day ensures optimal serotonin
levels, directly influencing nighttime melatonin production. Furthermore, infrared
light has been identified as a promising intervention for neurodegenerative diseases,
as it stimulates cytochrome c oxidase (complex IV) in the electron transport chain,
enhancing ATP production and cellular energy metabolism.[120] This process also facilitates the reduction of oxidative stress and supports mitochondrial
resilience, reinforcing its potential therapeutic role in aging and neuroprotection.
Insights from animal models also provide evidence of circadian disruption being linked
to NDDs pathology. For instance, a mouse model of amyloidosis-β with deletion of the
core clock gene Bmal1 has demonstrated that loss of central circadian rhythms leads
to disruption of daily hippocampal interstitial fluid amyloid-β oscillations and accelerates
plaque accumulation.[121] Another study found that orexin regulates the hippocampal clock and circadian oscillation
of AD risk genes.[122] Overall, circadian science is evolving and provides new insights into early detection
and modulation of NDDs.
Sleep and Stroke
Cardiovascular diseases remain the leading cause of all-cause mortality.[123] In the context of sleep and neurovascular health, the most relevant sleep disorder
is SDB, as it affects around 20% of the general population. SDB is related to wake-up
stroke through mechanisms including non-dipping blood pressure and impaired cerebral
hemodynamics.[124] On the other hand, SDB is common in stroke patients; a meta-analysis of 2,343 ischemic
or hemorrhagic stroke and TIA patients found the frequency of SDB with AHI > 5 to
be 72% and with AHI > 20 to be 38%.[125] In both the Wisconsin Sleep Cohort Study (1,189 subjects followed up for 4 years)
and the Sleep Heart Health Study (5,422 participants followed up for 8.7 years), there
was a 2- to 3-fold increase in the risk of stroke for subjects with untreated SDB.[126]
[127] Silent brain infarctions on MRI were more common among patients with moderate to
severe sleep apnea than among control subjects or patients with mild sleep apnea.[128] Importantly, this is an easily modifiable risk factor, as CPAP therapy with good
adherence, which is the gold standard for SDB, is associated with stroke risk reduction.[129] Notably, poor compliance with PAP therapy negates benefits concerning stroke risk
reduction. Beyond SDB, other sleep disorders, such as RLS, seem to possibly occur
post-stroke in the setting of lesions in the basal ganglia/corona radiata.[130] RLS is also likely linked to a higher prevalence of coronary artery disease and
cardiovascular disease, and this relationship appears to be stronger in individuals
who experience more frequent or severe RLS symptoms.[131] Furthermore, a recent study showed an association between insomnia and objective
(<6 hours confirmed by polysomnography) but not subjective short-sleep duration and
incident cardiovascular diseases after a median follow-up of 11.4 years.[132] Moreover, persistent insomnia symptoms were associated with an increased risk of
stroke in younger adults.[133]
Sleep changes are also frequent post-stroke, with poor sleep quality affecting up
to 53% of stroke patients.[134] Sleep architecture was shown to be significantly affected in 104 post-stroke patients
compared with 162 controls; changes included reduced total sleep time and sleep efficiency,
and increased wakefulness. Additionally, the percentage of REM sleep was shown to
be negatively associated with stroke severity. Of note, in the same study, sleep quality
and sleep architecture improved but did not normalize during the 3 months after stroke.[135]
In 437 stroke patients over 2 years follow-up (after one to seven days, one month,
three months, twelve months and twenty-four months), the frequencies of excessive
daytime sleepiness (EDS), fatigue, and insomnia varied between 10 and 14% for EDS,
22 and 28% for fatigue, and 20 and 28% for insomnia over the five follow-up visits.[136] Additionally, depending on the infarct area, not only RLS but also other sleep disorders
such as RBD or hypersomnolence disease can occur, albeit more rarely as small strategic
areas need to be affected by the stroke to cause these symptoms.[8] In conclusion, the complex bidirectional relationship between stroke and sleep requires
further investigation, given the high prevalence of these diseases and the potential
implications of treating sleep disorders in stroke prevention and management.
Therapeutic Implications and Future Directions
Therapeutic Implications and Future Directions
The most straightforward and broadly applicable intervention to safeguard against
the deleterious effects of sleep disturbances is maintaining adequate sleep duration
and rhythmicity and practicing sound sleep hygiene. Fundamental measures include establishing
a consistent bedtime and rise time, avoiding stimulants like caffeine in the late
afternoon or evening, and ensuring an environment conducive to rest—cool, dark, and
free from excessive noise. Such non-pharmacological strategies can substantially improve
sleep quality, reduce nocturnal awakenings, and bolster cognitive function, especially
in individuals experiencing early, mild sleep problems.[5]
[137] Moreover, by raising public awareness of sleep disorders, early detection and intervention
become more feasible, reducing the risk of serious complications. Strengthening sleep
education and implementing targeted healthcare strategies are, therefore, critical
steps toward improving overall sleep health and preventing long-term adverse outcomes
impacting brain health.[6]
When these general interventions fail to sufficiently address persistent sleep issues,
targeted treatments become necessary. For example, those suffering from insomnia can
often benefit from Cognitive Behavioral Therapy for Insomnia (CBT-I). This evidence-based
and currently first-line approach combines behavioral techniques (e.g., stimulus control,
sleep restriction) with cognitive strategies aimed at alleviating anxiety or maladaptive
thoughts about sleep.[138] Several studies have shown that CBT-I not only improves sleep continuity and reduces
insomnia severity but may also have a protective effect against cognitive decline
and reduce the rate of amyloid-β deposition in older adults.[139] Additional interventions, such as melatonin supplementation (to recalibrate the
sleep–wake cycle), emerge as promising candidates for mitigating AD pathology.[140] A meta-analysis of 22 randomized controlled trials in patients with AD who received
more than 12 weeks of melatonin treatment showed improvements in Mini-Mental State
Examination scores.[141] Additionally, higher melatonin levels in community-dwelling adults correlated with
lower cognitive impairment.[142] The orexin (hypocretin) signaling pathway offers a compelling frontier for novel
therapeutic strategies aimed at optimizing sleep architecture. Orexins regulate wakefulness
and stabilize sleep–wake transitions; thus, selective antagonists (orexin receptor
blockers) have been effective and are currently available for treating insomnia,[143] with emerging research suggesting, beyond insomnia treatment, potential roles in
modulating disease course in AD.[144] PD patients might instead benefit from orexin agonists,[145] as PD is associated with lower orexin levels.[146] As discussed above, treatment of obstructive sleep apnea reduces the risk of neurovascular
and neurodegenerative disorders. Newer interventions aiming at directly improving
the sleep structure, such as acoustic stimulation (to enhance slow-wave sleep), are
promising as they could improve glymphatic clearance and memory consolidation, but
research on this topic is still ongoing,[136]
[137] and longitudinal data to demonstrate such benefits are needed.
Role of Wearable/Nearable Devices and Artificial Intelligence
Role of Wearable/Nearable Devices and Artificial Intelligence
In parallel with pharmacologic advances, the steadily increasing availability of wearable
and nearable devices and AI-driven technologies for early identification and monitoring
of sleep alterations are starting to reshape both clinical practice and large-scale
screening. Automated analyses of polysomnography, actigraphy, other devices used in
the research field, or even consumer sleep-tracker data can detect subtle, prodromal
sleep pattern disruptions—such as sleep fragmentation or microarousals—years before
overt neurological symptoms appear.[147]
[148]
[149] Additionally, these technologies not only provide continuous measures of multiple
parameters, but they also allow applying a new way to score traditional sleep, introducing
the concept of “hypodensity” to score sleep in a probabilistic way instead of relying
on the traditional sleep stages.[150] Moreover, these technologies are widely available now and are getting more diverse
(wearables, nearables, and airables), offering multifaceted and continuous observation
for different groups (e.g., those who do not tolerate sleeping with a smart-watch
could use a smart-mattress or a smartphone which can detect movement or snoring) with
the potential to unlock new knowledge in preventing, diagnosing early, and managing
neurological diseases.[151] Furthermore, the emergence of commercial Large Language Models (LLM; e.g., GPT [OpenAI],
LLAMA [Meta], Gemini [Google]) offers new ways in which patients can interact with
the technology and get direct answers to their complaints,[152] but the thorough validation of these tools is still needed. By integrating these
AI insights into personalized and individualized sleep management plans, clinicians
may intervene earlier, tailoring therapies that could meaningfully delay disease onset
and progression.
Take-home Messages and Conclusion
Take-home Messages and Conclusion
Sleep is a cornerstone of brain health and should be prioritized accordingly. Subtle
sleep disturbances may precede neurological disease by years, providing a critical
window for early intervention. Prompt management of obstructive sleep apnea, insomnia,
sleep deprivation, or circadian disruptions reduces the risk of occurrence and disability
after the onset of stroke and neurodegenerative diseases. Meanwhile, AI-driven sleep
trackers and automated analyses will empower clinicians to detect prodromal and preclinical
changes, personalize treatments, and optimize outcomes, helping at the same time raising
awareness of the relevance of sleep health in the general population. Maintaining
a healthy sleep, through consistency in sleep–wake schedules and adequate sleep duration,
underpins brain health and overall well-being.
