POLSKI
Introduction
Sleep is an essential physiological process with profound implications for brain health. It plays a vital role in maintaining cognitive function, regulating neuroimmune interactions, facilitating waste clearance, and modulating neuroplasticity. Within the realm of neurology, sleep disturbances are both common and clinically significant, affecting disease presentation, progression, and overall quality of life. To fully understand this interplay, the following review explores the multifaceted roles of sleep in brain function, delineates the patterns of sleep disruption across key neurological disorders, and discusses contemporary and emerging strategies for therapeutic intervention. Neurological disorders, such as Parkinson‘s disease (PD), Alzheimer‘s disease (AD), multiple sclerosis (MS), and stroke are frequently accompanied by sleep-related issues, including insomnia, sleep apnea, restless legs syndrome (RLS), rapid eye movement (REM) sleep behavior disorder, and excessive daytime sleepiness. Recognizing the bidirectional relationship between neurological conditions and sleep disruption is critical to improving patient outcomes. Recent findings further emphasize the therapeutic potential of improving sleep as a strategy that may influence disease trajectories, especially in neurodegenerative disorders. This review integrates contemporary evidence regarding the bidirectional relationship between sleep and neurological disorders, highlights the underlying mechanisms of sleep disturbances, and summarizes current and emerging therapeutic strategies aimed at improving sleep quality and neurological outcomes.
Literature Review
Sleep underpins several interrelated processes that are essential for optimal brain health. The clearance of neurotoxic waste via the glymphatic system reduces the burden of potentially harmful metabolites, while the modulation of microglial immune activity helps maintain a balanced neuroimmune environment. These immune and clearance functions support synaptic homeostasis and facilitate memory consolidation through synaptic plasticity. Together, these processes contribute to the prevention of pathological protein accumulation, highlighting the integrative and mutually reinforcing roles of sleep in sustaining brain function.
The glymphatic system plays a central role in removing metabolic byproducts from the brain. Poor sleep in older adults has been linked to diminished glymphatic clearance and memory decline, suggesting that disrupted waste removal may contribute to cognitive aging.[1]Microglia, the brain’s innate immune cells, influence sleep by suppressing norepinephrine transmission through P2Y12 receptor activity. Activation of the Gi-GPCR pathway in microglia promotes sleep, whereas its inhibition leads to reduced sleep.[2]
Moreover, sleep facilitates synaptic pruning and memory consolidation. Sleep deprivation impairs spatial memory and disrupts CX3CR1 signaling in microglia, interfering with synaptic remodeling. [3] Additionally, sleep enables reactivation of memory traces and prepares neuronal networks for new learning through enhanced plasticity.[3,4]
Prolonged sleep disruption has also been implicated in the buildup of neurodegenerative proteins. Studies show that fragmented sleep correlates with increased β-amyloid and α-synuclein levels, indicating that poor sleep may contribute to proteinopathy through compromised clearance and dysregulated protein metabolism.[4,5]
Sleep disorders are highly prevalent in Parkinson’s disease (PD), affecting more than 80% of patients and contributing significantly to the non-motor symptom burden. These disturbances encompass a spectrum of issues, such as REM sleep behavior disorder (RBD), insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and excessive daytime sleepiness (EDS).[6]
RBD, characterized by dream enactment behaviors, often precedes the motor symptoms of PD and is associated with a more aggressive disease trajectory. In a study involving 452 patients, those with early RBD exhibited more rapid cognitive decline and a higher incidence of dementia.[7]especially in later stages. REM sleep behavior disorder (RBD Sleep-disordered breathing, particularly OSA, also contributes to cognitive impairment in PD, with treatment interventions, such as CPAP showing potential benefits.[8] only limited data are available regarding interactions of sleep disturbances and cognitive performance.\ nOBJECTIVE: This post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD.\nMETHODS: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients’ subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG
Disrupted slow-wave sleep in PD patients has been correlated with an increased volume of perivascular spaces, suggesting impaired glymphatic clearance as a possible mechanism for disease progression. Additionally, RLS is more common in PD than in the general population, with an estimated prevalence rate of 20%. This condition is associated with greater motor symptom severity and contributes to insomnia.[9]
Melatonin, particularly when administered in a clock-timed manner, has shown potential in delaying conversion from idiopathic RBD to PD or dementia, suggesting a possible neuroprotective effect.[10]a reliable prodromal stage marker of α-synucleinopathies like Parkinson’s disease or Lewy body dementia, offers an early window for disease-modifying intervention. Current treatments of iRBD, including the two level B therapies with clonazepam and melatonin, are considered symptomatic. However, numbers of reported patients treated with melatonin are low and whether melatonin has disease-modifying potential is unclear.\nMethods This single-center, prospective cohort study included 206 consecutive patients diagnosed with iRBD until January 2020. Thirty-nine patients had applied mixed treatments on the advice of the referring physician, 167 had administered melatonin according to our chronobiotic protocol (low dose, ≥ 6 months, always-at-the-same-clock-time, between 10 and 11 pm - corrected for chronotype However, much of the current evidence on therapeutic interventions, including melatonin and dopaminergic agents, is based on small observational studies or open-label trials. Larger randomized controlled trials are needed to establish efficacy and inform clinical guidelines.
Sleep–wake disturbances are common in Alzheimer’s disease (AD) and related dementias, encompassing disrupted circadian rhythms, reduced slow-wave and REM sleep, and increased nighttime activity.
Disruptions in sleep architecture correlate with the burden of tau pathology and cortical atrophy, independent of amyloid deposition.[11] Short sleep duration has been linked to elevated cerebrospinal fluid (CSF) tau levels, particularly in APOE ε4 carriers, supporting its role as a potential early biomarker. [12]
Longitudinal studies have demonstrated that individuals with poor sleep—especially those with fragmented REM and non-REM sleep—exhibit greater accumulation of β-amyloid over time and accelerated cognitive decline.[13][1-3] Furthermore, rapid eye movement latency has been associated with elevated CSF levels of amyloid and tau, indicating its value as a predictive biomarker. [14]
Circadian dysregulation, including late-day confusion and altered activity patterns, is common in AD. Interventions, such as timed light therapy and melatonin supplementation have shown potential to restore circadian rhythm integrity and improve both sleep and cognition [15,16] Despite promising associations between sleep markers and neurodegenerative biomarkers, causality remains difficult to establish due to the observational nature of most studies. Longitudinal data with standardized sleep assessments are still limited.
Multiple sclerosis (MS) is frequently accompanied by sleep disturbances, including insomnia, RLS, and sleep-disordered breathing, which collectively worsen fatigue and cognitive impairment.
Insomnia is one of the most prevalent sleep issues in MS, affecting approximately 66.5% of patients. It is strongly associated with elevated fatigue levels and diminished quality of life. [17]with incidence about four times higher compared to the general population. The most frequent primary sleep problems include insomnia, restless leg syndrome, sleep-related movement disorders, and sleep-disordered breathing. This study aims to assess the relationships between sleeping problems and the quality of life (QoL Additionally, RLS is more common in MS than in the general population, with prevalence estimates ranging from 19% to 41%. MS patients with RLS often exhibit greater disability and increased spinal lesion burden.[18]
OSA is present in 28.4% to 36% of MS patients, frequently in the absence of traditional risk factors, such as obesity. This suggests a possible link to brainstem or spinal lesions affecting respiratory control. [19,20] These sleep-disordered breathing events contribute to cognitive dysfunction and exacerbated fatigue.
The interplay between sleep quality and fatigue in MS forms a self-reinforcing cycle. Interventions aimed at improving sleep—through treatment of pain, depression, and adoption of sleep hygiene strategies—can help break this cycle and improve daily functioning.[21]compared to the general obstructive sleep apnea (OSA Studies evaluating sleep in MS often rely on self-reported measures, with limited use of polysomnography. Additionally, confounding factors, such as depression, pain, and medication effects complicate interpretation.
Sleep disturbances are common sequelae of stroke, manifesting as insomnia, obstructive sleep apnea, hypersomnia, and disrupted circadian rhythms, all of which can hinder recovery and increase the risk of recurrent events.
According to a systematic review and meta-analysis by Baylan et al., the pooled prevalence of post-stroke insomnia or insomnia symptoms is approximately 38.2% with studies using non-diagnostic tools reporting rates as high as 40.7%. Longitudinal data suggest that insomnia can persist chronically in around 30% of stroke survivors up to 12–18 months post-stroke.[22] Sleep-disordered breathing is even more widespread, with OSA found in 60–70% of stroke survivors, contributing to poor neurological recovery and heightened recurrence risk.[23]
Excessive daytime sleepiness (EDS) affects approximately 20–34% of stroke survivors, while post-stroke fatigue (PSF) is reported in about 42–50% of cases. Hypersomnia in this context may indicate disrupted sleep architecture or undiagnosed sleep-disordered breathing, particularly OSA, which is prevalent in up to 72% of stroke patients and is associated with impaired recovery and increased risk of recurrent stroke. Several studies report that post-stroke hypersomnia is highly prevalent, yet often overlooked in rehabilitation protocols. [24–27]decreased functional outcome, and recurrent stroke. Research on the effect of OSA on cognitive functioning following stroke is scarce. The primary objective of this study was to compare stroke patients with and without OSA on cognitive and functional status upon admission to inpatient rehabilitation.\nDESIGN: Case-control study.\nSETTING AND PATIENTS: 147 stroke patients admitted to a neurorehabilitation unit.\nINTERVENTIONS: N/A.\ nMEASUREMENTS: All patients underwent sleep examination for diagnosis of OSA. We assessed cognitive status by neuropsychological examination and functional status by two neurological scales and a measure of functional independence.\nRESULTS: We included 80 stroke patients with OSA and 67 stroke patients without OSA. OSA patients were older and had a higher body mass index than patients without OSA. OSA patients performed worse on tests of attention, executive functioning, visuoperception, psychomotor ability, and intelligence than those without OSA. No differences were found for vigilance, memory, and language. OSA patients had a worse neurological status, lower functional independence scores, and a longer period of hospitalization in the neurorehabilitation unit than the patients without OSA. OSA status was not associated with stroke type or classification.\nCONCLUSIONS: Obstructive sleep apnea (OSA
CPAP therapy has demonstrated efficacy in improving neurological function post-stroke. However, patient adherence remains a significant barrier. Efforts to enhance tolerance, such as the use of auto-titrating PAP devices or nasal interfaces, are under investigation to improve long-term outcomes.[28] While CPAP therapy shows benefit in post-stroke recovery, most trials report low adherence rates and short follow-up durations. Further research is needed to improve long-term implementation and assess neurological outcomes.
Huntington’s disease (HD) is a progressive neurodegenerative condition marked by motor, cognitive, and psychiatric disturbances. Sleep dysfunction is a significant non-motor manifestation of HD, frequently appearing in the prodromal phase and worsening as the disease advances.
Patients with HD commonly experience insomnia, fragmented sleep, reduced total sleep time, and diminished REM and slow-wave sleep. Circadian rhythm disruption is also prominent and has been linked to hypothalamic degeneration. Disruption of melatonin secretion and altered expression of core clock genes suggest that circadian dysfunction is a fundamental aspect of HD pathophysiology[29,30] Due to the rarity of HD, sleep-related studies are limited by small sample sizes and heterogeneous methodologies. More robust data are needed to support evidence-based interventions in this population.
These sleep abnormalities are associated with increased neuropsychiatric burden, including irritability and depression, as well as poorer cognitive performance. Sleep disruption also affects caregiver burden, contributing to emotional and physical stress.[29]
Therapeutic strategies include behavioral interventions, namely sleep hygiene education and CBT, melatonin supplementation, and environmental modifications that enhance circadian cues. Light therapy has shown promise in improving sleep-wake regulation and mood in HD patients.[29,31]
Non-pharmacological interventions serve as first-line strategies for managing sleep disturbances in neurological populations. These approaches include cognitive-behavioral therapy for insomnia (CBT-I), light therapy, structured physical activity, and mindfulness-based techniques.
CBT-I is effective across multiple neurological disorders. In a randomized controlled trial involving stroke patients, digital delivery of CBT-I significantly reduced insomnia severity and improved associated symptoms of depression and anxiety.[32]86 community-dwelling stroke survivors consented, of whom 84 completed baseline assessments (39 female, mean 5.5 years post-stroke, mean 59 years old
Timed light exposure, particularly with blue-enriched light in the morning, has shown efficacy in restoring circadian rhythms and enhancing sleep quality and cognitive performance in patients with Alzheimer’s disease.[16] Light therapy is also being explored in PD and stroke populations with promising results.
Physical activity enhances sleep architecture, particularly by improving sleep efficiency in PD and reducing fatigue in MS and post-stroke patients. Consistent daytime routines that include exercise, regular meals, and light exposure support circadian entrainment and sleep consolidation.
Mindfulness and relaxation training also provide benefit in neurological cohorts. These techniques can reduce anxiety, improve subjective sleep quality, and complement other behavioral strategies. For patients with REM sleep behavior disorder, environmental safety adaptations including bed padding and alarms are crucial to preventing injury.
When behavioral interventions are insufficient, pharmacologic therapies are employed. These must be selected carefully to avoid exacerbating neurological deficits or interacting with disease-specific treatments.
Melatonin is commonly used to address insomnia and circadian misalignment across PD, AD, MS, and stroke. In RBD, clock-timed melatonin may reduce dream enactment behaviors and potentially delay neurodegeneration.[10,33]a reliable prodromal stage marker of α-synucleinopathies like Parkinson’s disease or Lewy body dementia, offers an early window for disease-modifying intervention. Current treatments of iRBD, including the two level B therapies with clonazepam and melatonin, are considered symptomatic. However, numbers of reported patients treated with melatonin are low and whether melatonin has disease-modifying potential is unclear.\nMethods This single-center, prospective cohort study included 206 consecutive patients diagnosed with iRBD until January 2020. Thirty-nine patients had applied mixed treatments on the advice of the referring physician, 167 had administered melatonin according to our chronobiotic protocol (low dose, ≥ 6 months, always-at-the-same-clock-time, between 10 and 11 pm - corrected for chronotype
Dopaminergic agents, for example pramipexole and rotigotine effectively manage RLS and nocturnal motor symptoms in PD and MS. An open-label pilot study demonstrated that rotigotine improved sleep and reduced daytime sleepiness in PD patients.[34]
Sedative-hypnotics like zolpidem and clonazepam are used selectively. While clonazepam is standard for RBD, caution is required in dementia due to fall and confusion risks. Orexin receptor antagonists, for example suvorexant have been approved for insomnia in mild-to-moderate AD and may reduce amyloid and tau levels, highlighting a possible disease-modifying effect.[35,36]
Stimulants, such as modafinil and methylphenidate are used off-label for MS-related fatigue, though evidence of efficacy is mixed.[37]modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.\nMETHODS: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS
CPAP therapy remains central to treating sleep apnea in neurological conditions. Meta-analyses indicate that early use post-stroke can enhance recovery, though adherence remains a challenge.[28]
Innovative therapies are being developed to address the complex pathophysiology of sleep disorders in neurological populations. These include pharmacological agents with novel mechanisms, neurostimulation techniques, and circadian-modulating strategies.
Dual Orexin Receptor Antagonists (DORAs), including suvorexant and daridorexant have shown efficacy in treating insomnia by inhibiting orexin-mediated wakefulness. Recent preclinical studies suggest that DORAs may also enhance glymphatic clearance of neurotoxic proteins like amyloid-β and tau, potentially slowing neurodegeneration in Alzheimer’s disease.[35,38,39]
Repetitive Transcranial Magnetic Stimulation (rTMS) is emerging as a non-pharmacologic treatment for insomnia and hypersomnia. In a randomized controlled trial, low-frequency rTMS improved sleep latency and efficiency in patients with chronic insomnia, and is being explored in populations with neurological comorbidities.[40]
Hypoglossal Nerve Stimulation (HNS) has gained approval for treating moderate-to-severe obstructive sleep apnea, especially in patients intolerant to CPAP. It activates the hypoglossal nerve during sleep to maintain airway patency, with trials demonstrating significant reductions in apneahypopnea index and improvement in sleep architecture.[41]
Emerging strategies target circadian misalignment in neurodegenerative disorders. These include timed light therapy and appropriately dosed melatonin to reinforce circadian rhythms. Experimental pharmacologic agents targeting clock genes and melatonin receptors are under investigation.[10,16,33] a reliable prodromal stage marker of α-synucleinopathies like Parkinson’s disease or Lewy body dementia, offers an early window for disease-modifying intervention. Current treatments of iRBD, including the two level B therapies with clonazepam and melatonin, are considered symptomatic. However, numbers of reported patients treated with melatonin are low and whether melatonin has disease-modifying potential is unclear.\nMethods This single-center, prospective cohort study included 206 consecutive patients diagnosed with iRBD until January 2020. Thirty-nine patients had applied mixed treatments on the advice of the referring physician, 167 had administered melatonin according to our chronobiotic protocol (low dose, ≥ 6 months, always-at-the-same-clock-time, between 10 and 11 pm - corrected for chronotype
Novel agents, including clarithromycin and flumazenil have been trialed for idiopathic hypersomnia. These act on GABA A receptor subunits to mitigate excessive sleepiness and are being evaluated in neurologic cohorts with refractory hypersomnolence.[42,43]
These emerging treatments underscore a growing trend toward personalized and mechanistically targeted therapies for sleep disorders in neurology. A summary of common sleep disturbances, therapeutic approaches, and relevant clinical considerations across major neurological disorders is provided in Table 1.
Table 1
Summary of Sleep Disorders in Neurological Diseases: Type of Sleep Disorders, Interventions, and Clinical Notes.
Conclusion
Sleep disturbances are pervasive and consequential in neurological diseases. Their impact ranges from aggravating motor and cognitive symptoms to contributing to disease progression and reduced quality of life. As sleep dysfunction is increasingly recognized as both a marker and modifier of neurological disease, integrating sleep evaluation into routine neurological care becomes not just beneficial but essential.
Effective management of sleep disorders in neurology requires a multidisciplinary approach. Behavioral therapies like CBT-I, environmental adjustments, pharmacologic treatments tailored to neurological comorbidities, and novel therapeutics, such as orexin receptor antagonists or neurostimulation techniques provide clinicians with expanding tools. Importantly, there is growing evidence that addressing sleep problems may not only alleviate symptoms but could also potentially alter the underlying course of neurodegenerative conditions by improving glymphatic clearance, neuroplasticity, and immune homeostasis.
Future research should focus on personalized treatment approaches based on biomarkers, glymphatic function imaging, and circadian profiling. The integration of sleep screening into standard neurological care pathways remains an urgent clinical need. Addressing sleep disturbances may significantly reduce caregiver burden, enhance daily functioning, and improve patient-reported outcomes. Further research is needed to understand the bidirectional mechanisms linking sleep and neurological diseases and to refine personalized interventions. As this field evolves, sleep health may emerge as a cornerstone of preventative and therapeutic strategies in neurology, ultimately enhancing patient care and quality of life.
