# Sleep in neurodegenerative diseases: A focus on melatonin, melanin-concentrating hormone and orexin

Simon J Guillot, Pierre-hervé Luppi, Luc Dupuis, Matei Bolborea

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Simon J Guillot, Pierre-hervé Luppi, Luc Dupuis, Matei Bolborea. Sleep in neurodegenerative diseases: A focus on melatonin, melanin-concentrating hormone and orexin. Journal of Neuroendocrinology, 2025, 37 (11), pp.e70085. 10.1111/jne.70085 . inserm-05508980

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# Sleep in neurodegenerative diseases: A focus on melatonin, melanin-concentrating hormone and orexin

Simon J. Guillot<fnref n="1" /> ID | Pierre-Hervé Luppi<fnref n="2" /> ID | Luc Dupuis<fnref n="1" /> ID | Matei Bolborea<fnref n="1" /> ID

**Correspondence**

Luc Dupuis and Matei Bolborea, INSERM
UMR-S 1329, 1 rue Eugene Boeckel, CRBS,
Strasbourg, 67000, France.

Email: ldupuis@unistra.fr and mbolborea@unistra.fr

**Funding information**

Agence Nationale de la Recherche,
Grant/Award Numbers: ANR-16-CE16-0015,
ANR-16-CE92-0031, ANR-19-CE17-0016,
ANR-20-CE17-0008, ANR-24-CE37-4064;
TargetALS; Fondation Thierry Latran;
Association Francaise de Recherche sur la

Foundation for ALS Research; ARSLA;
University of Starsbourg fundation; Fondation
Bettencourt Schueller; Fondation pour la
Recherche Médicale, Grant/Award Number:
DEQ20180339179; Axa Research Funds

**Abstract**

Sleep and circadian rest-activity rhythm alterations are recognised as inherent clinical features of various neurodegenerative diseases. Traditionally viewed as secondary manifestations of neurodegeneration, recent studies have revealed that disruptions in circadian rhythm and sleep-wake cycles can precede clinical symptoms and significantly contribute to the underlying pathophysiological progression. In this review, we summarise recent research on the impact of sleep and circadian rhythm alterations in ageing and major neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal dementia, highlighting the roles of melatonin, orexin, and melanin-concentrating hormone (MCH) systems as key regulators at the intersection of sleep and neurodegeneration. We argue that sleep and circadian alterations may serve as early biomarkers and therapeutic targets for these diseases.

**KEYWORDS**

circadian rhythm, hypothalamus, neurodegenerative disease, sleep

# 1 | INTRODUCTION

Sleep is a core physiological process that is critical for maintaining optimal health and well-being. While asleep, the body undergoes a series of restorative processes, including memory consolidation, tissue repair, and metabolic regulation.<fnref n="1" /> However, sleep quality and quantity are not static and change progressively with age, influenced by both physiological ageing and neurodegenerative processes.<fnref n="2" />⁻⁴

In the fifties, sleep has been segmented into two distinct states, one showing rapid eye movements (REM) and muscle atonia named REM sleep and the other characterised by slow oscillations named non-rapid eye movement (NREM).⁵⁻⁷ NREM sleep is further divided into three progressive stages: NREM1, NREM2, and NREM3.⁸,⁹ NREM1 represents the transition from wakefulness to sleep and is characterised by a low amplitude of the EEG.¹⁰ NREM2 follows, during which sleep

deepens, body temperature drops, and the EEG shows 14 Hz oscillations named sleep spindles.¹¹ Finally, NREM3 is the deepest sleep stage, characterised by delta slow wave activity. Sleep is essential for physical restoration, memory consolidation, and immune function.⁹,¹² In diurnal species like humans, sleep occurs at night,¹³ while it mostly occurs during the day in nocturnal species such as rodents.¹⁴ REM and NREM sleep alternate during the rest period, with a predominance of NREM sleep at the beginning and of REM sleep at the end.⁹,¹⁵

Animal models are widely used in neurodegenerative research as surrogates for human disease. Multiple models are often employed for a single condition because no perfect model has yet been identified. The complexity of human pathologies, particularly in diseases like ALS or Alzheimer's, involves diverse genetic, cellular, and systemic factors that can only be partially modelled. Each animal model allows researchers to isolate and investigate a specific mechanism (e.g., protein aggregation, synaptic

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© 2025 The Author(s). *Journal of Neuroendocrinology* published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.

<footnote n="1">¹University of Strasbourg, INSERM, UMR-S 1329, Strasbourg Translational Neuroscience & Psychiatry, Strasbourg, France</footnote>

<footnote n="2">²Centre of Neuroscience of Lyon, CNRS/ INSERM, UMR 5292/UMR 1028, Lyon, France</footnote>
dysfunction) under controlled conditions. Furthermore, since these dis-
eases often arise from different gene mutations leading to distinct symp-
tom profiles, cross-validating findings across various models helps identify
therapeutic targets that are robust across multiple genetic contexts.

An interplay between circadian and homeostatic processes regu-
lates sleep timing, propensity, and quality. Two different homeostatic
processes regulate sleep depth and REM sleep duration. The homeo-
stasis of NREM sleep is characterised by the high power of slow oscil-
lations at the beginning of sleep, decreasing progressively until
awakening. REM sleep duration is homeostatically regulated. The reg-
ulation of slow oscillations' power interacts with the circadian rhythm
to generate a regenerative and robust period of sleep.<sup>16-19</sup> It regu-
lates wake and sleep timing and duration.<sup>20</sup> Complex neuronal net-
works are involved in the generation of the sleep-wake cycle. They
include the orexin/hypocretin neurons, aminergic and cholinergic neu-
rons for inducing wakefulness, the ventrolateral preoptic nucleus for
inducing NREM sleep, and brainstem and hypothalamic neurons like
the melanin-concentrating hormone (MCH) neurons to induce REM.<sup>21</sup>

The circadian timing system (CTS) is driven in mammals by a cen-
tral pacemaker located in the hypothalamic suprachiasmatic nuclei
(SCN), which oscillates with a near-24-h period and is synchronised to
the 24-h day by external cues such as light, food intake, and social
interactions.<sup>22,23</sup> The SCN regulates peripheral molecular clocks in all
nucleated cells through rhythmic signals like hormone fluctuations
and temperature cycles.<sup>24,25</sup>

Each molecular clock, composed of 15 major genes operating in
feedback loops, generates a circadian rhythm that coordinates feed-
ing, fasting, anabolism (nutrient storage during wakefulness),²⁶ and
catabolism (glycogenolysis and lipolysis during sleep).²⁷

Sleep is strongly modified across the lifespan, occupying most of
the time at birth and progressively decreasing during childhood before
stabilising in adults and declining again during ageing.²⁸ Alterations in
sleep can have far-reaching consequences for cognitive function,
emotional regulation, and physical health in older adults.²⁹ Further-
more, the ageing process itself is a major risk factor for the develop-
ment of neurodegenerative diseases.³⁰

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), have been shown to induce sleep alterations.<sup>31,32</sup> The pathophysiological mechanisms underlying these pathologies have been shown to involve neural circuits regulating sleep. For instance, amyloid-β (Aβ) plaque accumulation in Alzheimer's disease has been linked to sleep-wake cycle disruptions.<sup>33,34</sup> In Parkinson's disease, degeneration of dopami- nergic, glutamatergic, and glycinergic neurons composing the muscle atonia generating network occurring during REM sleep is involved in REM sleep behaviour disorder (RBD) and excessive daytime sleepi- ness.<sup>35,36</sup> ALS-related motor neuron loss can also lead to respiratory insufficiency, causing sleep-related breathing disorders like sleep apnoea and hypoventilation.<sup>37,38</sup>

In recent years, the bidirectional relationship between sleep and
neurodegeneration has gained significant attention. Insufficient sleep
quality may accelerate the progression of neurodegenerative diseases,
while the progression of these diseases further alters sleep

architecture.³⁹,⁴⁰ This vicious cycle highlights the need to investigate
the mechanisms underlying sleep alterations in ageing and neurode-
generative diseases and to develop targeted interventions to improve
sleep quality in these populations.⁴¹

This review delves into the intricate interplay between sleep, age-
ing, and neurodegeneration, discussing age-related sleep changes, the
impact of neurodegenerative diseases on sleep architecture, and
potential therapeutic approaches to mitigate sleep alterations in
affected individuals. We choose here to specifically focus on melato-
nin, MCH, and orexin neurons, as degeneration of these neuronal
populations appears frequent in most neurodegenerative diseases.
This does not exclude the involvement of other sleep-controlling neu-
rons, particularly monoaminergic ones, which are covered in other
reviews.<sup>42-48</sup>

2 | SLEEP ACROSS AGEING

As individuals age, they naturally experience changes in their sleep
patterns. These changes are part of the developmental and ageing
processes and occur throughout their lives, with sleep duration, qual-
ity, and architecture all undergoing modifications. One aspect of age-
ing that affects sleep is the shift in an individual's preferred timing of
sleep and wakefulness, known as chronotype.² Chronotype refers to
an individual's innate preference for sleeping early or late within a
24-h cycle. It is influenced by the circadian system, which regulates
sleep-wake cycles by means of internal biological clocks. Chronotype
is mostly regulated by genetic factors. There are three main chrono-
types: morning, intermediate, and evening types.⁴⁹ As we age, our
chronotype gradually shifts towards a morning type, leading to notice-
able changes in sleep timing and architecture.⁵⁰,⁵¹ Age-related
changes within the homeostatic sleep-regulating system can impact
sleep timing, quantity, and quality. Indeed, the discrepancy between
circadian and homeostatic processes results in sleep asynchrony dur-
ing ageing.⁵²,⁵³ Further, multiple endocrine and neuroendocrine
adjustments accompany chronotype shifts.⁵⁴⁻⁵⁷ Melatonin, serotonin,
and cortisol are three key regulators of circadian rhythm. Melatonin,
secreted by the pineal gland at dark onset, shows a gradual decline
during ageing due to pineal gland calcification.⁵⁸,⁵⁹ Conversely, ele-
vated levels of cortisol⁶⁰,⁶¹ and brain-derived serotonin correlate with
poorer ageing trajectories,⁶²⁻⁶⁴ which are themselves associated
with decreased sleep efficiency and increased sleep fragmenta-
tion.⁶⁵,⁶⁶ Interestingly, it has been shown that the function of MCH
and orexin neurons is altered as we age.⁶⁷⁻⁷⁹ For example, orexin
levels have been observed to rise in older individuals, and orexin neu-
rons become progressively hyperexcitable,⁷⁹ potentially contributing
to insomnia and sleep-wake disruptions.⁷⁷,⁸⁰,⁸¹ However, the number
of orexin neurons in the lateral hypothalamic area (LHA) decreases
with age.⁷⁴,⁷⁹ The fate of MCH-positive neurons across the ageing
continuum remains unknown. As neuronal networks gradually deterio-
rate, sleep macroarchitecture, including NREM and REM cycles,
undergoes progressive modifications, resulting in fragmented sleep.⁸²
Individuals across various life stages may encounter challenges in
falling asleep, reduced time spent in NREM2, NREM3, and REM sleep, and increased nighttime wakefulness. These sleep alterations can negatively impact cognitive function, quality of life, and neurodevelopmental trajectories.⁸³,⁸⁴ Recent investigations more specifically demonstrate that age-related changes significantly influence sleep oscillations at the microarchitectural level, affecting their density and duration.⁸⁵,⁸⁶ A decline in homeostatic sleep pressure leads to reorganisation of NREM3, marked by a reduction in slow oscillations' amplitude and density.⁸⁵ Sleep spindles, slow oscillations, and K-complexes progressively decrease with age, even before reaching advanced age.⁸⁷⁻⁸⁹ These changes impact sleep stability and cognitive function. Furthermore, ageing disrupts the coupling between ripples, sleep spindles, and delta oscillations, impairing neuronal communication and memory consolidation.⁹⁰

Several sleep disorders, including sleep apnoea, insomnia, sleep-disordered breathing, restless leg syndrome, and periodic limb movements, are associated with lifelong sleep alterations, though their prevalence may increase with age.

Ageing progressively affects sleep throughout life, not solely in old age. Sleep alterations, including circadian rhythm disruption, hormonal shifts, and changes in brainwave patterns, begin at earlier life stages and continue evolving over time. These disruptions contribute to daily functional challenges and hinder the ability to maintain cognitive and physical health. Furthermore, neurodegenerative diseases, which become more prevalent later in life, exacerbate sleep alterations, creating a complex interplay between ageing, sleep regulation, and neurodegeneration.

# 3 | SLEEP IN NEURODEGENERATIVE DISEASES

## 3.1 | Alzheimer's disease

Circadian rhythm disruption and sleep alterations are commonly observed in Alzheimer's disease patients, contributing to cognitive decline.⁹¹⁻⁹³ Neurodegenerative changes, including hypothalamic neuronal loss and abnormal circadian rhythms, such as reduced core body temperature, are documented in patients and mouse models.⁹⁴,⁹⁵ Transgenic 3xTg-AD mice, which exhibit amyloid-β (Aβ) and tau pathologies, display similar circadian disruptions, with decreased VIP-positive cells suggesting an early predictive marker.⁹⁶,⁹⁷ Melatonin levels are reduced in AD mouse models,⁵⁹ while elevated cortisol levels in patients further support circadian rhythm impairment in early disease stages.⁹⁸ The involvement of neurotransmitter systems in AD pathology is well documented. Serotonin plays a critical role in memory and learning via hippocampal modulation,⁹⁹,¹⁰⁰ yet its levels are profoundly decreased in both patients and mouse models before Aβ accumulation, linking serotonin loss to exacerbated cognitive deficits.¹⁰¹,¹⁰² Additionally, disruptions in orexinergic signalling have been implicated in AD progression. While cerebrospinal fluid (CSF) orexin levels are often found increased and positively correlated with Aβ burden,¹⁰³⁻¹⁰⁵ some studies report no significant difference between patients and controls,¹⁰⁶

suggesting complex regulatory mechanisms. In AD mouse models, orexin knockout leads to reduced Aβ formation and improved sleep architecture.¹⁰⁷ Furthermore, orexin dysregulation is associated with tau pathology, as increased orexin levels enhance tau and phosphorylated tau (P-tau) accumulation, subsequently altering sleep macroarchitecture.¹⁰⁸,¹⁰⁹ Beyond orexin, melanin-concentrating hormone (MCH) neurons are implicated in AD pathology. MCH-positive neurons are vulnerable in early disease stages, and increased CSF MCH correlates with P-tau, total tau (T-tau), disease severity, and dementia risk.¹⁰⁶ Impaired MCH regulation may contribute to cognitive deficits, as disrupted REM sleep prevents effective memory consolidation.¹¹⁰⁻¹¹² In AD models, progressive morphological alterations in MCH axons lead to aberrant neuronal activity and sleep alterations. Impairments in MCH trafficking and release further exacerbate pathology due to Aβ accumulation.¹¹³ Alterations in sleep architecture are strongly associated with AD progression. Increased sleep fragmentation accelerates cognitive impairment in the presence of Aβ and tau pathology.¹¹⁴,¹¹⁵ Aβ further disrupts NREM3 sleep and memory consolidation.¹¹⁶ Mouse models exhibit fragmented sleep-wake cycles and shorter sleep bouts,¹¹⁷ while patients display altered sleep microarchitecture, particularly reduced sleep spindle density and slow oscillation activity.¹¹⁸ Sleep spindle deficits negatively correlate with P-tau and T-tau pathology, and disrupted sleep spindles-slow oscillations coupling is linked to early Aβ burden, serving as an effective predictor of cognitive decline.¹¹⁹⁻¹²¹ Emerging evidence suggests that sleep spindles and slow oscillations may function as biomarkers for early AD diagnosis.¹²²

## 3.2 | Parkinson's disease

In Parkinson's disease, circadian rhythms are also disrupted. Melatonin levels were found to be decreased, and cortisol levels increased in patients.⁹⁸,¹²³,¹²⁴ Serotonin levels are diminished in patients' CSF, which intrinsically correlates with the severity of motor and cognitive symptoms.¹²⁵ Serotonin release was also affected, indicating a possible contribution to the worsening of non-motor symptoms.¹²⁵⁻¹²⁷ In Parkinson's disease, there is a reduction in orexin levels, as evidenced by decreased concentrations in the CSF and a lower number of orexin-positive neurons.¹²⁸⁻¹³² The loss of orexin-positive neurons in the lateral hypothalamus specifically disrupts the sleep-wake cycle of patients.¹²⁸ This finding was confirmed in both a rat model of Parkinson's and a mouse model, where circadian rhythms and stability are impaired.¹²⁹,¹³³ Alongside orexinergic loss, patients also had a loss of MCH-positive neurons.¹²⁸,¹³² Patients experience excessive daytime sleepiness, as well as alterations in sleep patterns and increased occurrence of sleep apnoea.¹³⁴ Several sleep disorders, including restless legs syndrome, REM behaviour disorder (RBD), and insomnia, have been associated with the pathophysiology of PD.¹³⁵ Evidence suggests that RBD is a prodromal marker of PD, appearing 5 to 15 years ahead of Parkinson's onset.¹³⁶,¹³⁷ Patients with RBD exhibit a lack of muscle atonia during REM sleep, physically acting out vivid, often unpleasant dreams accompanied by vocal sounds and sudden, usually violent, arm and leg movements.¹³⁸,¹³⁹ The neuronal network
<figure><img src="image_3.png" /></figure>

responsible for muscle atonia comprises glutamatergic and glycinergic neurons located in the brainstem, and alpha-synuclein deposits have been observed in the nuclei containing these neurons.<sup>140-145</sup> Patients show significant alterations in NREM3, which resulted in negative associations with cognitive functioning.<sup>146,147</sup> A mouse model also exhibits these circadian and homeostatic disruptions and sleep alterations, leading to a decline in locomotor activity.<sup>148</sup> The disease also affects sleep microarchitecture, altering properties of sleep spindles such as their amplitude, which predicts cognitive deterioration and early decline of cortical regions.<sup>149,150</sup> Sleep spindles were found to be more profoundly impacted in patients who later developed Parkinson's dementia compared to patients without dementia and control individuals.<sup>151</sup> The coupling between sleep spindles and slow oscillations can predict cognitive impairment in patients with Parkinson's disease. Sleep spindles are now considered potential biomarkers for predicting cognitive decline and disease progression.<sup>152,153</sup>

## 3.3 | Huntington's disease

Few studies have investigated circadian rhythms in Huntington's disease, particularly in patients. In Huntington's mouse models, mice exhibited complete loss of circadian rhythms, as well as disruption in NREM and REM sleep, with increased percentages of the two sleep stages.<sup>154-156</sup> In patients, melatonin was found to be diminished compared to healthy individuals; conversely, cortisol levels were elevated.<sup>157-159</sup> Melatonin biosynthesis is also disrupted in a mouse model.<sup>160</sup> Unlike in Alzheimer's and Parkinson's, serotonin is only diminished in specific brain regions due to Huntington's aetiology in patients.<sup>161</sup> Serotonin alterations were found in the R6/1 mouse model, which associates this loss with depression-related behaviour.<sup>162</sup> Several studies have shown a decrease in orexin levels and a loss of orexin-positive neurons in individuals with Huntington's.<sup>163-165</sup> Rodent models of Huntington's have also demonstrated a loss of orexin-positive neurons,<sup>166,167</sup> and MCH-positive neurons are lost in mouse models.<sup>168</sup> Neuropathological investigations have revealed that patients suffer from hypothalamic atrophy and depletion of various hypothalamic neuropeptides, including orexin and oxytocin.<sup>164,165,169</sup> Patients also show increased occurrence of insomnia and advanced sleep phase, and more rarely, restless legs syndrome or RBD. Huntington's patients also show reduced NREM 3 and REM sleep,<sup>170</sup> increased wake after sleep onset and excessive daytime sleepiness.<sup>171</sup> Q175 knock-in mouse model has shown increased wakefulness and reduced NREM duration.<sup>155</sup>

## 3.4 | Amyotrophic lateral sclerosis

Circadian rhythms have been poorly investigated in amyotrophic lateral sclerosis. Recent findings indicate circadian impairment and disruption of sleep-wake cycles. However, the circadian circuitry was devoid of pTDP-43, an ALS hallmark.<sup>172</sup> Circadian rhythms are also altered in ALS mouse models and have been linked to metabolic

impairment and redox deficit.<sup>173</sup> The mouse model displayed significant motor neuron loss, inflammation, and weight loss, resulting in an accelerated disease onset and progression.<sup>174</sup> ALS patients were found to have significantly higher morning cortisol levels, leading to early wakefulness and disruption of their sleep-wake cycle.<sup>175</sup> ALS is characterised by the degeneration of serotonergic neurons, resulting in reduced levels of serotonin.<sup>176,177</sup> The study found that the loss of serotonin exacerbates the progression of the disease and the severity of symptoms in mouse models, which was also replicated in humans.<sup>178</sup> Despite hypothalamic atrophy prior to symptom onset, orexin levels remained unchanged in ALS patients.<sup>179,180</sup> The loss of MCH-positive neurons early in the pathology is linked to weight loss and metabolic shifts in both patients and mouse models.<sup>181</sup>

Respiratory insufficiency developed by patients because of disease progression leads to increased sleep apnoea, which remains one of the most common sleep problems associated with amyotrophic lateral sclerosis. Sleep-related disorders, such as hypoventilation, are also frequent due to the weakening of the diaphragm and paralysis of respiratory muscles.<sup>182,183</sup> Several studies suggest that individuals with ALS experience excessive daytime sleepiness, decreased total sleep time, insomnia, and increased sleep fragmentation, as well as RBD and restless legs syndrome.<sup>184,185</sup> Further investigation remains challenging due to the loss of innervation and early death caused by cardiorespiratory failure. In *TDP-43*-expressing *Drosophila*, severe sleep alterations are observed, characterised by reduced sleep duration and heightened sleep fragmentation. Yet, no circadian or homeostatic disruption was observed in this TDP-43-expressing fly model.<sup>186</sup> However, in TDP-43 knock-out mouse models, clock gene expression is impaired, and locomotor activity is disturbed.<sup>187</sup> SOD1<sup>G93A</sup> mouse models have reduced core body temperature rhythm, indicating early central circadian dysfunction that progresses to peripheral thermogenic deficits as the disease advances, thus impacting sleep.<sup>188</sup> In knock-in rat model of FUS gene, REM sleep is deceased and wakefulness is increased at the beginning of the active dark phase. These are associated with circadian deficits characterised by a dampened activity amplitude.<sup>190</sup> Recent findings indicate that patients experience notable sleep alterations, including a reduction in restorative NREM3 sleep and increased wakefulness throughout the night. Similar findings were observed in presymptomatic gene carriers of ALS, indicating that sleep alterations may occur decades before the onset of the disease. Sleep alterations were also replicated in three different mouse models of amyotrophic lateral sclerosis, all of which exhibited increased wakefulness and disrupted NREM.<sup>191</sup>

## 3.5 | Frontotemporal dementia

Sleep alterations have been the subject of extensive investigation regarding their disruptive impact on individuals with dementia yet have largely neglected frontotemporal dementia (FTD). Alterations in circadian rhythms have been observed in patients with FTD, with a tendency towards late wake-up calls and later bedtime hours, suggestive of an evening chronotype.<sup>192</sup> The findings were replicated in a
Drosophila model of C9ORF72-FTD, thereby providing evidence that circadian rhythms are indeed a hallmark of neurodegeneration.¹⁹³
Another fly model of FTD for CHMP2B mutation also exhibited circadian defects, resulting in the disruption of circadian locomotor rhythms.¹⁹⁴

It is noteworthy that patients with FTD display circadian rhythm impairments, as well as alterations in body temperature rhythm, that differ from those observed in Alzheimer's and control subjects.¹⁹⁵ There is a paucity of studies that focus on circadian regulators. Several studies have attempted to assess the role of cortisol, and a causal link between cortisol levels and FTD has yet to be established.¹⁹⁶ The most common diagnoses among FTD patients presenting with sleep-related issues are sleep-disordered breathing, excessive daytime sleepiness, and insomnia.¹⁹⁷ A further decrease in plasmatic levels of orexin has been observed in patients with frontotemporal dementia in comparison to Alzheimer's and Parkinson's associated with mild cognitive impairments.¹⁹⁸ This results in pronounced alterations to the sleep cycle, particularly in the NREM stage, accompanied by an increase in REM sleep.¹⁹⁹,²⁰⁰ A FUS-FTD model replicated the neuronal loss observed in patients, including regions associated with orexinergic signalling. However, this loss was only detected in the locus coeruleus, where orexinergic neurons are not typically found.²⁰¹ Additionally, elevated levels of tau were observed in the LHA, locus coeruleus and hippocampus of this mouse model. Despite the observation that CSF orexin levels are unchanged between patients and healthy individuals,²⁰² disruptions in orexin signalling,²⁰³ such as altered receptor sensitivity or neuronal dysfunction, may still play a role in increased daytime sleepiness.²⁰⁴⁻²⁰⁶ In a FUS-FTD rat model, impairment of circadian rhythms and alterations in sleep patterns precede cognitive decline.²⁰⁷

# 4 | THERAPEUTIC APPROACHES TO SLEEP ALTERATIONS IN NEURODEGENERATIVE DISEASES

## 4.1 | Melatonin

Melatonin has demonstrated neuroprotective effects across multiple neurodegenerative diseases. In Alzheimer's disease (AD) models, melatonin administration (10 mg/kg, intraperitoneally, daily for 4 weeks) reduced P-tau and Aβ plaque accumulation, improving cognitive function and mitophagy.²⁰⁸ In Parkinson's patients, melatonin (3–5 mg orally, taken 30–60 min before bedtime) has shown efficacy in restoring circadian rhythms, improving sleep quality, and reducing sleep fragmentation.²⁰⁹⁻²¹² It has also demonstrated neuroprotective effects in various Parkinson's models by reducing oxidative stress, inflammation, and apoptotic events and inhibiting synaptic dysfunctions as well as excitotoxicity.²¹³⁻²¹⁹ In Huntington's, melatonin (5 mg/kg, orally, daily for 3 weeks) restored circadian rhythms and locomotor abilities in a *Drosophila* model.²²⁰ The effect of melatonin has also been investigated in amyotrophic lateral sclerosis in both patients and mouse models. This indolamine (10 mg/kg, intraperitoneally, daily

for 6 weeks) has been shown to have a neuroprotective effect on motor neurons, resulting in prolonged survival in mouse models and an antioxidant effect.²²¹⁻²²³ It has been proposed as a potential candidate for altering the disease progression.²²⁴,²²⁵ The efficacy of melatonin in frontotemporal dementia was evaluated in a clinical trial. However, in frontotemporal dementia (FTD) patients, melatonin (6 mg orally, nightly for 4 weeks) was found to exacerbate apathy, suggesting caution in its use.²²⁶

## 4.2 | Melanin-concentrating hormone

MCH supplementation has been explored in Alzheimer's disease models, where intracerebroventricular (ICV) administration of MCH (0.5 µg/day for 2 weeks) restored REM sleep and reduced abnormal hippocampal neuronal activity, improving memory retention.¹¹³,²²⁷ In Parkinson's models, MCH supplementation (1 µg/day, ICV, for 3 weeks) exhibited neuroprotective effects on dopaminergic neurons, enhancing locomotor performance.²²⁸ The uptake of MCH has not previously been the subject of investigation in Huntington's patients or models. MCH supplementation (0.5 µg/day, ICV, for 2 weeks) was also performed in two ALS mouse models, but only partial rescue of sleep alterations was observed.¹⁹¹ MCH supplementation in these ALS models seemed to be able to prevent the neurodegeneration of motor neurons early in the disease course. A major limitation of current methods to target MCH is that MCH does not cross the blood-brain barrier and that its use is limited by its chronic intracerebroventricular delivery, while MCH neurons are mostly active during REM sleep. Better drugs targeting the MCH system would enable the activation of MCH at the appropriate period of the circadian rhythm.

## 4.3 | Dual orexin receptor antagonist

Suvorexant, a dual orexin receptor antagonist (DORA), demonstrated a positive effect in Alzheimer's disease. Clinical studies indicate that suvorexant (10–20 mg, orally, taken 30 min before bedtime) reduces P-tau and Aβ levels, improves sleep quality, and enhances memory retention.¹²⁹,²²⁹ Currently, no clinical trials have evaluated DORAs in Parkinson's disease, though preclinical studies suggest potential benefits. In Huntington's model, suvorexant (15 mg/kg, orally, daily for 4 weeks) rescued sleep alterations and improved cognitive function.²³⁰ A recent study from our group also unveiled that suvorexant administration (10 mg/kg, orally, acute) in mouse models of ALS effectively rescued sleep alterations at a presymptomatic stage.¹⁹¹

## 4.4 | Other therapeutical approaches

Non-pharmacological interventions have also been explored. In Alzheimer's patients, behavioural interventions, phototherapy (10,000 lux for 1 h in the morning), and continuous positive air pressure (CPAP) improved sleep quality, NREM2-3 stability, and cognitive function.²³¹⁻²³⁴ In
Huntington's disease, the administration of Ghrelin (0.3 mg/kg, subcutaneous injection, daily for 2 weeks) or Alprazolam (0.5 mg, orally, nightly for 4 weeks) reversed circadian rhythm disruptions, normalised sleep-wake cycles, and mitigated cognitive decline.²³⁰,²³⁵,²³⁶

5 | DISCUSSION

The intricate relationship between sleep, lifelong ageing, and neurodegeneration underscores the critical role of sleep in maintaining neurological health. Sleep alterations, including reduced sleep duration, increased fragmentation, and shifts in chronotype, occur progressively with age, influencing both circadian rhythms and homeostatic sleep regulation. These disruptions, driven by hormonal imbalances, neurological dysfunction, and alterations in sleep microarchitecture, have profound implications for cognitive function, emotional stability, and overall well-being. Given that ageing itself is a continuous process that influences brain function, understanding how sleep disturbances contribute to neurodegenerative pathology is essential.

In neurodegenerative diseases, sleep disruptions are often severe, multifaceted, and emerge early (Figure 1). Patients with Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal dementia experience progressive alterations in sleep architecture and circadian rhythms, frequently exhibiting sleep fragmentation, REM sleep abnormalities, and excessive daytime sleepiness. These disruptions correlate with the degeneration of key sleep-regulating neural circuits, including the hypothalamic orexin and MCH systems. Furthermore, the bidirectional nature of these disruptions complicates intervention strategies, as neurodegeneration not only disrupts sleep, but inadequate sleep may also accelerate disease progression.

One of the most compelling aspects of recent research is the identification of sleep alterations as potential early biomarkers of neurodegenerative diseases. Changes in sleep microarchitecture, such as altered sleep spindle activity and reduced slow oscillations, have been associated with higher amyloid-β and tau burden in Alzheimer's disease, and cognitive decline in Parkinson's disease. Similarly, sleep alterations in ALS and Huntington's disease precede clinical symptom onset, highlighting the need for early detection and intervention. Given that these alterations can emerge decades before overt neurological symptoms, incorporating sleep assessments into routine neurological screenings could provide valuable diagnostic insights.

Beyond diagnostic implications, the interplay between sleep and neurodegeneration may have direct mechanistic associations that further exacerbate disease progression. Sleep alterations impair glymphatic clearance, leading to reduced removal of neurotoxic proteins such as amyloid-β and tau, which accelerates neuronal dysfunction.²³⁷⁻²³⁹ Additionally, fragmented sleep disrupts synaptic plasticity, memory consolidation, and neurotransmitter homeostasis, all of which are implicated in cognitive decline.²⁴⁰⁻²⁴²

Therapeutic strategies targeting sleep and circadian disruptions present promising opportunities for intervention (Table 1). Melatonin supplementation has shown efficacy in restoring circadian rhythm stability and improving sleep quality, particularly in Alzheimer's and Parkinson's disease models. Additionally, MCH supplementation has demonstrated neuroprotective effects, particularly in enhancing REM sleep and mitigating cognitive deficits. However, limitations such as the blood-brain barrier restrictions of MCH necessitate more precise therapeutic approaches. Dual orexin receptor antagonists, such as suvorexant, have shown promise in reducing amyloid-β and tau accumulation in Alzheimer's disease, as well as ameliorating sleep alterations in Huntington's and ALS models. Beyond pharmacological

<figure><img src="image_4.png" /><figcaption>**FIGURE 1** Interactions between sleep alterations, lifelong ageing and neurodegeneration. Sankey plot generated using the HoloViews package.¹⁸⁹</figcaption></figure>
<table><caption>TABLE 1 Therapeutic approaches targeting sleep alterations across neurodegenerative diseases.</caption><thead><tr><th></th><th>Alzheimer</th><th>Parkinson</th><th>Huntington</th><th>Amyotrophic lateral sclerosis</th><th>Frontotemporal dementia</th></tr></thead><tbody><tr><td>Melatonin</td><td>Reduced P-tau and Aβ plaque<br>Improved mitophagy<br>Stabilised circadian rhythms</td><td>Restored circadian rhythms, sleep quality<br>Reduced oxidative stress, inflammation, excitotoxicity</td><td>Restored circadian rhythms and locomotor abilities</td><td>Neuroprotective effect on motor neurons<br>Improved oxidative balance</td><td>Exacerbate apathy</td></tr><tr><td>Melanin-concentrating hormone (MCH)</td><td>Restored REM sleep<br>Reduced abnormal hippocampal neuronal activity<br>Enhanced memory retention<br>Lowered soluble Aβ</td><td>Neuroprotective effect on dopaminergic neurons<br>Enhanced locomotor performance</td><td>—</td><td>Partial restoration of sleep alterations<br>Early neuroprotection on motor neurons</td><td>—</td></tr><tr><td>Dual orexin receptor antagonists (DORAs)</td><td>Reduced P-tau and Aβ plaque<br>Improved sleep stability and memory retention</td><td>—</td><td>Restored sleep patterns and cognitive stability (preclinical evidence)</td><td>Restored sleep patterns and neuroprotective effects (preclinical evidence)</td><td>—</td></tr><tr><td>Light therapy</td><td>Improved NREM patterns<br>Prevented excessive daylight sleepiness<br>Enhanced cognitive functions</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Ghrelin</td><td>—</td><td>—</td><td>Reversed atypical circadian rhythms<br>Stabilised sleep-wake cycles<br>Slowed down cognitive decline</td><td>—</td><td>—</td></tr><tr><td>Alprazolam</td><td>—</td><td>—</td><td>Reversed atypical circadian rhythms<br>Stabilised sleep-wake cycles<br>Slowed down cognitive decline</td><td>—</td><td>—</td></tr></tbody></table>

interventions, non-drug strategies, including light therapy, behavioural modifications, and continuous positive airway pressure, have demonstrated efficacy in stabilising sleep patterns and improving cognitive function in affected individuals.

Further personalisation of sleep therapies is essential, as the heterogeneity of sleep alterations across neurodegenerative diseases necessitates targeted treatment strategies. For Parkinson's disease, interventions may focus on dopaminergic modulation and light therapy, whereas Alzheimer's patients may benefit from sleep spindles-enhancing therapies aimed at stabilising NREM3 sleep. The complexity of sleep regulation suggests that multimodal therapeutic strategies, combining behavioural, pharmacological, and chronotherapeutic interventions, may be required for optimal outcomes.

Despite these promising developments, significant challenges remain. Future research should clarify the precise mechanistic connections between sleep alterations and neurodegeneration and identify optimal intervention windows for therapeutic efficacy. Additionally, longitudinal studies tracking sleep biomarkers over decades could improve our understanding of how sleep changes predict neurodegenerative disease risk.

By advancing our understanding of the interplay between sleep, lifelong ageing, and neurodegeneration, we can develop more effective and targeted therapeutic interventions. The integration of behavioural, pharmacological, and chronotherapeutic strategies holds potential not only to enhance sleep quality but also to slow disease progression and improve the quality of life for affected individuals. Moving forward, prioritising sleep research in neurodegenerative disease models and clinical studies will be instrumental in uncovering novel treatment paradigms and refining early diagnostic methodologies.

## AUTHOR CONTRIBUTIONS

Simon J. Guillot: Conceptualization; visualization; writing – original draft; writing – review and editing. Pierre-Hervé Luppi: Writing – review and editing; visualization; validation. Luc Dupuis: Conceptualization; supervision; writing – original draft; writing – review and editing; validation; funding acquisition. Matei Bolborea: Conceptualization; funding acquisition; writing – original draft; writing – review and editing; validation; supervision.
## ACKNOWLEDGEMENTS

Thanks to the patients who inspired this work. Work related to this review was funded by Agence Nationale de la Recherche (ANR-16-CE92-0031, ANR-16-CE16-0015, ANR-19-CE17-0016, ANR-20-CE17-0008 to Luc Dupuis and ANR-24-CE37-4064 to Luc Dupuis), by the University of Starsbourg foundation, as part of the ITI 2021-2028 (Idex Unistra ANR-10-IDEX-0002, ANR-20-SFRI-0012), by Fondation Bettencourt (Coup d'élan 2019 to Luc Dupuis), Fondation pour la recherche médicale (FRM, DEQ20180339179), Axa Research Funds (rare diseases award 2019, to Luc Dupuis), Fondation Thierry Latran (HypmotALS to Luc Dupuis), Association Française de Recherche sur la sclérose latérale amyotrophique (2016, 2021 to Luc Dupuis), Radala Foundation for ALS Research (to Luc Dupuis), the ARSLA (AFM-Téléthon, #23646 to Luc Dupuis), TargetALS (to Luc Dupuis) and JPND (HiCALS project, to Luc Dupuis). Luc Dupuis is USIAS fellow 2019. Fondation Anne-Marie et Roger Dreyfus (hosted by Fondation de France) provided salary for Simon J. Guillot.

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

## PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/jne.70085.

## DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

## ORCID

Simon J. Guillot https://orcid.org/0000-0002-1623-7091

Pierre-Hervé Luppi https://orcid.org/0000-0002-0503-423X

Luc Dupuis https://orcid.org/0000-0002-0902-5824

Matei Bolborea https://orcid.org/0000-0003-2313-2770

## REFERENCES

1. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. *Lancet*. 1999;354(9188):1435-1439. doi:10.1016/S0140-6736(99)01376-8

2. Schuster M, Oberliner C, Claus M. Shift-specific associations between age, chronotype and sleep duration. *Chronobiol Int*. 2019; 36(6):784-795. doi:10.1080/07420528.2019.1586719

3. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. *JAMA Neurol*. 2014;71(4):463-469. doi:10.1001/jamaneurol.2013.6239

4. Weisssova K, Bartos A, Sladek M, Novakova M, Sumova A. Moderate changes in the circadian system of Alzheimer's disease patients detected in their home environment. *PLoS One*. 2016;11(1): e0146200. doi:10.1371/journal.pone.0146200

5. Benington JH, Heller HC. REM-sleep timing is controlled homeostatically by accumulation of REM-sleep propensity in non-REM sleep. *Am J Physiol*. 1994;266(6 Pt 2):R1992-R2000. doi:10.1152/ajpregu.1994.266.6.R1992

6. Shuster AE, Morehouse A, McDevitt EA, et al. REM refines and rescues memory representations: a new theory. *Sleep Adv*. 2025;6(1): zpaf004. doi:10.1093/sleepadvances/zpaf004

7. Vivaldi EA, Ocampo A, Wyneken U, Roncagliolo M, Zapata AM. Short-term homeostasis of active sleep and the architecture of sleep in the rat. *J Neurophysiol*. 1994;72(4):1745-1755. doi:10.1152/jn.1994.72.4.1745

8. Kishi A, Yasuda H, Matsumoto T, et al. NREM sleep stage transitions control ultradian REM sleep rhythm. *Sleep*. 2011;34(10):1423-1432. doi:10.5665/SLEEP.1292

9. Vyazovskiy VV, Delogu A. NREM and REM sleep: complementary roles in recovery after wakefulness. *Neuroscientist*. 2014;20(3):203-219. doi:10.1177/1073858413518152

10. Ioannides AA, Liu L, Poghosyan V, Kostopoulos GK. Using MEG to understand the progression of light sleep and the emergence and functional roles of spindles and K-complexes. *Front Hum Neurosci*. 2017;11:313. doi:10.3389/fnhum.2017.00313

11. Laventure S, Fogel S, Lungu O, et al. NREM2 and sleep spindles are instrumental to the consolidation of motor sequence memories. *PLoS Biol*. 2016;14(3):e1002429. doi:10.1371/journal.pbio.1002429

12. Zavecz Z, Shah VD, Murillo OG, et al. NREM sleep as a novel protective cognitive reserve factor in the face of Alzheimer's disease pathology. *BMC Med*. 2023;21(1):156. doi:10.1186/s12916-023-02811-z

13. Nunn CL, Samson DR, Krystal AD. Shining evolutionary light on human sleep and sleep disorders. *Evol Med Public Health*. 2016; 2016(1):227-243. doi:10.1093/emph/eow018

14. Sanchez REA, Kalume F, de la Iglesia HO. Sleep timing and the circadian clock in mammals: past, present and the road ahead. *Semin Cell Dev Biol*. 2022;126:3-14. doi:10.1016/j.semcdb.2021.05.034

15. Le Bon O. An asymmetrical hypothesis for the NREM-REM sleep alternation—what is the NREM-REM cycle? Hypothesis and theory. *Front Neurosci*. 2021;15:627193. doi:10.3389/fnins.2021.627193

16. Borbely AA, Daan S, Wirz-Justice A, Deboer T. The two-process model of sleep regulation: a reappraisal. *J Sleep Res*. 2016;25(2):131-143. doi: 10.1111/jsr.12371

17. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. *J Neurosci*. 1995;15(5 Pt 1):3526-3538. doi:10.1523/JNEUROSCI.15-05-03526.1995

18. Borbely AA. A two process model of sleep regulation. *Hum Neurobiol*. 1982;1(3):195-204.

19. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. *J Biol Rhythms*. 1999;14(6):557-568. doi:10.1177/074873099129000894

20. Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. *J Physiol*. 1999;516(Pt 2):611-627. doi:10.1111/j.1469-7793.1999.0611v.x

21. Eban-Rothschild A, Appelbaum L, de Lecea L. Neuronal mechanisms for sleep/wake regulation and modulatory drive. *Neuropsychopharmacology*. 2018;43(5):937-952. doi:10.1038/npp.2017.294

22. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. *Annu Rev Physiol*. 2010;72(1):517-549. doi:10.1146/annurev-physiol-021909-135821

23. Astiz M, Heyde I, Oster H. Mechanisms of communication in the mammalian circadian timing system. *Int J Mol Sci*. 2019;20(2):343. doi:10.3390/ijms20020343

24. Stenvers DJ, Scheer F, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. *Nat Rev Endocrinol*. 2019;15(2): 75-89. doi:10.1038/s41574-018-0122-1

25. Fagiani F, Di Marino D, Romagnoli A, et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. *Signal Transduct Target Ther*. 2022;7(1):41. doi:10.1038/s41392-022-00899-y

26. Trakada G. Dietary nutrient intake and sleep. *Nutrients*. 2023;15(10): 2276. doi:10.3390/nu15102276
27. Petit JM, Burlet-Godinot S, Magistretti PJ, Allaman I. Glycogen metabolism and the homeostatic regulation of sleep. *Metab Brain Dis*. 2015;30(1):263-279. doi:10.1007/s11011-014-9629-x

28. Bathory E, Tomopoulos S. Sleep regulation, physiology and development, sleep duration and patterns, and sleep hygiene in infants, toddlers, and preschool-age children. *Curr Probl Pediatr Adolesc Health Care*. 2017;47(2):29-42. doi:10.1016/j.cppeds.2016.12.001

29. Walker MP. The role of sleep in cognition and emotion. *Ann N Y Acad Sci*. 2009;1156:168-197. doi:10.1111/j.1749-6632.2009.04416.x

30. Hou Y, Dan X, Babbar M, et al. Ageing as a risk factor for neurodegenerative disease. *Nat Rev Neurol*. 2019;15(10):565-581. doi:10.1038/s41582-019-0244-7

31. Ferini-Strambi L, Liguori C, Lucey BP, et al. Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum. *Neurol Sci*. 2024;45(2):749-767. doi:10.1007/s10072-023-07232-7

32. Fifel K, Videnovic A. Circadian and sleep dysfunctions in neurodegenerative disorders-An update. Mini Review. *Front Neurosci*. 2021; 14:627330. doi:10.3389/fnins.2020.627330

33. Lee YF, Gerashchenko D, Timofeev I, Bacskai BJ, Kastanenka KV. Slow wave sleep is a promising intervention target for Alzheimer's disease. *Review Front Neurosci*. 2020;14:705. doi:10.3389/fnins.2020.00705

34. Ju YS, Ooms SJ, Sutphen C, et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. *Brain*. 2017;140(8): 2104-2111. doi:10.1093/brain/awx148

35. Kalinderi K, Papaliagkas V, Fidani L. The genetic landscape of sleep disorders in Parkinson's disease. *Diagnostics (Basel)*. 2024;14(1):106. doi:10.3390/diagnostics14010106

36. Suzuki K, Fujita H, Kobayashi S. Managing sleep issues in Parkinson's disease: an up-to-date review. *Expert Rev Neurother*. 2025;25(2): 211-226. doi:10.1080/14737175.2025.2450789

37. Boentert M. Sleep and sleep disruption in amyotrophic lateral sclerosis. *Curr Neurol Neurosci Rep*. 2020;20(7):25. doi:10.1007/s11910-020-01047-1

38. Silva F, Silva J, Salgueira S, Mendes A, Matos E, Conde B. Sleep disturbances in amyotrophic lateral sclerosis and prognostic impact-a retrospective study. *Life*. 2024;14(10):1284. doi:10.3390/life14101284

39. Lv YN, Cui Y, Zhang B, Huang SM. Sleep deficiency promotes Alzheimer's disease development and progression. *Front Neurol*. 2022;13:1053942. doi:10.3389/fneur.2022.1053942

40. Mahiar M, Elie M. The impact of sleep on the progression of Parkinson's disease: a mendelian randomization study. *BMJ Neurology Open*. 2024;4(Suppl 1):A31.1. doi:10.1136/bmjno-2022-ANZAN.80

41. Voysey ZJ, Barker RA, Lazar AS. The treatment of sleep dysfunction in neurodegenerative disorders. *Neurotherapeutics*. 2021;18(1):202-216. doi:10.1007/s13311-020-00959-7

42. Saper CB. The intermediate nucleus in humans: Cytoarchitecture, chemoarchitecture, and relation to sleep, sex, and Alzheimer disease. *Handb Clin Neurol*. 2021;179:461-469. doi:10.1016/B978-0-12-819975-6.00030-3

43. Sathyanarayana S, Pavese N, Ledingham D. The cholinergic system in dementia with Lewy bodies. *Handb Clin Neurol*. 2025;211:231-245. doi:10.1016/B978-0-443-19088-9.00008-1

44. Pasquini J, Brooks DJ, Pavese N. The involvement of the cholinergic system in Parkinson disease. *Handb Clin Neurol*. 2025;211:215-229. doi:10.1016/B978-0-443-19088-9.00001-9

45. Sun YY, Wang Z, Zhou HY, Huang HC. Sleep-wake disorders in Alzheimer's disease: a review. *ACS Chem Nerosci*. 2022;13(10):1467-1478. doi:10.1021/acschemneuro.2c00097

46. Foustoukos G, Luthi A. Monoaminergic signaling during mammalian NREM sleep—recent insights and next-level questions. *Curr Opin Neurobiol*. 2025;92:103025. doi:10.1016/j.conb.2025.103025

47. Khowdiary MM, Al-Kuraishy HM, Al-Gareeb Al, et al. Dysregulation of serotonergic neurotransmission in Parkinson disease: a key duet. *Eur J Pharmacol*. 2025;995:177419. doi:10.1016/j.ejphar.2025.177419

48. Nikolenko VN, Borminskaya ID, Nikitina AT, Golyshkina MS, Rizaeva NA, Oganesyan MV. Locus coeruleus-norepinephrine system: spheres of influence and contribution to the development of neurodegenerative diseases. *Front Biosci (Landmark Ed)*. 2024;29(3): 118. doi:10.31083/j.fbl2903118

49. Monk TH, Buysse DJ. Chronotype, bed timing and total sleep time in seniors. *Chronobiol Int*. 2014;31(5):655-659. doi:10.3109/07420528.2014.885981

50. Druiven SJM, Riese H, Kamphuis J, et al. Chronotype changes with age; seven-year follow-up from the Netherlands study of depression and anxiety cohort. *J Affect Disord*. 2021;295:1118-1121. doi:10.1016/j.jad.2021.08.095

51. Randler C, Fassl C, Kalb N. From lark to owl: developmental changes in morningness-eveningness from new-borns to early adulthood. *Sci Rep*. 2017;7(1):45874. doi:10.1038/srep45874

52. Schmidt C, Peigneux P, Cajochen C. Age-related changes in sleep and circadian rhythms: impact on cognitive performance and underlying neuroanatomical networks. *Front Neurol*. 2012;3:118. doi:10.3389/fneur.2012.00118

53. Yoon IY, Kripke DF, Elliott JA, Youngstedt SD, Rex KM, Hauger RL. Age-related changes of circadian rhythms and sleep-wake cycles. *J Am Geriatr Soc*. 2003;51(8):1085-1091. doi:10.1046/j.1532-5415.2003.51356.x

54. Kryger MH, Roth T, Dement WC. *Principles and Practice of Sleep Medicine E-Book: Expert Consult-Online and Print*. Elsevier Health Sciences; 2010.

55. Duffy JF, Dijk DJ, Klerman EB, Czeisler CA. Later endogenous circadian temperature nadir relative to an earlier wake time in older people. *Am J Physiol*. 1998;275(5 Pt 2):R1478-R1487. doi:10.1152/ajpregu.1998.275.5.r1478

56. Duffy JF, Zeitzer JM, Rimmer DW, Klerman EB, Dijk DJ, Czeisler CA. Peak of circadian melatonin rhythm occurs later within the sleep of older subjects. *Am J Physiol Endocrinol Metab*. 2002;282(2):E297-E303. doi:10.1152/ajpendo.00268.2001

57. Daan S, Beersma DG, Borbely AA. Timing of human sleep: recovery process gated by a circadian pacemaker. *Am J Physiol*. 1984;246(2 Pt 2):R161-R183. doi:10.1152/ajpregu.1984.246.2.R161

58. Brzezinski A. Melatonin in humans. *N Engl J Med*. 1997;336(3):186-195. doi:10.1056/NEJM199701163360306

59. Chen C, Yang C, Wang J, et al. Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer's disease. *J Pineal Res*. 2021;71(4):e12774. doi:10.1111/jpi.12774

60. Amir Hamzah K, Toms LM, Kucharski N, et al. Sex-dimorphism in human serum endocannabinoid and n-acyl ethanolamine concentrations across the lifespan. *Sci Rep*. 2023;13(1):23059. doi:10.1038/s41598-023-50426-4

61. Moffat SD, An Y, Resnick SM, Diamond MP, Ferrucci L. Longitudinal change in cortisol levels across the adult life span. *J Gerontol A Biol Sci Med Sci*. 2020;75(2):394-400. doi:10.1093/gerona/gly279

62. Iyo M, Yamasaki T. The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. *Prog Neuropsychopharmacol Biol Psychiatry*. 1993;17(3):415-421. doi:10.1016/0278-5846(93)90075-4

63. Wong DF, Wagner HN Jr, Dannals RF, et al. Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. *Science*. 1984;226(4681):1393-1396. doi:10.1126/science.6334363

64. Markova TZ, Ciampa CJ, Parent JH, et al. Poorer aging trajectories are associated with elevated serotonin synthesis capacity. *Mol Psychiatry*. 2023;28(10):4390-4398. doi:10.1038/s41380-023-02177-x
<figure><img src="image_5.png" /></figure>

65. Morgan E, Schumm LP, McClintock M, Waite L, Lauderdale DS. Sleep characteristics and daytime cortisol levels in older adults. *Sleep*. 2017;40(5):zsx043. doi:10.1093/sleep/zsx043

66. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA. 2000;284(7):861-868. doi:10.1001/jama.284.7.861

67. O'Leary LA. Orexin and melanin-concentrating hormone neurons: a hypothalamic interface for sleep and feeding regulation. *Biosci Horiz.* 2014;7:hzu008. doi:10.1093/biohorizons/hzu008

68. Bouaouda H, Jha PK. Orexin and MCH neurons: regulators of sleep and metabolism. *Front Neurosci.* 2023;17:1230428. doi:10.3389/fnins.2023.1230428

69. Bastianini S, Alvente S, Berteotti C, et al. Ageing-related modification of sleep and breathing in orexin-knockout narcoleptic mice. *J Sleep Res.* 2025;34(2):e14287. doi:10.1111/jsr.14287

70. Kessler BA, Stanley EM, Frederick-Duus D, Fadel J. Age-related loss of orexin/hypocretin neurons. Neuroscience. 2011;178:82-88. doi:10.1016/j.neuroscience.2011.01.031

71. Zhong HH, Yu B, Luo D, et al. Roles of aging in sleep. *Neurosci Biobehav Rev.* 2019;98:177-184. doi:10.1016/j.neubiorev.2019.01.013

72. Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA. Sleep disorders, obesity, and aging: the role of orexin. *Ageing Res Rev.* 2015;20:63-73. doi:10.1016/j.arr.2014.11.001

73. Zink AN, Perez-Leighton CE, Kotz CM. The orexin neuropeptide system: physical activity and hypothalamic function throughout the aging process. *Front Syst Neurosci.* 2014;8:211. doi:10.3389/fnsys.2014.00211

74. Hunt NJ, Rodriguez ML, Waters KA, Machaalani R. Changes in orexin (hypocretin) neuronal expression with normal aging in the human hypothalamus. *Neurobiol Aging.* 2015;36(1):292-300. doi:10.1016/j.neurobiolaging.2014.08.010

75. Stanley EM, Fadel JR. Aging-related alterations in orexin/hypocretin modulation of septo-hippocampal amino acid neurotransmission. *Neuroscience.* 2011;195:70-79. doi:10.1016/j.neuroscience.2011.08.033

76. Sawai N, Ueta Y, Nakazato M, Ozawa H. Developmental and aging change of orexin-A and -B immunoreactive neurons in the male rat hypothalamus. *Neurosci Lett.* 2010;468(1):51-55. doi:10.1016/j.neulet.2009.10.061

77. Matsumura T, Nakayama M, Nomura A, et al. Age-related changes in plasma orexin-A concentrations. *Exp Gerontol.* 2002;37(8-9):1127-1130. doi:10.1016/s0531-5565(02)00092-x

78. Downs JL, Dunn MR, Borok E, et al. Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. *Neurobiol Aging.* 2007; 28(8):1286-1295. doi:10.1016/j.neurobiolaging.2006.05.025

79. Li SB, Damonte VM, Chen C, et al. Hyperexcitable arousal circuits drive sleep instability during aging. *Science.* 2022;375(6583): eabh3021. doi:10.1126/science.abh3021

80. Lividini A, Pizza F, Filardi M, et al. Narcolepsy type 1 features across the life span: age impact on clinical and polysomnographic phenotype. *J Clin Sleep Med.* 2021;17(7):1363-1370. doi:10.5664/jcsm.9198

81. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. *Neuron.* 2000;27(3):469-474. doi:10.1016/s0896-6273(00)00058-1

82. Carrier J, Monk TH, Buysse DJ, Kupfer DJ. Sleep and morningness-eveningness in the 'middle' years of life (20-59 y). *J Sleep Res.* 1997; 6(4):230-237. doi:10.1111/j.1365-2869.1997.00230.x

83. Dijk DJ, Duffy JF, Czeisler CA. Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep. *Chronobiol Int.* 2000;17(3):285-311. doi:10.1081/cbi-100101049

84. Hayashi Y, Endo S. All-night sleep polygraphic recordings of healthy aged persons: REM and slow-wave sleep. Sleep. 1982;5(3):277-283. doi:10.1093/sleep/5.3.277

85. Feinberg I. Effects maturation and aging on slow wave sleep in man. In Wanquier A, Dugovic C, Radulovacki M. eds., *Slow Wave Sleep*,

*Pathological and Functional Aspects*. New York: Raven Press; 1989: 31-48.

86. Poirson B, Vandel P, Bourdin H, Galli S. Age-related changes in sleep spindle characteristics in individuals over 75 years of age: a retrospective and comparative study. BMC Geriatr. 2020;24(1):778. doi:10.1186/s12877-024-05364-9

87. Schwarz JFA, Akerstedt T, Lindberg E, Gruber G, Fischer H, Theorell-Haglow J. Age affects sleep microstructure more than sleep macrostructure. *J Sleep Res.* 2017;26(3):277-287. doi:10.1111/jsr.12478

88. Carrier J, Viens I, Poirier G, et al. Sleep slow wave changes during the middle years of life. *Eur J Neurosci.* 2011;33(4):758-766. doi:10.1111/j.1460-9568.2010.07543.x

89. Martin N, Lafortune M, Godbout J, et al. Topography of age-related changes in sleep spindles. *Neurobiol Aging.* 2013;34(2):468-476. doi:10.1016/j.neurobiolaging.2012.05.020

90. Staresina BP, Niediek J, Borger V, Surges R, Mormann F. How coupled slow oscillations, spindles and ripples coordinate neuronal processing and communication during human sleep. *Nat Neurosci.* 2023;26(8):1429-1437. doi:10.1038/s41593-023-01381-w

91. Saper CB, German DC. Hypothalamic pathology in Alzheimer's disease. *Neurosci Lett.* 1987;74(3):364-370. doi:10.1016/0304-3940(87)90325-9

92. Homolak J, Mudrovcic M, Vukic B, Toljan K. Circadian rhythm and Alzheimer's disease. *Med Sci (Basel).* 2018;6(3):52. doi:10.3390/medsci6030052

93. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology—a bidirectional relationship. *Nat Rev Neurol.* 2014;10(2): 115-119. doi:10.1038/nrneurol.2013.269

94. Satlin A, Volicer L, Stopa EG, Harper D. Circadian locomotor activity and core-body temperature rhythms in Alzheimer's disease. *Neurobiol Aging.* 1995;16(5):765-771. doi:10.1016/0197-4580(95)00059-n

95. van Someren EJ, Hagebeek EE, Lijzenga C, et al. Circadian rest-activity rhythm disturbances in Alzheimer's disease. *Biol Psychiatry.* 1996;40(4):259-270. doi:10.1016/0006-3223(95)00370-3

96. Sterniczuk R, Dyck RH, Laferla FM, Antle MC. Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 1. Circadian changes. *Brain Res.* 2010;1348:139-148. doi:10.1016/j.brainres.2010.05.013

97. Sterniczuk R, Antle MC, Laferla FM, Dyck RH. Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 2. Behavioral and cognitive changes. *Brain Res.* 2010;1348:149-155. doi:10.1016/j.brainres.2010.06.011

98. Hartmann A, Veldhuis JD, Deuschle M, Standhardt H, Heuser I. Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: ultra-dian secretory pulsatility and diurnal variation. *Neurobiol Aging.* 1997;18(3):285-289. doi:10.1016/s0197-4580(97)80309-0

99. Olvera-Cortes ME, Gutierrez-Guzman BE, Lopez-Loeza E, Hernandez-Perez JJ, Lopez-Vazquez MA. Serotonergic modulation of hippocampal theta activity in relation to hippocampal information processing. *Exp Brain Res.* 2013;230(4):407-426. doi:10.1007/s00221-013-3679-x

100. Lecouflet P, Roux CM, Potier B, et al. Interplay between 5-HT4 receptors and GABAergic system within CA1 hippocampal synaptic plasticity. *Cereb Cortex.* 2021;31(1):694-701. doi:10.1093/cercor/bhaa253

101. Smith GS, Kuwabara H, Yan H, et al. Serotonin degeneration and amyloid-beta deposition in mild cognitive impairment: relationship to cognitive deficits. *J Alzheimers Dis.* 2023;96(1):215-227. doi:10.3233/JAD-230570

102. Smith GS, Protas H, Kuwabara H, et al. Molecular imaging of the association between serotonin degeneration and beta-amyloid deposition in mild cognitive impairment. *Neuroimage Clin.* 2023;37: 103322. doi:10.1016/j.nicl.2023.103322
103. Liguori C, Nuccetelli M, Izzi F, et al. Rapid eye movement sleep dis-ruption and sleep fragmentation are associated with increased orexin-A cerebrospinal-fluid levels in mild cognitive impairment due to Alzheimer's disease. *Neurobiol Aging*. 2016;40:120-126. doi:10.1016/j.neurobiolaging.2016.01.007

104. Liguori C, Romigi A, Nuccetelli M, et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. *JAMA Neurol*. 2014;71(12):1498-1505. doi:10.1001/jamaneurol.2014.2510

105. Gabelle A, Jaussent I, Hirtz C, et al. Cerebrospinal fluid levels of orexin-A and histamine, and sleep profile within the Alzheimer process. *Neurobiol Aging*. 2017;53:59-66. doi:10.1016/j.neurobiolaging.2017.01.011

106. Schmidt FM, Kratzsch J, Gertz HJ, et al. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease. *PLoS One*. 2013;8(5):e63136. doi:10.1371/journal.pone.0063136

107. Roh JH, Jiang H, Finn MB, et al. Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease. *J Exp Med*. 2014;211(13):2487-2496. doi:10.1084/jem.20141788

108. Deuschle M, Schilling C, Leweke FM, et al. Hypocretin in cerebrospinal fluid is positively correlated with Tau and pTau. *Neurosci Lett*. 2014;561:41-45. doi:10.1016/j.neulet.2013.12.036

109. Liguori C, Spanetta M, Izzi F, et al. Sleep-wake cycle in Alzheimer's disease is associated with tau pathology and orexin dysregulation. *J Alzheimers Dis*. 2020;74(2):501-508. doi:10.3233/Jad-191124

110. Adamantidis A, de Lecea L. A role for melanin-concentrating hormone in learning and memory. *Peptides*. 2009;30(11):2066-2070. doi:10.1016/j.peptides.2009.06.024

111. Concetti C, Peleg-Raibstein D, Burdakov D. Hypothalamic MCH neurons: from feeding to cognitive control. *Function (Oxf).* 2024; 5(1):zqad059. doi:10.1093/function/zqad059

112. Blanco-Centurion C, Luo S, Spergel DJ, et al. Dynamic network activation of hypothalamic MCH neurons in REM sleep and exploratory behavior. *J Neurosci*. 2019;39(25):4986-4998. doi:10.1523/JNEUROSCI.0305-19.2019

113. Calafate S, Ozturan G, Thrupp N, et al. Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease. *Nat Neurosci*. 2023;26(6): 1021-1031. doi:10.1038/s41593-023-01325-4

114. Lee JH, Bliwise DL, Ansari FP, et al. Daytime sleepiness and functional impairment in Alzheimer disease. *Am J Geriatr Psychiatry*. 2007;15(7):620-626. doi:10.1097/JGP.0b013e3180381521

115. Wang P, Wing YK, Xing J, et al. Rapid eye movement sleep behavior disorder in patients with probable Alzheimer's disease. *Aging Clin Exp Res*. 2016;28(5):951-957. doi:10.1007/s40520-015-0382-8

116. Mander BA, Marks SM, Vogel JW, et al. Beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. *Nat Neurosci*. 2015;18(7):1051-1057. doi:10.1038/nn.4035

117. Sethi M, Joshi SS, Webb RL, et al. Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer's disease. *Neuroscience*. 2015;290:80-89. doi:10.1016/j.neuroscience.2015.01.035

118. Minakawa EN, Wada K, Nagai Y. Sleep disturbance as a potential modifiable risk factor for Alzheimer's disease. *Int J Mol Sci*. 2019; 20(4):803. doi:10.3390/ijms20040803

119. Katsuki F, Gerashchenko D, Brown RE. Alterations of sleep oscillations in Alzheimer's disease: a potential role for GABAergic neurons in the cortex, hippocampus, and thalamus. *Brain Res Bull.* 2022;187: 181-198. doi:10.1016/j.brainresbull.2022.07.002

120. Weng YY, Lei X, Yu J. Sleep spindle abnormalities related to Alzheimer's disease: a systematic mini-review. *Sleep Med*. 2020;75:37-44. doi:10.1016/j.sleep.2020.07.044

121. Muehlroth BE, Sander MC, Fandakova Y, et al. Precise slow oscillation-spindle coupling promotes memory consolidation in

younger and older adults. *Sci Rep*. 2019;9(1):1940. doi:10.1038/s41598-018-36557-z

122. Kam K, Parekh A, Sharma RA, et al. Sleep oscillation-specific associations with Alzheimer's disease CSF biomarkers: novel roles for sleep spindles and tau. *Mol Neurodegener*. 2019;14(1):10. doi:10.1186/s13024-019-0309-5

123. Breen DP, Vuono R, Nawarathna U, et al. Sleep and circadian rhythm regulation in early Parkinson disease. *JAMA Neurol*. 2014; 71(5):589-595. doi:10.1001/jamaneurol.2014.65

124. Videnovic A, Lazar AS, Barker RA, Overeem S. 'The clocks that time us'—circadian rhythms in neurodegenerative disorders. *Nat Rev Neurol*. 2014;10(12):683-693. doi:10.1038/nrneurol.2014.206

125. Tohgi H, Abe T, Takahashi S, Takahashi J, Hamato H. Concentrations of serotonin and its related substances in the cerebrospinal fluid of parkinsonian patients and their relations to the severity of symptoms. *Neurosci Lett*. 1993;150(1):71-74. doi:10.1016/0304-3940(93)01111-w

126. Kerenyi L, Ricaurte GA, Schretlen DJ, et al. Positron emission tomography of striatal serotonin transporters in Parkinson disease. *Arch Neurol*. 2003;60(9):1223-1229. doi:10.1001/archneur.60.9.1223

127. Jorgensen LM, Henriksen T, Mardosiene S, et al. Parkinson patients have a presynaptic serotonergic deficit: a dynamic deep brain stimulation PET study. *J Cereb Blood Flow Metab*. 2021;41(8):1954-1963. doi:10.1177/0271678X20982389

128. Fronczek R, Overeem S, Lee SY, et al. Hypocretin (orexin) loss in Parkinson's disease. *Brain*. 2007;130(Pt 6):1577-1585. doi:10.1093/brain/awm090

129. Ten-Blanco M, Flores A, Cristino L, Pereda-Perez I, Berrendero F. Targeting the orexin/hypocretin system for the treatment of neuro-psychiatric and neurodegenerative diseases: from animal to clinical studies. *Front Neuroendocrinol*. 2023;69:101066. doi:10.1016/j.yfrne.2023.101066

130. Asai H, Hirano M, Furiya Y, et al. Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease. *Clin Neurol Neurosurg*. 2009;111(4):341-344. doi:10.1016/j.clineuro.2008.11.007

131. Wienecke M, Werth E, Poryazova R, et al. Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness? *J Sleep Res*. 2012;21(6):710-717. doi:10.1111/j.1365-2869.2012.01027.x

132. Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in Parkinson's disease. *Brain*. 2007;130(Pt 6):1586-1595. doi:10.1093/brain/awm097

133. Fifel K, Cooper HM. Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson's disease. *Neurobiol Dis*. 2014;71:359-369. doi:10.1016/j.nbd.2014.08.024

134. Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J. Day-time sleepiness and other sleep disorders in Parkinson's disease. *Neurology*. 2001;57(8):1392-1396. doi:10.1212/wnl.57.8.1392

135. Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. *Mov Disord*. 2009;24(15): 1641-1649. doi:10.1002/mds.22643

136. Rolinski M, Szewczyk-Krolikowski K, Tomlinson PR, et al. REM sleep behaviour disorder is associated with worse quality of life and other non-motor features in early Parkinson's disease. *J Neurol Neurosurg Psychiatry*. 2014;85(5):560-566. doi:10.1136/jnnp-2013-306104

137. de Natale ER, Wilson H, Politis M. Predictors of RBD progression and conversion to synucleinopathies. *Curr Neurol Neurosci Rep*. 2022;22(2):93-104. doi:10.1007/s11910-022-01171-0

138. Iranzo A, Santamaria J, Rye DB, et al. Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. *Neurology*. 2005;65(2):247-252. doi:10.1212/01.wnl.0000168864.97813.e0
<figure><img src="image_6.png" /></figure>

139. Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. *Brain*. 2019;142(3):744-759. doi:10.1093/brain/awz030

140. Krenzer M, Anaclet C, Vetrivelan R, et al. Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia. *PLoS One*. 2011; 6(10):e24998. doi:10.1371/journal.pone.0024998

141. Iranzo A. The REM sleep circuit and how its impairment leads to REM sleep behavior disorder. *Cell Tissue Res*. 2018;373(1):245-266. doi:10.1007/s00441-018-2852-8

142. Vetrivelan R, Bandaru SS. Neural control of REM sleep and motor Atonia: current perspectives. *Curr Neurol Neurosci Rep*. 2023;23(12): 907-923. doi:10.1007/s11910-023-01322-x

143. Schenck CH, Mahowald MW. A novel animal model offers deeper insights into REM sleep behaviour disorder. *Brain*. 2017;140(2):256-259. doi:10.1093/brain/aww329

144. Uchida S, Soya S, Saito YC, et al. A discrete glycinergic neuronal population in the ventromedial medulla that induces muscle Atonia during REM sleep and cataplexy in mice. *J Neurosci*. 2021;41(7): 1582-1596. doi:10.1523/JNEUROSCI.0688-20.2020

145. Stefani A, Antelmi E, Arnaldi D, et al. From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease. *Mol Neurodegener*. 2025;20(1):19. doi:10.1186/s13024-025-00809-0

146. O'Dowd S, Galna B, Morris R, et al. Poor sleep quality and progression of gait impairment in an incident Parkinson's disease cohort. *J Parkinsons Dis*. 2017;7(3):465-470. doi:10.3233/JPD-161062

147. Pont-Sunyer C, Iranzo A, Gaig C, et al. Sleep disorders in parkinsonian and nonparkinsonian LRRK2 mutation carriers. *PLoS One*. 2015; 10(7):e0132368. doi:10.1371/journal.pone.0132368

148. Kudo T, Loh DH, Truong D, Wu Y, Colwell CS. Circadian dysfunction in a mouse model of Parkinson's disease. *Exp Neurol*. 2011;232(1): 66-75. doi:10.1016/j.expneurol.2011.08.003

149. Papp A, Horvath A, Gombos F, Bodizs R, Kamondi A, Szucs A. Analysis of slow and fast sleep spindle properties in Parkinson's disease—a comparative EEG study. *Int J Psychophysiol*. 2022;182:220-230. doi:10.1016/j.ijpsycho.2022.11.001

150. Emser W, Brenner M, Stober T, Schimrigk K. Changes in nocturnal sleep in Huntington's and Parkinson's disease. *J Neurol*. 1988;235(3): 177-179. doi:10.1007/BF00314313

151. Latreille V, Carrier J, Lafortune M, et al. Sleep spindles in Parkinson's disease may predict the development of dementia. *Neurobiol Aging*. 2015;36(2):1083-1090. doi:10.1016/j.neurobiolaging.2014.09.009

152. Amara A, Memon A, Catiul C, et al. Spindles and Slow Waves Predict Parkinson's Disease-Mild Cognitive Impairment. Research Square; 2022.

153. Brunner H, Wetter TC, Hogl B, Yassouridis A, Trenkwalder C, Friess E. Microstructure of the non-rapid eye movement sleep electroencephalogram in patients with newly diagnosed Parkinson's disease: effects of dopaminergic treatment. *Mov Disord*. 2002;17(5): 928-933. doi:10.1002/mds.10242

154. Fisher SP, Black SW, Schwartz MD, et al. Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington's disease. *Brain*. 2013;136(Pt 7):2159-2172. doi:10.1093/brain/awt132

155. Fisher SP, Schwartz MD, Wurts-Black S, et al. Quantitative electroencephalographic analysis provides an early-stage indicator of disease onset and progression in the zQ175 knock-in mouse model of Huntington's disease. *Sleep*. 2016;39(2):379-391. doi:10.5665/sleep.5448

156. Kantor S, Szabo L, Varga J, Cuesta M, Morton AJ. Progressive sleep and electroencephalogram changes in mice carrying the Huntington's disease mutation. *Brain*. 2013;136(Pt 7):2147-2158. doi:10.1093/brain/awt128

157. Aziz NA, Pijl H, Frolich M, van der Graaf AW, Roelfsema F, Roos RA. Increased hypothalamic-pituitary-adrenal axis activity in Huntington's disease. *J Clin Endocrinol Metab*. 2009;94(4):1223-1228. doi:10.1210/jc.2008-2543

158. Heuser IJ, Chase TN, Mouradian MM. The limbic-hypothalamic-pituitary-adrenal axis in Huntington's disease. *Biol Psychiatry*. 1991; 30(9):943-952. doi:10.1016/0006-3223(91)90007-9

159. Kalliolia E, Silajdzic E, Nambron R, et al. Plasma melatonin is reduced in Huntington's disease. *Mov Disord*. 2014;29(12):1511-1515. doi: 10.1002/mds.26003

160. Kim J, Li W, Wang J, et al. Biosynthesis of neuroprotective melatonin is dysregulated in Huntington's disease. *J Pineal Res*. 2023;75(4): e12909. doi:10.1111/jpi.12909

161. Cross AJ, Reynolds GP, Hewitt LM, Slater P. Brain serotonin receptors in Huntington's disease. *Neurochem Int*. 1986;9(3):431-435. doi: 10.1016/0197-0186(86)90085-9

162. Pang TY, Du X, Zajac MS, Howard ML, Hannan AJ. Altered serotonin receptor expression is associated with depression-related behavior in the R6/1 transgenic mouse model of Huntington's disease. *Hum Mol Genet*. 2009;18(4):753-766. doi:10.1093/hmg/ddn385

163. Gabery S, Murphy K, Schultz K, et al. Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses. *Acta Neuropathol*. 2010;120(6):777-788. doi: 10.1007/s00401-010-0742-6

164. Petersen A, Gil J, Maat-Schieman ML, et al. Orexin loss in Huntington's disease. *Hum Mol Genet*. 2005;14(1):39-47. doi:10.1093/hmg/ddi004

165. Aziz A, Fronczek R, Maat-Schieman M, et al. Hypocretin and melanin-concentrating hormone in patients with Huntington disease. *Brain Pathol*. 2008;18(4):474-483. doi:10.1111/j.1750-3639.2008.00135.x

166. Williams RH, Morton AJ, Burdakov D. Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington's disease. *Neurobiol Dis*. 2011;42(3):438-445. doi:10.1016/j.nbd.2011.02.006

167. Gabery S, Sajjad MU, Hult S, Soylu R, Kirik D, Petersen A. Characterization of a rat model of Huntington's disease based on targeted expression of mutant huntingtin in the forebrain using adeno-associated viral vectors. *Eur J Neurosci*. 2012;36(6):2789-2800. doi: 10.1111/j.1460-9568.2012.08193.x

168. Henningsen JB, Soylu-Kucharz R, Bjorkqvist M, Petersen A. Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease. *Heliyon*. 2021;7(8):e07808. doi:10.1016/j.heliyon.2021.e07808

169. Kremer HP, Roos RA, Dingjan G, Marani E, Bots GT. Atrophy of the hypothalamic lateral tuberal nucleus in Huntington's disease. *J Neuropathol Exp Neurol*. 1990;49(4):371-382. doi:10.1097/00005072-199007000-00002

170. Arnulf I, Nielsen J, Lohmann E, et al. Rapid eye movement sleep disturbances in Huntington disease. *Arch Neurol*. 2008;65(4):482-488. doi:10.1001/archneur.65.4.482

171. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. *Lancet Neurol*. 2006;5(7):572-577. doi: 10.1016/S1474-4422(06)70476-8

172. Dedeene L, Van Schoor E, Vandenberghe R, Van Damme P, Poesen K, Thal DR. Circadian sleep/wake-associated cells show dipeptide repeat protein aggregates in C9orf72-related ALS and FTLD cases. *Acta Neuropathol Commun*. 2019;7(1):189. doi:10.1186/s40478-019-0845-9

173. Killoy KM, Pehar M, Harlan BA, Vargas MR. Altered expression of clock and clock-controlled genes in a hSOD1-linked amyotrophic lateral sclerosis mouse model. *FASEB J*. 2021;35(2):e21343. doi:10.1096/fj.202000386RR

174. Huang Z, Liu Q, Peng Y, et al. Circadian rhythm dysfunction accelerates disease progression in a mouse model with amyotrophic lateral sclerosis. *Front Neurol*. 2018;9:218. doi:10.3389/fneur.2018.00218
175. Spataro R, Volanti P, Vitale F, et al. Plasma cortisol level in amyotrophic lateral sclerosis. *J Neurol Sci.* 2015;358(1-2):282-286. doi: 10.1016/j.jns.2015.09.011

176. Dentel C, Palamiuc L, Henriques A, et al. Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity. *Brain*. 2013;136(Pt 2):483-493. doi:10.1093/brain/aws274

177. Dupuis L, Spreux-Varoquaux O, Bensimon G, et al. Platelet serotonin level predicts survival in amyotrophic lateral sclerosis. *PLoS One*. 2010;5(10):e13346. doi:10.1371/journal.pone.0013346

178. He P, He B, Li S, et al. Distribution features and potential effects of serotonin in the cerebrum of SOD1 G93A transgenic mice. *eNeuro*. 2022; 9(6):ENEURO.0001-22.2022. doi:10.1523/ENEURO.0001-22.2022

179. Van Rooij FG, Schelhaas HJ, Lammers GJ, Verbeek MM, Overeem S. CSF hypocretin-1 levels are normal in patients with amyotrophic lateral sclerosis. *Amyotroph Lateral Scler*. 2009;10(5-6):487-489. doi: 10.3109/17482960802315024

180. Chang J, Shaw TB, Holdom CJ, et al. Lower hypothalamic volume with lower body mass index is associated with shorter survival in patients with amyotrophic lateral sclerosis. *Eur J Neurol*. 2023;30(1): 57-68. doi:10.1111/ene.15589

181. Bolborea M, Vercruysse P, Daria T, et al. Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis. *Acta Neuropathol*. 2023;145(6):773-791. doi:10.1007/s00401-023-02569-x

182. Ackrivo J, Geronimo A. Transcutaneous carbon dioxide monitoring in ALS: assessment of hypoventilation heats up. *Muscle Nerve*. 2022; 65(4):371-373. doi:10.1002/mus.27502

183. Boentert M, Glatz C, Helmle C, Okegwo A, Young P. Prevalence of sleep apnoea and capnographic detection of nocturnal hypoventilation in amyotrophic lateral sclerosis. *J Neurol Neurosurg Psychiatry*. 2018;89(4):418-424. doi:10.1136/jnnp-2017-316515

184. Ebben MR, Shahbazi M, Lange DJ, Krieger AC. REM behavior disorder associated with familial amyotrophic lateral sclerosis. *Amyotroph Lateral Scler*. 2012;13(5):473-474. doi:10.3109/17482968.2012. 673172

185. Lo Coco D, Puligheddu M, Mattaliano P, et al. REM sleep behavior disorder and periodic leg movements during sleep in ALS. *Acta Neurol Scand*. 2017;135(2):219-224. doi:10.1111/ane.12593

186. Perlegos AE, Durkin J, Belfer SJ, et al. TDP-43 impairs sleep in *Drosophila* through Ataxin-2-dependent metabolic disturbance. *Sci Adv*. 2024;10(2):eadj4457. doi:10.1126/sciadv.adj4457

187. Zhang H, Chen C, Zhang EE, Huang X. TDP-43 deficiency in supra-Chiasmatic nucleus perturbs rhythmicity of neuroactivity in prefrontal cortex. *iScience*. 2024;27(4):109522. doi:10.1016/j.isci.2024. 109522

188. Braun MC, Castillo-Ruiz A, Indic P, et al. Defective daily temperature regulation in a mouse model of amyotrophic lateral sclerosis. *Exp Neurol*. 2019;311:305-312. doi:10.1016/j.expneurol.2018.07.008

189. Holoviews. Version 1.19.1. Zenodo; 2024. Holoviews. https://github.com/holoviz/holoviews

190. Zhang T, Jiang X, Xu M, et al. Sleep and circadian abnormalities precede cognitive deficits in R521C FUS knockin rats. *Neurobiol Aging*. 2018;72:159-170. doi:10.1016/j.neurobiolaging.2018.08.025.

191. Guillot SJ, Lang C, Simonot M, et al. Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models. *Sci Transl Med*. 2025;17(783): eadm7580. doi:10.1126/scitranslmed.adm7580

192. Anderson KN, Hatfield C, Kipps C, Hastings M, Hodges JR. Disrupted sleep and circadian patterns in frontotemporal dementia. *Eur J Neurol*. 2009;16(3):317-323. doi:10.1111/j.1468-1331.2008. 02414.x

193. d'Almeida NA, Tipping M. Flight to insight: maximizing the potential of drosophila models of C9orf72-FTD. *Front Mol Neurosci*. 2024;17: 1434443. doi:10.3389/fnmol.2024.1434443

194. Lee D, Zheng X, Shigemori K, et al. Expression of mutant CHMP2B linked to neurodegeneration in humans disrupts circadian rhythms

in *Drosophila*. *FASEB Bioadv.* 2019;1(8):511-520. doi:10.1096/fba. 2019-00042

195. Harper DG, Stopa EG, McKee AC, et al. Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration. *Arch Gen Psychiatry*. 2001;58(4):353-360. doi: 10.1001/archpsyc.58.4.353

196. Li H, Chen K, Yang L, Wang Q, Zhang J, He J. The role of plasma cortisol in dementia, epilepsy, and multiple sclerosis: a Mendelian randomization study. *Front Endocrinol (Lausanne)*. 2023;14:1107780. doi:10.3389/fendo.2023.1107780

197. McCarter SJ, St Louis EK, Boeve BF. Sleep disturbances in frontotemporal dementia. *Curr Neurol Neurosci Rep*. 2016;16(9):85. doi:10. 1007/s11910-016-0680-3

198. Heywood WE, Hallqvist J, Heslegrave AJ, et al. CSF pro-orexin and amyloid-beta38 expression in Alzheimer's disease and frontotemporal dementia. *Neurobiol Aging*. 2018;72:171-176. doi:10.1016/j. neurobiolaging.2018.08.019

199. Coban A, Bilgic B, Lohmann E, et al. Reduced orexin-A levels in frontotemporal dementia: possible association with sleep disturbance. *Am J Alzheimers Dis Other Demen*. 2013;28(6):606-611. doi:10. 1177/1533317513494453

200. Maestri M, Carnicelli L, Economou NT, et al. NREM sleep transient events in fronto-temporal dementia: beyond sleep stage architecture. *Arch Ital Biol*. 2015;153(2-3):214-224. doi:10.12871/ 0003982920152346

201. Keenan RJ, Oberrauch S, Bron R, et al. Decreased orexin receptor 1 mRNA expression in the locus coeruleus in both tau transgenic rTg4510 and tau knockout mice and accompanying ascending arousal system tau invasion in rTg4510. *J Alzheimer's Dis*. 2021; 79(2):693-708. doi:10.3233/JAD-201177

202. Lozano-Tovar S, Cremascoli R, Nuccetelli M, et al. Cerebrospinal-fluid Orexin-A levels in different neurocognitive disorders: a comparison study. *Neurol Sci*. 2025;46:3631-3638. doi:10.1007/ s10072-025-08148-0

203.RVetafF, Marcinino A, Cremascoli R, et al. Increased orexin A concentrations in cerebrospinal fluid of patients with behavioural variant frontotemporal dementia. *Neurol Sci*. 2022;43(1):313-317. doi: 10.1007/s10072-021-05250-x

204. Raheel K, See QR, Munday V, et al. Orexin and sleep disturbances in alpha-synucleinopathies: a systematic review. *Curr Neurol Neurosci Rep*. 2024;24(9):389-412. doi:10.1007/s11910-024-01359-6

205. Kumar S, Behl T, Sehgal A, et al. Exploring the role of orexinergic neurons in Parkinson's disease. *Neurotox Res*. 2021;39(6):2141- 2153. doi:10.1007/s12640-021-00411-4

206. Liguori C, Romigi A, Mercuri NB, et al. Cerebrospinal-fluid orexin levels and daytime somnolence in frontotemporal dementia. *J Neurol*. 2014;261(9):1832-1836. doi:10.1007/s00415-014-7455-z

207. Zhang T, Jiang X, Xu M, et al. Sleep and circadian abnormalities precede cognitive deficits in R521C FUS knockin rats. *Neurobiol Aging*. 2018;72:159-170. doi:10.1016/j.neurobiolaging.2018.08.025

208. Rosales-Corral S, Tan DX, Reiter RJ, et al. Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E. *J Pineal Res*. 2003;35(2):80-84. doi:10. 1034/j.1600-079x.2003.00057.x

209. Delgado-Lara DL, Gonzalez-Enriquez GV, Torres-Mendoza BM, et al. Effect of melatonin administration on the PER1 and BMAL1 clock genes in patients with Parkinson's disease. *Biomed Pharmacother*. 2020;129:110485. doi:10.1016/j.biopha.2020.110485

210. Ahn JH, Kim M, Park S, et al. Prolonged-release melatonin in Parkinson's disease patients with a poor sleep quality: a randomized trial. *Parkinsonism Relat Disord*. 2020;75:50-54. doi:10.1016/j.parkreldis.2020.03.029

211. Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. *J Sleep Res*. 2010;19(4):591-596. doi:10.1111/j.1365-2869.2010.00848.x
<figure><img src="image_7.png" /></figure>

212. Schenck CH, Montplaisir JY, Frauscher B, et al. Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. *Sleep Med*. 2013;14(8):795-806. doi:10.1016/j.sleep.2013.02.016

213. Singhal NK, Srivastava G, Agrawal S, Jain SK, Singh MP. Melatonin as a neuroprotective agent in the rodent models of Parkinson's disease: is it all set to irrefutable clinical translation? *Mol Neurobiol*. 2012;45(1):186-199. doi:10.1007/s12035-011-8225-x

214. Sharma R, McMillan CR, Tenn CC, Niles LP. Physiological neuroprotection by melatonin in a 6-hydroxydopamine model of Parkinson's disease. *Brain Res*. 2006;1068:230-236. doi:10.1016/j.brainres.2005.10.084

215. Li J, Liu H, Wang X, et al. Melatonin ameliorates Parkinson's disease via regulating microglia polarization in a RORalpha-dependent pathway. *NPJ Parkinsons Dis*. 2022;8(1):90. doi:10.1038/s41531-022-00352-5

216. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. *Endocrine*. 2005;27(2):119-130. doi:10.1385/endo:27:2:119

217. Ran D, Xie B, Gan Z, Sun X, Gu H, Yang J. Melatonin attenuates hLRKK2-induced long-term memory deficit in a drosophila model of Parkinson's disease. *Biomed Rep*. 2018;9(3):221-226. doi:10.3892/br.2018.1125

218. Sun X, Ran D, Zhao X, et al. Melatonin attenuates hLRKK2-induced sleep disturbances and synaptic dysfunction in a *Drosophila* model of Parkinson's disease. *Mol Med Rep*. 2016;13(5):3936-3944. doi:10.3892/mmr.2016.4991

219. Su LY, Li H, Lv L, et al. Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/alpha-synuclein aggregation. *Autophagy*. 2015;11(10):1745-1759. doi:10.1080/15548627.2015.1082020

220. Khyati, Malik I, Agrawal N, Kumar V. Melatonin and curcumin reestablish disturbed circadian gene expressions and restore locomotion ability and eclosion behavior in drosophila model of Huntington's disease. *Chronobiol Int*. 2021;38(1):61-78. doi:10.1080/07420528.2020.1842752

221. Jacob S, Poeggeler B, Weishaupt JH, et al. Melatonin as a candidate compound for neuroprotection in amyotrophic lateral sclerosis (ALS): high tolerability of daily oral melatonin administration in ALS patients. *J Pineal Res*. 2002;33(3):186-187. doi:10.1034/j.1600-079x.2002.02943.x

222. Weishaupt JH, Bartels C, Polking E, et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. *J Pineal Res*. 2006;41(4):313-323. doi:10.1111/j.1600-079X.2006.00377.x

223. Shen X, Tang C, Wei C, Zhu Y, Xu R. Melatonin induces autophagy in amyotrophic lateral sclerosis mice via upregulation of SIRT1. *Mol Neurobiol*. 2022;59(8):4747-4760. doi:10.1007/s12035-022-02875-7

224. Bald EM, Nance CS, Schultz JL. Melatonin may slow disease progression in amyotrophic lateral sclerosis: findings from the Pooled Resource Open-Access ALS Clinic Trials database. *Muscle Nerve*. 2021;63(4):572-576. doi:10.1002/mus.27168

225. Zhang Y, Cook A, Kim J, et al. Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. *Neurobiol Dis*. 2013;55:26-35. doi:10.1016/j.nbd.2013.03.008

226. Callegari I, Mattei C, Benassi F, et al. Agomelatine improves apathy in frontotemporal dementia. *Neurodegener Dis*. 2016;16(5-6):352-356. doi:10.1159/000445873

227. Oh ST, Liu QF, Jeong HJ, et al. Nasal cavity administration of melanin-concentrating hormone improves memory impairment in memory-impaired and Alzheimer's disease mouse models. *Mol Neurobiol*. 2019;56(12):8076-8086. doi:10.1007/s12035-019-01662-1

228. Park JY, Kim SN, Yoo J, et al. Novel neuroprotective effects of melanin-concentrating hormone in Parkinson's disease. *Mol Neurobiol*. 2017;54(10):7706-7721. doi:10.1007/s12035-016-0258-8

229. Lucey BP, Liu H, Toedebusch CD, et al. Suvorexant acutely decreases tau phosphorylation and Abeta in the human CNS. *Ann Neurol*. 2023;94(1):27-40. doi:10.1002/ana.26641

230. Cabanas M, Pistono C, Puygrenier L, et al. Neurophysiological and behavioral effects of anti-orexinergic treatments in a mouse model of Huntington's disease. *Neurotherapeutics*. 2019;16(3):784-796. doi:10.1007/s13311-019-00726-3

231. Barrick AL, Sloane PD, Williams CS, et al. Impact of ambient bright light on agitation in dementia. *Int J Geriatr Psychiatry*. 2010;25(10):1013-1021. doi:10.1002/gps.2453

232. Rubino JA, Gamundi A, Akaarir M, Canellas F, Rial R, Nicolau MC. Bright light therapy and circadian cycles in institutionalized elders. *Front Neurosci*. 2020;14:359. doi:10.3389/fnins.2020.00359

233. Troussiere AC, Charley CM, Salleron J, et al. Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer's disease. *J Neurol Neurosurg Psychiatry*. 2014;85(12):1405-1408. doi:10.1136/jnnp-2013-307544

234. Wang L, Wu B, Tao H, et al. Effects and mediating mechanisms of a structured limbs-exercise program on general cognitive function in older adults with mild cognitive impairment: a randomized controlled trial. *Int J Nurs Stud*. 2020;110:103706. doi:10.1016/j.ijnurstu.2020.103706

235. Pallier PN, Maywood ES, Zheng Z, et al. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington's disease. *J Neurosci*. 2007;27(29):7869-7878. doi:10.1523/JNEUROSCI.0649-07.2007

236. Rudenko O, Springer C, Skov LJ, et al. Ghrelin-mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease. *J Neuroendocrinol*. 2019;31(7):e12699. doi:10.1111/jne.12699

237. Shirolapov IV, Zakharov AV, Smirnova DA, Lyamin AV, Gayduk AJ. The role of glymphatic clearance in the mechanisms linking the sleep-wake cycle with the development of neurodegenerative processes. *Neurosci Behav Physiol*. 2024;54(3):398-403. doi:10.1007/s11055-024-01604-y

238. Kroesbergen E, Riesselmann LV, Gomolka RS, et al. Glymphatic clearance is enhanced during sleep. *bioRxiv*. 2024. doi:10.1101/2024.08.24.609514

239. Eide PK, Lashkarivand A, Pripp A, et al. Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders. *Nat Commun*. 2023;14(1):2084. doi:10.1038/s41467-023-37685-5

240. Seibt J, Frank MG. Primed to sleep: the dynamics of synaptic plasticity across brain states. Hypothesis and theory. *Front Syst Neurosci*. 2019;13:2. doi:10.3389/fnsys.2019.00002

241. Coulson RL, Mourrain P, Wang GX. The intersection of sleep and synaptic translation in synaptic plasticity deficits in neurodevelopmental disorders. *J Comp Physiol B*. 2024;194(3):253-263. doi:10.1007/s00360-023-01531-3

242. Alfonsa H, Chakrabarty A, Vyazovskiy VV, Akerman CJ. Sleep-wake-related changes in intracellular chloride regulate plasticity at glutamatergic cortical synapses. *Curr Biol*. 2025;35(6):1373-1381.e3. doi:10.1016/j.cub.2025.01.050

**How to cite this article:** Guillot SJ, Luppi P-H, Dupuis L, Bolborea M. Sleep in neurodegenerative diseases: A focus on melatonin, melanin-concentrating hormone and orexin. *J Neuroendocrinol*. 2025;37(11):e70085. doi:10.1111/jne.70085