[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

Reversible modulation of circadian time with chronophotopharmacology.

The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Hypothalamic NAD+-Sirtuin Axis: Function and Regulation.

The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD+-dependence of sirtuin activity, adequate hypothalamic NAD+ contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD+-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD+ biology-targeting drugs in aging/obesity-related metabolic and circadian disorders.

The role of melatonin and melatonin receptor agonist in the prevention of sleep disturbances and delirium in intensive care unit - a clinical review.

AIM: The intensive care unit (ICU) environment contributes to the development of sleep disturbances. Sleep disturbances, sleep fragmentation, and multiple awakening episodes lead to the circadian rhythm disorder, which increases the risk of delirium. Melatonin and melatonin receptor agonist is widely used agent in the therapy of sleep disturbances. However, there is also some for its efficacy in ICU delirium. Enteral melatonin and ramelteon supplementation eliminates (partially) the delirium inducing factors. METHODS: PubMed/MEDLINE, OVID, Embase, Cochrane Library, and Web of Science databases were searched using adequate key words. We reviewed the literature on the role of melatonin and ramelteon in the prevention of sleep disturbances and delirium in intensive care units and analysed the methods of melatonin therapy in an ICU setting. Review followed the PRISMA statement. A review written protocol was not drafted. RESULTS: Originally 380 studies were searched in five scientific databases. After rejecting the duplicate results, 125 results were obtained. Finally, 10 scientific studies were included in the review. In selected articles, the leading topics analysed were the role of melatonin and ramelteon in the prevention of delirium and sleep disorders. In addition, the noted effect of therapy with these agents on reducing the ventilation time of mechanical time and the demand for psychoactive substances in the ICU environment. CONCLUSION: Reduction of either the incidence or the severity of delirium course is possible by eliminating its risk factors. Risk factors are directly related to sleep disorders. To reduce the problem, therefore, a holistic approach to the source is necessary. The efficacy of melatonin therapy in an ICU setting requires confirmation in studies including a greater number of participants as the impact of melatonin on these factors is yet to be fully elucidated. However, the prognosis is predictive because this concept provides patients with a minimally invasive and natural form of therapy.

Omics Analyses of Gut Microbiota in a Circadian Rhythm Disorder Mouse Model Fed with Oolong Tea Polyphenols.

Microbiome has been revealed as a key element involved in maintaining the circadian rhythms. Oolong tea polyphenols (OTP) has been shown to have potential prebiotic activity. Therefore, this study focused on the regulation mechanisms of OTP on host circadian rhythms. After 8 weeks of OTP administration, a large expansion in the relative abundance of Bacteroidetes with a decrease in Firmicutes was observed, which reflected the positive modulatory effect of OTP on gut flora. In addition, Kyoto Encyclopedia of Genes and Genomes pathways of ATP-binding cassette transporters, two-component system, and the biosynthesis of amino acids enriched the most differentially expressed genes after OTP treatment. Of the differentially expressed proteins identified, most were related to metabolism, genetic information processing, and environmental information processing. It underscores the ability of OTP to regulate circadian rhythm by enhancing beneficial intestinal microbiota and affecting metabolic pathways, contributing to the improvement of host microecology.

Therapeutic effects of curcumin on age-induced alterations in daily rhythms of clock genes and Sirt1 expression in the SCN of male Wistar rats.

The aging brain is linked to accumulation of oxidative stress and increase in damage to biomolecules which in turn may cause or promote circadian dysfunction by disruption of biological clock, the suprachiasmatic nucleus (SCN). Age associated alterations in clock gene expression in the SCN has been reported earlier. In the present study we have examined therapeutic effects of the antioxidant curcumin on age induced alterations in daily rhythms and levels of core clock genes in SCN of young [3 months (m)], middle (12 months) and old (24 months) male Wistar rats. Curcumin was administered orally at ZT-11, 1 hour (h) before the onset of darkness. The effect of curcumin administration on daily rhythms and levels of expression of clock genes such as rBmal1, rPer1, rPer2, rCry1, rCry2 and rRev-erbα as well as on the clock modulator rSirt1 were studied. There was restoration of phase of rPer1, rPer2, rCry1, rCry2 and daily pulse of rPer2 in middle aged animals. However, in old aged rats the phase and daily pulse of rPer1 were restored with curcumin treatment. rSirt1 did not show age related alterations in its transcript levels though the rhythms were abolished in old aged rat SCN. Pearson correlation analysis showed that curcumin administration to 12 and 24 months animals had resulted in restorations of several correlations among clock genes which were found to be altered/abolished in age matched control groups. In addition, strong interlocking interactions between rSirt1 and clock genes were observed in young age which were disrupted with aging and curcumin administration resulted in partial restoration.

Molecular Targets for Small-Molecule Modulators of Circadian Clocks.

BACKGROUND: Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. METHODS: Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. RESULTS: Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. CONCLUSION: Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases.

Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder.

INTRODUCTION: Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. AREAS COVERED: This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. EXPERT OPINION: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development.

[Sleep problems in dementia].

Sleep disturbance is common in patients with dementia. Circadian rhythm sleep disorders are caused by the disturbance of sleep-wake regulation in the central nervous system, disturbed input into the sensory organs, and decreased social activities. Diurnal change of serum melatonin level in Alzheimer's disease showed decreased amplitude and shifted peak secretion. Age related sleep disturbances and sleep disorders due to the neurodegeneration including REM sleep behavior disorder also increase in dementia. Identifying and treating underlying sleep disorders along with therapeutic approach to circadian mechanism is effective. Treatment of circadian abnormality in dementia require light therapy and increased daytime activity. Use of oral melatonin is also effective for the improvement of nocturnal sleep. Treatment of sleep problems in dementia also contribute to the better management of dementia.

Rest-activity circadian rhythms in aged Nothobranchius korthausae. The effects of melatonin.

Adult (48-week-old) and senescent (72-week-old) individually-kept Nothobranchius korthausae were used as experimental subjects to characterise circadian system (CS) function and age-related changes in senescent fish. This species was specifically chosen because it has already shown potential for use as a model system in gerontological studies. The rest-activity rhythm (RAR) in fish can be easily monitored and used to characterise the state of the CS, and it has also been proposed as a reliable model to study sleep-like periods in fish. As they aged, N. korthausae experienced a significant decrease in total daily activity and a progressive impairment of the RAR, accompanied by changes in the regularity, fragmentation and amplitude of the rhythm. The ability of the CS to oscillate autonomously when the two main synchronizers, photoperiod and feeding time, were absent (continuous darkness and random feeding), was also impaired with age, as the capacity to re-synchronise to the light-dark (LD) cycle declined. Melatonin treatment improved the regularity, fragmentation and amplitude of the RAR in senescent fish, and it also improved sleep efficiency. In conclusion, N. korthausae represents a viable model for studying the aging of the circadian system and the restorative effect of chronobiotic substances, such as melatonin.

The role of melatonin treatment in chronic kidney disease.

The pineal hormone melatonin plays a major role in circadian sleep-wake rhythm. Patients with Chronic Kidney Disease (CKD), especially those who are on hemodialysis, frequently suffer from sleep disturbances. In this review an overview is given of the classification of stages of chronic kidney disease, followed by a presentation of the circadian rhythm disorders in renal disease involving sleep disturbances in relation to melatonin deficiency. The therapeutic benefit of melatonin treatment in sleep disorders related to chronic kidney disease including the controlled trials solving this topic, is described. Furthermore, the beneficial effect of melatonin on blood pressure alterations in CKD states and the protection of melatonin in oxidative stress and inflammation in renal disorders are explored. Finally a hypothetic model is described for the relation between circadian rhythm disorders and CKD.

Circadian rhythms in obsessive-compulsive disorder.

The etiopathology and neurobiology of obsessive-compulsive disorder (OCD) are not fully understood. As for altered circadian rhythms associated with OCD, hormonal dysregulation and a delayed sleep phase have come into the focus of research. The novel antidepressant agomelatine is able to resynchronize circadian rhythms and the augmentative administration of this compound has been shown to be of benefit in some OCD patients who are refractory to common forms of pharmacotherapy. Adjunctive chronotherapy might also enhance the outcome in treatment-refractory OCD. The present review summarises the findings regarding circadian abnormalities in OCD.

Circadian cycle and chronotherapeutics: recent trend for the treatment of various biological disorders.

Chronotherapeutics is a novel approach in the treatment of various biological disorders. Circadian rhythms are the important factor in the biological cycle through which the drug dosing should be matched with the rhythms of the diseases for the successful treatment of the illness or the disorder. Through this review it shows that different chronotherapeutic approaches have been successfully employed for treating different biological disorders through different formulation methods, and discussion of recent patents.

Circadian rhythms, melatonin and depression.

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT(2C) receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT(2C) receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression.

[Dysfunctions of biological clocks and their treatments]. / Dysfonctionnements de l'horloge biologique et leurs traitements.

Biological rhythms are periodic phenomena entrained to environmental changes by exogenous factors called synchronizers or entraining agents namely the light-dark cycle, the rest-activity cycle and the seasons, among others. In humans the major synchronizers are the light-dark and rest activity cycles. The endogenous component of a biological rhythm is dependent upon a number of clock genes. The main biological clock (oscillator or pacemaker) is the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The photoperiod (light-dark cycle) perceived by the retina acts on the SCN genes. Peripheral clocks have also been described in a number of tissues e.g. retina, adrenals. In a number of occurrences the synchronizers are badly perceived (transmeridian flights, shiftwork, nightwork...) or are not at all perceived (blindness). This situation is named rhythm desynchronization, it is external when the desynchronization is strictly related to the environment or internal when it is related to a dysfunction of the clock like in e.g. aging, Alzheimer disease, seasonal affective disorders (SAD) or hormone-dependent cancers which results in fatigue, sleep and mood disorders... A number of drugs called resynchronizing agents or chronobiotics which act on the biological clock are able to resynchronize the clock and to improve the patients' condition. Bright light is used in the treatment of SAD, melatonin, the pineal hormone, is also of interest when administered at precise timings in the 24hours scale. Other drugs like B12 vitamin or psychotropic drugs have also been proposed as chronobiotics.