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OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.
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Dopamina , Doença por Corpos de Lewy , Aprendizado de Máquina , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Masculino , Feminino , Idoso , Sinucleinopatias/diagnóstico por imagem , Pessoa de Meia-Idade , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/complicações , Dopamina/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Terminações Pré-Sinápticas/metabolismo , Imageamento DopaminérgicoAssuntos
Envelhecimento , Sono , Humanos , Estudos Longitudinais , Estações do Ano , Canadá/epidemiologia , Ritmo CircadianoRESUMO
INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.
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Disfunção Cognitiva , Doença por Corpos de Lewy , Doença de Parkinson , Transtornos Parkinsonianos , Transtorno do Comportamento do Sono REM , Humanos , Doença por Corpos de Lewy/diagnóstico , Transtorno do Comportamento do Sono REM/diagnóstico , Disfunção Cognitiva/diagnósticoRESUMO
Study Objectives. To present and evaluate an automatic scoring algorithm for quantification of REM-sleep without atonia (RWA) in patients with REM-sleep behaviour disorder (RBD) based on a generally accepted, well-validated visual scoring method, ("Montreal" phasic and tonic) and a recently developed, concise scoring method (Ikelos-RWA). Methods. Video-polysomnographies of 20 RBD patients (68.2 ± 7.2 years) and 20 control patients with periodic limb movement disorder (65.9 ± 6.7 years) were retrospectively analysed. RWA was estimated from chin electromyogram during REM-sleep. Visual and automated RWA scorings were correlated, and agreement (a) and Cohen's Kappa (k) calculated for 1735â minutes of REM-sleep of the RBD patients. Discrimination performance was evaluated with receiver operating characteristic (ROC) analysis. The algorithm was then applied on the polysomnographies of a cohort of 232 RBD patients (total analysed REM-sleep: 17,219â minutes) and evaluated, while correlating the different output parameters. Results. Visual and computer-derived RWA scorings correlated significantly (tonic Montreal: rTM = 0.77; phasic Montreal: rPM = 0.78; Ikelos-RWA: rI = 0.97; all p < 0.001) and showed good to excellent Kappa coefficients (kTM = 0.71; kPM = 0.79; kI = 0.77). The ROC analysis showed high sensitivities (95%-100%) and specificities (84%-95%) at the optimal operation points, with area under the curve (AUC) of 0.98, indicating high discriminating capacity. The automatic RWA scorings of 232 patients correlated significantly (rTM{I} = 0.95; rPM{I} = 0.91, p < 0.0001). Conclusions. The presented algorithm is an easy-to-use and valid tool for automatic RWA scoring in patients with RBD and may prove effective for general use being publicly available.
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The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.
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Doença por Corpos de Lewy , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Transtorno do Comportamento do Sono REM/diagnóstico , Estudos Prospectivos , Progressão da Doença , Biomarcadores , Sintomas ProdrômicosRESUMO
While short-term effects of artificial light on human sleep are increasingly being studied, reports on long-term effects induced by season are scarce. Assessments of subjective sleep length over the year suggest a substantially longer sleep period during winter. Our retrospective study aimed to investigate seasonal variation in objective sleep measures in a cohort of patients living in an urban environment. In 2019, three-night polysomnography was performed on 292 patients with neuropsychiatric sleep disturbances. Measures of the diagnostic second nights were averaged per month and analyzed over the year. Patients were advised to sleep "as usual" including timing, except alarm clocks were not allowed. Exclusion criteria: administration of psychotropic agents known to influence sleep (N = 96), REM-sleep latency > 120 min (N = 5), technical failure (N = 3). Included were 188 patients: [46.6 ± 15.9 years (mean ± SD); range 17-81 years; 52% female]; most common sleep-related diagnoses: insomnia (N = 108), depression (N = 59) and sleep-related breathing disorders (N = 52). Analyses showed: 1. total sleep time (TST) longer during winter than summer (up to 60 min; not significant); 2. REM-sleep latency shorter during autumn than spring (about 25 min, p = 0.010); 3. REM-sleep longer during winter than spring (about 30 min, p = 0.009, 5% of TST, p = 0.011); 4. slow-wave-sleep stable winter to summer (about 60-70 min) with 30-50 min shorter during autumn (only significant as % of TST, 10% decrease, p = 0.017). Data suggest seasonal variation in sleep architecture even when living in an urban environment in patients with disturbed sleep. If replicated in a healthy population, this would provide first evidence for a need to adjust sleep habits to season.
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The global north is facing an unprecedented rise in the prevalence of neurodegenerative diseases. The increasing incidence of Parkinson's disease is being referred to as a pandemic. The reason for the enormous increase is only partly understood. Lifestyle factors are known to play a role, but they alone cannot account for the surge. One factor that-although being recognized as important-has not been explored in detail so far is the influence of circadian rhythms. Sleep and circadian rhythm disruption are known as key factors in neurodegeneration, and their occurrence during early disease stages suggests a causal role in the pathogenesis. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as a prodromal state of α-synucleinopathies, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy offering a window for insights into the early development of these diseases. Even though REM sleep is the sleep state most pronounced, driven and modulated by the circadian timing system, specific circadian abnormalities have not been described in iRBD. Novel experimental and clinical approaches exploiting the molecular circuitry underlying circadian timekeeping hold promise to disentangle some of the pathophysiologic mechanisms of α-synucleinopathies. In this review, we summarize current knowledge on sleep and circadian rhythm disruptions in α-synucleinopathies with an emphasis on molecular aspects and therapeutic potentials. These insights might contribute to our understanding of the pathogenesis of neurodegenerative diseases and may allow therapeutic interventions addressing the disturbed circadian system at the early stage of disease.
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Doenças Neurodegenerativas , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Doença de Parkinson/epidemiologia , Transtorno do Comportamento do Sono REM/tratamento farmacológico , Transtorno do Comportamento do Sono REM/epidemiologia , Ritmo Circadiano , SonoRESUMO
BACKGROUND: Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a prodromal state of clinical α-synucleinopathies such as Parkinson's disease and Lewy body dementia. The lead-time until conversion is unknown. The most reliable marker of progression is reduced striatal dopamine transporter (DAT) binding, but low availability of imaging facilities limits general use. Our prospective observational study aimed to relate metrics of REM sleep without atonia (RWA)-a hallmark of RBD-to DAT-binding ratios in a large, homogeneous sample of patients with RBD to explore the utility of RWA as a marker of progression in prodromal α-synucleinopathies. METHODS: DAT single-photon emission CT (SPECT) and video polysomnography (vPSG) were performed in 221 consecutive patients with clinically suspected RBD. RESULTS: vPSG confirmed RBD in 176 patients (162 iRBD, 14 phenoconverted, 45 non-synucleinopathies). Specific DAT-binding ratios differed significantly between groups, but showed considerable overlap. Most RWA metrics correlated significantly with DAT-SPECT ratios (eg, Montreal tonic vs most-affected-region: r=-0.525; p<0.001). In patients taking serotonergic/noradrenergic antidepressants or dopaminergic substances or with recent alcohol abuse, correlations were weaker, suggesting a confounding influence, unlike other possible confounders such as beta-blocker use or comorbid sleep apnoea. CONCLUSIONS: In this large single-centre prospective observational study, we found evidence that DAT-binding ratios in patients with iRBD can be used to describe a continuum in the neurodegenerative process. Overlap with non-synucleinopathies and clinical α-synucleinopathies, however, precludes the use of DAT-binding ratios as a precise diagnostic marker. The parallel course of RWA metrics and DAT-binding ratios suggests in addition to existing data that RWA, part of the routine diagnostic workup in these patients, may represent a marker of progression. Based on our findings, we suggest ranges of RWA values to estimate whether patients are in an early, medium or advanced state within the prodromal phase of α-synucleinopathies, providing them with important information about time until possible conversion.
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Doença por Corpos de Lewy , Transtorno do Comportamento do Sono REM , Sinucleinopatias , Humanos , Sinucleinopatias/diagnóstico , Sono REM , Prognóstico , Doença por Corpos de Lewy/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/metabolismo , Proteínas de Membrana Transportadoras , BiomarcadoresRESUMO
BACKGROUND AND OBJECTIVE: Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. In two phase III, 12-week studies in patients with insomnia disorder, daridorexant improved sleep and daytime functioning while maintaining a favorable safety profile. The objective of this 40-week extension study was to assess the long-term safety and tolerability of daridorexant. METHODS: Adults with insomnia disorder who completed the 12-week studies were invited to enroll in this double-blind extension study. Patients originally randomised to daridorexant (10 mg/25 mg/50 mg) remained on their respective treatments; patients randomised to placebo were re-randomised to daridorexant 25 mg or placebo. The 40-week treatment period was followed by a 7-day placebo run-out. The primary objective was to assess safety/tolerability. Exploratory objectives were to evaluate the efficacy of daridorexant on sleep (self-reported total sleep time) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire). RESULTS: In total, 804 patients were enrolled in the study, of whom 801 received at least one dose of the study treatment and 550 patients (68.4%) completed the study. Overall incidence of treatment-emergent adverse events was similar across groups (35-40%). Daridorexant did not induce next-morning sleepiness and no withdrawal-related symptoms or rebound were observed after treatment discontinuation. Improvements in sleep and daytime functioning were maintained through to the end of the study and were most pronounced with daridorexant 50 mg. Daridorexant 50 mg, compared with placebo, increased self-reported total sleep time by a least-squares mean of 20.4 (95% confidence interval [CI] 4.2, 36.5), 15.8 (95% CI - 0.8, 32.5) and 17.8 (95% CI - 0.4, 35.9) minutes and decreased (i.e., improved) Insomnia Daytime Symptoms and Impacts Questionnaire total scores by a least-squares mean of - 9.3 (95% CI - 15.1, - 3.6), - 9.5 (95% CI - 15.4, - 3.5) and - 9.1 (95% CI - 15.6, - 2.7), at weeks 12, 24 and 36 of the extension study, respectively. CONCLUSIONS: Treatment with daridorexant, for up to 12 months, was generally safe and well tolerated. Exploratory efficacy analyses suggest that the sustained improvements in sleep and daytime functioning with daridorexant 50 mg support its use for long-term treatment of insomnia disorder, without concerns of new safety signals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03679884) [first posted: 21 September, 2018], https://clinicaltrials.gov/ct2/show/NCT03679884 .
Insomnia disorder is the long-term inability to fall asleep or stay asleep with a significant impact on daily life. Left inadequately treated, this disorder may increase the risk of other health problems. For patients with insomnia disorder who require a sleep medication, many drugs are not recommended for long-term use and there is an unmet need for one that can be used safely and effectively over the long term. Daridorexant is a new insomnia treatment that was approved for adults following positive results in two 12-week clinical studies. Both studies showed that, in patients with insomnia disorder, daridorexant improved night-time sleep and patients' ability to function during the day, while avoiding major safety concerns. Patients who completed these two studies could continue into a 40-week extension study enabling the safety and tolerability of daridorexant to be investigated for up to 1 year. Treatment remained double blind for the entire 1-year period. The extension study showed that daridorexant, at all doses studied (10 mg, 25 mg, 50 mg), continued to be generally safe and well tolerated. Patients showed no signs of tolerance, physical dependence, rebound nor any excessive daytime sleepiness. Exploratory efficacy analyses suggest that improved night-time and daytime symptoms of insomnia were sustained, in particular with the highest approved dose, 50 mg, and there were no signs that the benefits of the drug were wearing off at the end of the 1 year. These results support the use of daridorexant 50 mg for the long-term treatment of insomnia disorder in adults.
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Distúrbios do Início e da Manutenção do Sono , Adulto , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Imidazóis , Pirrolidinas/efeitos adversos , Sono , Método Duplo-Cego , Resultado do TratamentoRESUMO
The skin is the largest human organ with a circadian clock that regulates its function. Although circadian rhythms in specific functions are known, rhythms in the proximal clock output, gene expression, in human skin have not been thoroughly explored. This work reports 24 h gene expression rhythms in two skin layers, epidermis and dermis, in a cohort of young, healthy adults, who maintained natural, regular sleep-wake schedules. 10% of the expressed genes showed such diurnal rhythms at the population level, of which only a third differed between the two layers. Amplitude and phases of diurnal gene expression varied more across subjects than layers, with amplitude being more variable than phases. Expression amplitudes in the epidermis were larger and more subject-variable, while they were smaller and more consistent in the dermis. Core clock gene expression was similar across layers at the population-level, but were heterogeneous in their variability across subjects. We also identified small sets of biomarkers for internal clock phase in each layer, which consisted of layer-specific non-core clock genes. This work provides a valuable resource to advance our understanding of human skin and presents a novel methodology to quantify sources of variability in human circadian rhythms.
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Neurodegenerative processes in the brain are reflected by structural retinal changes. As a possible biomarker of cognitive state in prodromal α-synucleinopathies, we compared melanopsin-mediated post-illumination pupil response (PIPR) with cognition (CERAD-plus) in 69 patients with isolated REM-sleep behavior disorder. PIPR was significantly correlated with cognitive domains, especially executive functioning (râ=â0.417, pâ<â0.001), which was more pronounced in patients with lower dopamine-transporter density, suggesting advanced neurodegenerative state (nâ=â26; râ=â0.575, pâ=â0.002). Patients with mild neurocognitive disorder (nâ=â10) had significantly reduced PIPR (smaller melanopsin-mediated response) compared to those without (pâ=â0.001). Thus, PIPR may be a functional-possibly monitoring-marker for impaired cognitive state in (prodromal) α-synucleinopathies.
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Doença de Parkinson , Sinucleinopatias , Biomarcadores , Cognição , Humanos , Iluminação , Pupila/fisiologia , Reflexo Pupilar/fisiologia , Células Ganglionares da Retina/fisiologiaRESUMO
The pineal hormone melatonin is the natural transducer of the environmental light-dark signal to the body. Although the responsiveness to photoperiod is well-conserved in humans, only about 25 percent of the human population experiences seasonal changes in behavior. As a consequence, humans seem to have adapted-at least partly-to the seasonal changes in day length. The aim of the study was to demonstrate that the individual melatonin deficit marker DOC (degree of pineal calcification) is related to variation of seasonal phenomena in humans. Out of 3,011 patients in which cranial computer tomography (cCT) was performed for diagnostic reasons, 97 consecutive "healthy" subjects (43 female, 54 male; age 18-68 yrs, mean ± SD: 35.0 ± 13.1) were included. Exclusion criteria were pathological finding in cCT, acute/chronic illness including alcohol/drug abuse, shift work, and medication, which are known to influence melatonin excretion. The degree of pineal calcification (DOC) was semiquantitatively determined using the previously validated method. The Seasonal Pattern Assessment Questionnaire (SPAQ) was performed in a telephone interview. Twenty-six subjects fulfilled the criteria for seasonal affective disorder (SAD) or subsyndromal (S) SAD. Seasonality was more pronounced in women than in men (SPAQ seasonality score: 7.8 ± 4.0 vs. 4.9 ± 4.5; p = 0.001) and negatively and significantly associated with age (r = -0.178; p = 0.04). The subjective sleep length significantly varied between seasons (one-way repeated measures ANOVA: F = 45.75; p < 0.0001), with sleep during winter being 53 min (±70 min) longer than during summer. Controlling for age, the total seasonality score was negatively and significantly associated with DOC (r94 = -0.214; p = 0.036). Data confirm earlier studies with respect to distribution of seasonality with sex and age. The survival of seasonality in the sleep length of people living in an urban environment underlines functionality of the circadian timing system in modern societies. Moreover, data confirm for the first time that diminished experience of seasonality in behavior is associated with a reduced individual capacity to produce melatonin.
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Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our chronobiotic protocol (2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (ρ = 0.9, P < .001), test-retest reliability (ρ = 0.9, P < .001) and convergent validity (ρ = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin.
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Melatonina , Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/induzido quimicamente , Transtorno do Comportamento do Sono REM/tratamento farmacológico , Reprodutibilidade dos Testes , Sono REMRESUMO
The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.
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Ensaios Clínicos como Assunto , Transtorno do Comportamento do Sono REM/tratamento farmacológico , Sono REM/efeitos dos fármacos , Humanos , Projetos de PesquisaRESUMO
OBJECTIVE: To assess the dose-response of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset (WASO). METHODS: Elderly (≥65 years) participants (n = 58) with insomnia were randomly allocated (Latin square design) to receive 5 treatments (5, 10, 25, and 50 mg daridorexant and placebo) during 5 treatment periods, each consisting of 2 treatment nights followed by a 5- to 12-day washout period. Main efficacy endpoints were the absolute change from baseline in WASO (primary) and latency to persistent sleep (LPS; secondary) to days 1 and 2 (mean of 2 treatment nights assessed by polysomnography) in each period. Safety and tolerability were also assessed. RESULTS: Of 58 participants included, 67% were female, and the median age was 69 years (range 65-85 years). WASO and LPS were dose-dependently reduced from baseline to days 1 and 2 after daridorexant administration (multiple comparison procedure modeling, p < 0.0001 and p = 0.004, respectively); reductions were statistically significant for doses ≥10 mg compared with placebo (WASO: -32.0, -45.1, -61.4 minutes; LPS: -44.9, -43.8, -45.4 minutes for 10, 25, and 50 mg, respectively, p ≤ 0.025). Treatment-emergent adverse events were similar for daridorexant and placebo; the most frequent were fatigue, nasopharyngitis, gait disturbance, and headache (≤7% in any group). CONCLUSIONS: Daridorexant was well tolerated. Dose-dependent improvements in WASO and LPS were statistically significant (dose range 10-50 mg) in elderly people with insomnia disorder. CLINICALTRIALSGOV IDENTIFIER: NCT02841709. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for elderly people with insomnia, daridorexant reduced WASO.
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Benzimidazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imidazóis , Masculino , Antagonistas dos Receptores de Orexina/uso terapêutico , Polissonografia , Pirrolidinas/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
Nighttime melatonin suppression is the most commonly used method to indirectly quantify acute nonvisual light effects. Since light is the principal zeitgeber in humans, there is a need to assess its strength during daytime as well. This is especially important since humans evolved under natural daylight but now often spend their time indoors under artificial light, resulting in a different quality and quantity of light. We tested whether the pupillary light response (PLR) could be used as a marker for nonvisual light effects during daytime. We also recorded the wake electroencephalogram to objectively determine changes in daytime sleepiness between different illuminance levels and/or spectral compositions of light. In total, 72 participants visited the laboratory 4 times for 3-h light exposures. All participants underwent a dim-light condition and either 3 metameric daytime light exposures with different spectral compositions of polychromatic white light (100 photopic lux, peak wavelengths at 435 nm or 480 nm, enriched with longer wavelengths of light) or 3 different illuminances (200, 600, and 1200 photopic lux) with 1 metameric lighting condition (peak wavelength at 435 nm or 480 nm; 24 participants each). The results show that the PLR was sensitive to both spectral differences between metameric lighting conditions and different illuminances in a dose-responsive manner, depending on melanopic irradiance. Objective sleepiness was significantly reduced, depending on melanopic irradiance, at low illuminance (100 lux) and showed fewer differences at higher illuminance. Since many people are exposed to such low illuminance for most of their day-living in biological darkness-our results imply that optimizing the light spectrum could be important to improve daytime alertness. Our results suggest the PLR as a noninvasive physiological marker for ambient light exposure effects during daytime. These findings may be applied to assess light-dependent zeitgeber strength and evaluate lighting improvements at workplaces, schools, hospitals, and homes.
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Escuridão , Luz , Pupila/fisiologia , Sonolência , Adulto , Ritmo Circadiano , Eletroencefalografia , Feminino , Humanos , Masculino , Melatonina/biossíntese , Adulto JovemRESUMO
Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
Assuntos
Demência/fisiopatologia , Doença de Parkinson/fisiopatologia , Transtorno do Comportamento do Sono REM/fisiopatologia , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Previsões/métodos , Humanos , Estimativa de Kaplan-Meier , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico , Polissonografia , Sintomas Prodrômicos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de RiscoRESUMO
Under entrained conditions, the accumulation of homeostatic sleep pressure in the evening is opposed by a strong circadian arousal signal prior to the dim light melatonin onset, called the Wake Maintenance Zone (WMZ). This study aimed at investigating the impact of the WMZ on different cognitive performance tests, as well as on subjective and objective sleepiness. Twelve young male participants completed a constant routine protocol with 40 h of extended wakefulness that included two WMZs. Cognitive tests and saliva samples were assessed hourly, while the electroencephalogram (EEG) was recorded continuously. Participants improved in cognitive response inhibition during WMZ1 (13.5 h awake) and sustained attention during WMZ2 (37.5 h awake), but not in higher executive function tests. There were significant EEG power density reductions in the delta/theta frequency range during WMZ1 and in delta/theta, alpha, and sigma/beta ranges during WMZ2, with a greater change in the sigma/beta range during WMZ2 compared to WMZ1. EEG power reductions coincided during WMZ1 with stable subjective sleepiness and sustained attention. During WMZ2, EEG power reductions were more pronounced and coincided with improved sustained attention. Our results suggest the circadian arousal signal in the evening differently modulates cognitive functions and EEG power depending on the duration of prior wakefulness.
Assuntos
Cognição/fisiologia , Privação do Sono/fisiopatologia , Vigília/fisiologia , Adulto , Nível de Alerta/fisiologia , Atenção/fisiologia , Ritmo Circadiano/fisiologia , Eletroencefalografia/métodos , Humanos , Masculino , Saliva/química , Sono/fisiologia , Privação do Sono/metabolismo , Fases do Sono/fisiologia , Adulto JovemRESUMO
BACKGROUND: The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing. METHODS: To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes. RESULTS: We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost. CONCLUSION: The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock. FUNDING: This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.