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Abstract Study Objectives REM sleep behavior disorder (RBD) is a parasomnia affecting 33% to 46% of patients with Parkinson’s disease (PD). The existence of a unique and specific impaired cognitive profile in PD patients with RBD is still controversial. We extensively assessed cognitive functions to identify whether RBD is associated with more severe cognitive deficits in nondemented patients with PD. Methods One hundred sixty-two participants, including 53 PD patients with RBD, 40 PD patients without RBD, and 69 healthy subjects, underwent polysomnography, a neurological assessment and an extensive neuropsychological exam to assess attention, executive functions, episodic learning and memory, visuospatial abilities, and language. Results PD patients with RBD had poorer and clinically impaired performance in several cognitive tests compared to PD patients without RBD and healthy subjects. These two latter groups were similar on all cognitive measures. Mild cognitive impairment (MCI) diagnosis frequency was almost threefold higher in PD patients with RBD compared to PD patients without RBD (66% vs. 23%, p < .001). Moreover, subjective cognitive decline was reported in 89% of PD patients with RBD compared to 58% of PD patients without RBD (p = .024). Conclusions RBD in PD is associated with a more impaired cognitive profile and higher MCI diagnosis frequency, suggesting more severe and widespread neurodegeneration. This patient subgroup and their caregivers should receive targeted medical attention to better detect and monitor impairment and to enable the development of management interventions for cognitive decline and its consequences.

Rapid eye movement sleep behavior disorder (RBD) is diagnosed by a clinical history of dream enactment accompanied by polysomnographic rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia). Rapid eye movement sleep behavior disorder is strongly associated with neurodegenerative disease, especially synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. A history of RBD may begin several years to decades before onset of any clear daytime symptoms of motor, cognitive, or autonomic impairments, suggesting that RBD is the presenting manifestation of a neurodegenerative process. Evidence that RBD is a synlucleinopathy includes the frequent presence of subtle prodromal neurodegenerative abnormalities including hyposmia, constipation, and orthostatic hypotension, as well as abnormalities on various neuroimaging, neurophysiological, and autonomic tests. Up to 90.9% of patients with idiopathic RBD ultimately develop a defined neurodegenerative disease over longitudinal follow-up, although the prognosis for younger patients and antidepressant-associated RBD is less clear. Patients with RBD should be treated with either melatonin 3 to 12 mg or clonazepam 0.5 to 2.0 mg to reduce injury potential. Prospective outcome and treatment studies of RBD are necessary to enable accurate prognosis and better evidence for symptomatic therapy and future neuroprotective strategies.

To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up. Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) were dementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, and mild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents.

To compare three different methods, two visual and one automatic, for the quantification of rapid eye movement (REM) sleep without atonia (RSWA) in the diagnosis of REM sleep behavior disorder (RBD) in Parkinson's disease (PD) patients. Sixty-two consecutive patients with idiopathic PD underwent video-polysomnographic recording and showed more than 5 minutes of REM sleep. The electromyogram during REM sleep was analyzed by means of two visual methods (Montréal and SINBAR) and one automatic analysis (REM Atonia Index or RAI). RBD was diagnosed according to standard criteria and a series of diagnostic accuracy measures were calculated for each method, as well as the agreement between them. RBD was diagnosed in 59.7% of patients. The accuracy (85.5%), receiver operating characteristic (ROC) area (0.833) and Cohen's K coefficient (0.688) obtained with RAI were similar to those of the visual parameters. Visual tonic parameters, alone or in combination with phasic activity, showed high values of accuracy (93.5-95.2%), ROC area (0.92-0.94), and Cohen's K (0.862-0.933). Similarly, the agreement between the two visual methods was very high, and the agreement between each visual methods and RAI was substantial. Visual phasic measures alone performed worse than all the other measures. The diagnostic accuracy of RSWA obtained with both visual and automatic methods was high and there was a general agreement between methods. RAI may be used as the first line method to detect RSWA in the diagnosis of RBD in PD, together with the visual inspection of video-recorded behaviors, while the visual analysis of RSWA might be used in doubtful cases.

Abstract Study Objectives Symptomatic therapies for rapid-eye-movement (REM) sleep behavior disorder (RBD) are limited. Sodium oxybate (SXB), a gamma-aminobutyric acid (GABA)-B agonist, could be effective but has not been evaluated against placebo. Methods This double-blind, parallel-group, randomized, placebo-controlled trial in 24 participants was conducted at the Stanford Sleep Center. Patients were adults with definite iRBD or Parkinson’s disease and probable RBD (PD-RBD), and persistence of ≥ 2 weekly episodes despite standard therapy. Patients were randomized 1:1 to receive SXB during a 4-week titration followed by a 4-week stable dosing period. Primary outcome was number of monthly RBD episodes according to a diary filled by patients and partners. Secondary outcomes were severity, number of severe RBD episodes, and objective RBD activity on video polysomnography. Results Twelve iRBD and 12 PD-RBD participated (mean 65.8 years), and 22 (n = 10 SXB, 12 placebo) completed the study. Although no significant between-group difference was found, SXB showed reduction of monthly RBD episodes by 23.1 (95% CI −36.0, −10.2; p = 0.001) versus 10.5 with placebo (95% CI, −22.6, 1.6; p = 0.087). Improvement from baseline was similarly observed for RBD overall severity burden (each episode weighted for severity), number of severe episodes, and objective RBD activity per video-polysomnography. Two participants receiving SXB withdrew due to anxiety and dizziness. The majority of adverse events are otherwise resolved with dose adjustment. Conclusion SXB could reduce RBD symptoms; however, response was inconsistent and a large placebo effect was observed across patient-reported outcomes. Larger studies using objective endpoints are needed. Clinical Trial Treatment of REM Sleep Behavior Disorder (RBD) With Sodium Oxybate https://clinicaltrials.gov/ct2/show/NCT04006925 ClinicalTrials.gov identifier: NCT04006925 Graphical abstract Graphical Abstract

Values for normative REM sleep without atonia (RSWA) remain unclear. Older age and male sex are associated with greater RSWA, and isolated elevated RSWA has been reported. We aimed to describe normative RSWA and characterize isolated RSWA frequency in adults without REM sleep behavior disorder (RBD). We visually quantified phasic, \"any,\" and tonic RSWA in the submentalis (SM) and anterior tibialis (AT) muscles, and the automated Ferri REM Atonia Index during polysomnography in adults without RBD aged 21-88. We calculated RSWA percentiles across age and sex deciles and compared RSWA in older (≥ 65) versus younger (<65) men and women. Isolated RSWA (exceeding diagnostic RBD cutoffs, or >95th percentile) frequency was also determined. Overall, 95th percentile RSWA percentages were SM phasic, any, tonic = 8.6%, 9.1%, 0.99%; AT phasic and \"any\" = 17.0%; combined SM/AT phasic, \"any\" = 22.3%, 25.5%; and RAI = 0.85. Most phasic RSWA burst durations were ≤1.0 s (85th percentiles: SM = 1.07, AT = 0.86 seconds). Older men had significantly higher AT RSWA than older women and younger patients (all p < 0.04). Twenty-nine (25%, 18 men) had RSWA exceeding the cohort 95th percentile, while 17 (14%, 12 men) fulfilled diagnostic cutoffs for phasic or automated RBD RSWA thresholds. RSWA levels are highest in older men, mirroring the demographic characteristics of RBD, suggesting that older men frequently have altered REM sleep atonia control. These data establish normative adult RSWA values and thresholds for determination of isolated RSWA elevation, potentially aiding RBD diagnosis and discussions concerning incidental RSWA in clinical sleep medicine practice.

Background Parkinson's disease (PD) patients experience gut microbiota dysbiosis. Probiotic intervention could potentially serve as a safe and effective adjunctive therapeutic approach for PD, but its effects on rapid eye movement sleep behavior disorder (RBD) and motor symptoms in PD patients warrant further investigation. Objectives To examine the influence of probiotics on RBD, motor symptoms, gut microbiota, and serum metabolites in individuals with PD. Methods In this randomized controlled trial, PD patients were randomly allocated to either a probiotics or a control group while maintaining standard treatments. Clinical outcomes, including Unified Parkinson's Disease Rating Scale (UPDRS) and RBD Questionnaire‐Hong Kong (RBDQ‐HK) were assessed at baseline and post‐treatment. Furthermore, fecal and blood samples were collected from PD patients at both timepoints, with additional samples obtained from healthy controls for comparison. The 16S rRNA gene V3‐V4 region sequencing method was used to analyze gut microbiota composition, and untargeted metabolomic techniques were utilized to assess serum metabolite alterations, followed by correlation analysis. Results Fifty eligible PD patients were enrolled and randomly allocated into two groups. After 12 weeks of intervention, the probiotic group showed significant reductions in both UPDRS total scores (−4.8 ± 7.5 vs. 1.8 ± 13.1, p = 0.009) and RBDQ‐HK scores (−7.5 ± 6.5 vs. 0 ± 5.8, p = 0.015) compared to controls. Gut microbiota analysis revealed increased abundance of Actinobacteria, Negativicutes, and Bacillus, with reductions in Lactococcus, Comamonas, and Enterococcus after probiotic intervention. Furthermore, compared to normal controls, PD patients exhibited 9 significantly elevated and 11 significantly reduced metabolites; probiotic intervention altered the serum metabolome in PD patients. Conclusions This study demonstrated probiotics' potential to ameliorate RBD and motor symptoms while positively affecting the composition of the gut microbiota and serum metabolites in PD patients. Twelve‐week probiotics supplementation in Parkinson's disease (PD) patients demonstrated significant improvements in motor symptoms and REM sleep behavior disorder (RBD) symptoms. Additionally, the intervention exerted a modulatory effect on gut microbiota composition and plasma metabolite profiles, suggesting a potential role of probiotics in modulating the gut‐brain axis in PD.

Slow-wave sleep and rapid eye movement (or paradoxical) sleep have been found in mammals, birds and lizards, but it is unclear whether these neuronal signatures are found in non-amniotic vertebrates. Here we develop non-invasive fluorescence-based polysomnography for zebrafish, and show—using unbiased, brain-wide activity recording coupled with assessment of eye movement, muscle dynamics and heart rate—that there are at least two major sleep signatures in zebrafish. These signatures, which we term slow bursting sleep and propagating wave sleep, share commonalities with those of slow-wave sleep and paradoxical or rapid eye movement sleep, respectively. Further, we find that melanin-concentrating hormone signalling (which is involved in mammalian sleep) also regulates propagating wave sleep signatures and the overall amount of sleep in zebrafish, probably via activation of ependymal cells. These observations suggest that common neural signatures of sleep may have emerged in the vertebrate brain over 450 million years ago. Fluorescence-based polysomnography in zebrafish reveals two major sleep signatures that share features with those of amniotes, which suggests that common neural sleep signatures emerged in the vertebrate brain over 450 million years ago.

To evaluate the role of sleep cyclic alternating pattern (CAP) in patients with isolated REM sleep behavior disorder (IRBD) and ascertain whether CAP metrics might represent a marker of phenoconversion to a defined neurodegenerative condition. Sixty-seven IRBD patients were included and classified into patients who phenoconverted to a neurodegenerative disease (RBD converters: converter REM sleep behavior disorder [cRBD]; n = 34) and remained disease-free (RBD non-converters: non-converter REM sleep behavior disorder [ncRBD]; n = 33) having a similar follow-up duration. Fourteen age- and gender-balanced healthy controls were included for comparisons. Compared to controls, CAP rate and CAP index were significantly decreased in IRBD mainly due to a decrease of A1 phase subtypes (A1 index) despite an increase in duration of both CAP A and B phases. The cRBD group had significantly lower values of CAP rate and CAP index when compared with the ncRBD group and controls. A1 index was significantly reduced in both ncRBD and cRBD groups compared to controls. When compared to the ncRBD group, A3 index was significantly decreased in the cRBD group. The Kaplan-Meier curve applied to cRBD estimated that a value of CAP rate below 32.9% was related to an average risk of conversion of 9.2 years after baseline polysomnography. IRBD is not exclusively a rapid eye movement (REM) sleep parasomnia, as non-rapid eye movement (non-REM) sleep microstructure can also be affected by CAP changes. Further studies are necessary to confirm that a reduction of specific CAP metrics is a marker of neurodegeneration in IRBD.

Abstract Study Objectives To evaluate the prevalence and clinical characteristics of isolated REM sleep behavior disorder (iRBD) among a general population of elderly Japanese people. Methods This epidemiological study targeted 2714 elderly residents (76.0 ± 8.0 years, 52.9% female) of a rural community. Questionnaires including the REM sleep behavior disorder single question and demographic information were distributed. All respondents with the question positive were interviewed by telephone. Respondents suspected of having iRBD proceeded to face-to-face interviews and underwent video-polysomnography and neurological/neuropsychological examination. These results were compared to those of previously diagnosed clinical iRBD patients in our sleep clinic. Results Of 1464 respondents to the questionnaire, 18 respondents were diagnosed as iRBD (1.23 [0.66–1.79]%), including eight respondents who satisfied diagnostic criteria with REM sleep without atonia (RWA) above the cut-off value (0.54 [0.17–0.92]%) and 10 respondents who had clear dream enactment behaviors but not RWA above the cut-off (provisionally diagnosed iRBD; p-iRBD) (0.69 [0.26–1.11]%). Severity of RBD and RWA of the population-based iRBD were compatible with those of the clinical iRBD. Half of the population-based iRBD showed orthostatic hypotension and they showed lower olfactory function than population-based p-iRBD and non-RBD. However, their olfactory and cognitive functions were higher than those in the clinical iRBD patients. Conclusions Prevalence of iRBD in Japanese elderly people was comparable with the rate reported from other countries. Population-based iRBD/p-iRBD showed lower neurodegenerative loading than clinical iRBD in spite of comparable disease duration of RBD, that may indicate their lower risk of future neurodegeneration.