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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.

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

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.

Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson’s disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT ( ρ  = −0.377, p  = 0.048), with olfactory function ( ρ  = −0.668, p  = 0.002), and positively correlated with the total LR for RBD to present prodromal PD ( ρ  = 0.531, p  = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs.

Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD), a parasomnia with dream enactment behaviors and excessive muscle activity during REM sleep, is an early stage synucleinopathy. The neurophysiological hallmark of RBD is REM sleep without atonia (RWSA), i.e. the loss of physiological muscle atonia during REM sleep. RBD pathophysiology is not fully clarified yet, but clinical and basic science suggest that ɑ-syn pathology begins in the lower brainstem where REM atonia circuits are located, including the sublaterodorsal tegmental/subcoeruleus nucleus and the ventral medulla, then propagates rostrally to brain regions such as the substantia nigra, limbic system, cortex. Genetically, there is only a partial overlap between RBD, PD and DLB, and individuals with iRBD may represent a specific subpopulation. A genome-wide association study identified five loci, which all seem to revolve around the GBA1 pathway. iRBD patients often show subtle motor, cognitive, autonomic and/or sensory signs, neuroimaging alterations as well as biofluid and tissue markers of neurodegeneration (in particular pathologic α-synuclein aggregates), which can be useful for risk stratification. Patients with iRBD represent thus the ideal population for neuroprotective/neuromodulating trials. This review provides insights into these aspects, highlighting and substantiating the central role of iRBD in treatment development strategies for synucleinopathies.

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.

ObjectivesTo investigate the impact of sleep disturbances on Parkinson’s disease (PD) clinical motor subtypes and disease-related disability in a multicentre setting.MethodsWe report a cross-sectional relationship between sleep-related symptoms and clinical motor subtypes (tremor dominant (TD); intermediate; postural instability and gait disturbances (PIGDs)) identified in a multicentre study, including 436 patients with PD and 401 age-matched controls. PD-related sleep problems (PD-SP), excessive daytime sleepiness (EDS) and probable REM sleep behaviour disorder (pRBD) were evaluated using the PD sleep scale (PDSS)-2, Epworth Sleepiness Scale (ESS) and RBD screening questionnaire-Japanese version (RBDSQ-J), respectively.ResultsPD-SP (PDSS-2 ≥18; 35.1% vs 7.0%), EDS (ESS ≥10; 37.8% vs 15.5%) and pRBD (RBDSQ-J ≥5; 35.1% vs 7.7%) were more common in patients with PD than in controls. The prevalence of restless legs syndrome did not differ between patients with PD and controls (3.4% vs 2.7%). After adjusting for age, sex, disease duration and Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) part III score, the PIGD group had higher PDSS-2 and ESS scores than the TD group. The RBDSQ-J scores did not differ among the TD, intermediate and PIGD groups. A stepwise regression model predicting the MDS-UPDRS part II score identified the Hoehn and Yahr stage, followed by the number of sleep-related symptoms (PD-SP, EDS and pRBD), disease duration, MDS-UPDRS part III score, PIGD subtype, depression and MDS-UPDRS part IV score as significant predictors.ConclusionOur study found a significant relationship between sleep disturbances and clinical motor subtypes. An increased number of sleep-related symptoms had an impact on disease-related disability.

Rapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models. Clinical assessments were performed in 171 RBD, 296 control, and 119 untreated Parkinson's (PD) participants. Putative risk measures were assessed as predictors of prodromal neurodegeneration, and Movement Disorders Society (MDS) criteria for prodromal PD were applied. Participants were screened for common leucine-rich repeat kinase 2 (LRRK2)/glucocerebrosidase gene (GBA) gene mutations. Compared to controls, participants with RBD had higher rates of solvent exposure, head injury, smoking, obesity, and antidepressant use. GBA mutations were more common in RBD, but no LRRK2 mutations were found. RBD participants performed significantly worse than controls on Unified Parkinson's Disease Rating Scale (UPDRS)-III, timed \"get-up-and-go\", Flamingo test, Sniffin Sticks, and cognitive tests and had worse measures of constipation, quality of life (QOL), and orthostatic hypotension. For all these measures except UPDRS-III, RBD and PD participants were equally impaired. Depression, anxiety, and apathy were worse in RBD compared to PD participants. Stratification of people with RBD according to antidepressant use, obesity, and age altered the odds ratio (OR) of hyposmia compared to controls from 3.4 to 45.5. 74% (95% confidence interval [CI] 66%, 80%) of RBD participants met the MDS criteria for probable prodromal Parkinson's compared to 0.3% (95% CI 0.009%, 2%) of controls. RBD are impaired across a range of clinical measures consistent with prodromal PD and suggestive of a more severe nonmotor subtype. Clinical risk stratification has the potential to select higher risk patients for neuroprotective interventions.

REM sleep behavior disorder (RBD) is a prodromal non-motor symptom of Parkinson's disease (PD) and other α-synucleinopathies, affecting approximately 30%-60% of PD patients. It is closely associated with α-synuclein (α-syn) aggregation, with its primary pathophysiology involving the impairment of brainstem circuits, resulting in movement disorders and circadian rhythm dysfunction. Although exercise is recognized for improving motor symptoms and delaying neurodegenerative disease progression, a comprehensive framework of its underlying mechanisms for RBD symptoms has not yet been thoroughly analyzed. This review examines current literature and evidence regarding the various mechanisms and neuroprotective effects of exercise interventions specifically targeting RBD and its associated symptoms. Exercise exerts neuroprotective effects for RBD through multiple underlying mechanisms. The analysis highlights key pathways, including the enhancement of α-syn clearance, the regulation of neurocircuits and circadian rhythms, the modulation of oxidative stress and mitochondrial function, and the reduction of neuroinflammation. Exercise demonstrates significant potential as a multi-targeted intervention. By addressing these underlying pathophysiological mechanisms, exercise provides supportive benefits that may positively influence the disease trajectory for patients with RBD and PD.

Isolated REM sleep behavior disorder, characterized by dream-enacting movements during REM sleep, is a male-predominant parasomnia and the strongest prodromal marker of synucleinopathies. Individuals with this disorder show cortical atrophy whose regional distribution covaries with gene expression patterns measured in the healthy human brain. However, the effect of sex on these brain changes remains unknown. The study objective is to comprehensively assess sex differences in cortical morphology and to characterize the healthy-brain gene expression correlates of brain abnormalities using the largest international multicentric MRI dataset of polysomnography-confirmed patients. Males have significantly more extensive and severe cortical thinning compared to females, despite similar age and clinical features. Imaging transcriptomics analyses indicate that regions affected in female patients map onto areas with higher expression of estrogen-related receptor genes, particularly ESRRG and ESRRA , in the healthy brain. These findings support  potential sex-specific neuroprotection in the prodromal stages of synucleinopathies and may inform personalized and targeted therapeutic strategies. This study reveals that females with isolated REM sleep behavior disorder show less neurodegeneration than males. The least affected regions in females are regions that overexpress estrogen-related genes, suggesting potential sex-specific neuroprotection.