Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1, PLEKHM1, LRP2, P2RX1, and HAP1. Subsequent analysis of these genes in Parkinson's disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

Isolated rapid eye movement sleep behavior disorder is a strong clinical marker of future alpha-synucleinopathy, but earlier stages of this risk pathway remain insufficiently characterized. Rapid eye movement sleep without atonia is the polysomnographic substrate of this disorder and may also be detected in individuals without clinical dream-enactment behavior. Whether isolated rapid eye movement sleep without atonia is a benign finding or an early risk state for future rapid eye movement sleep behavior disorder and neurodegeneration remains unknown. DREAMER is a multicenter, prospective, observational cohort protocol designed to identify adults without clinical rapid eye movement sleep behavior disorder who show isolated rapid eye movement sleep without atonia during full-night laboratory video-polysomnography. Four Italian sleep centers will use harmonized eligibility criteria, standardized clinical and sleep assessment, quantitative REM Atonia Index scoring, secure web-based data capture, and planned longitudinal follow-up. Adults aged 40 years or older undergoing video-polysomnography will be screened. Participants with prior rapid eye movement sleep behavior disorder or technically inadequate REM sleep/chin electromyographic data will be excluded. Isolated rapid eye movement sleep without atonia will be defined in participants without clinical rapid eye movement sleep behavior disorder using a REM Atonia Index threshold of <0.85. The target recruitment is more than 500 participants over 18 months, with an expected enriched subgroup of approximately 85 individuals with isolated rapid eye movement sleep without atonia. Ancillary neurophysiological assessments and blood sampling for future biomarker studies will be obtained when feasible. DREAMER is intended to create a harmonized, trial-ready cohort for evaluating isolated rapid eye movement sleep without atonia as a potential early risk marker for incident rapid eye movement sleep behavior disorder and subsequent neurodegenerative outcomes. The study is registered at ClinicalTrials.gov as DREAMER, ClinicalTrials.gov Identifier NCT06140511.

Clinical progression from prodromal to overt stages of alpha-synucleinopathies is highly heterogeneous, and there is an urgent need for reliable clinical progression markers. Exploiting the Disease Course Map (DCM) model, we investigated how clinical signs evolve in patients with idiopathic/isolated rapid-eye-movement sleep behavior disorder (iRBD), extracting clinical progression measures for use at the single-subject level. Furthermore, we correlated them with both established and innovative neurodegeneration biomarkers. We trained a DCM model using cognitive and motor scores of a longitudinal cohort of 766 iRBD patients (166 female, 67.9 ± 7.4 years). We personalized the model by extracting three parameters to describe the single subject in comparison to the averaged population data. We tested the model on a blind set of 49 iRBD patients (7 female, 68.5 ± 7.1 years) who underwent both longitudinal clinical evaluations and instrumental evaluation at the first observation. In the blind set, we correlated the individual model parameters with presynaptic dopaminergic impairment, an established biomarker of substantia nigra neurodegeneration, and cortical electrophysiological dysfunction-measured by high-density electroencephalography (HD-EEG)-an innovative neurodegeneration biomarker. We identified three individual clinical markers reflecting early/late (time shift, τ) and fast/slow (acceleration factor, α) disease progression, as well as the individual clinical trajectory (i.e., earlier motor or cognitive impairment, intermarker spacing, ω). The individual model parameters are significantly associated with phenoconversion, with a 73% chance of distinguishing between clinically stable patients (non-converters) and those converting during the longitudinal observation to an overt alpha-synucleinopathy (converters). Motor scores progress 35% faster than cognitive scores in our iRBD cohort. Converter iRBD patients exhibited a faster and earlier disease progression than non-converters, and, on average, they showed an earlier worsening of motor scores than cognitive scores, regardless of the clinical diagnosis of overt parkinsonism. Patients with iRBD who developed parkinsonism worsened earlier than those who develop dementia. At baseline, an earlier progression was related to presynaptic dopaminergic impairment and higher phase synchronization in the theta band (4-8 Hz). Higher synchronization in the theta band was also associated with an earlier worsening of motor scores than cognitive scores. In this study, we investigated a large longitudinal iRBD cohort, applying an advanced disease progression model. We found three individual clinical markers that were able to monitor disease progression and showed significant association with both established and innovative neurodegeneration biomarkers. We suggest that these clinical markers could be used as efficacy endpoints in disease-modifying clinical trials.

Restless legs syndrome (RLS) is usually framed as a sleep-related movement disorder, but its clinical burden often depends on psychiatric symptoms, insomnia, cognitive complaints, and reduced quality of life. This review reframes recent evidence on RLS and mental health for a treatment-oriented neurology audience. Recent observational and interventional studies support a bidirectional and complex relationship between RLS and depression, anxiety, and different mental health disturbances, which may worsen the RLS itself and the quality of life of patients. In this context, suicidal ideation deserves specific attention because it may persist even when depressive symptoms improve. Current treatment guidance has also shifted toward systematic evaluation of iron status, correction of exacerbating factors, and preferential use of alpha-2-delta ligands or iron therapy, with more cautious dopaminergic prescribing. RLS management should routinely include screening for mental health symptoms, sleep disruption, suicide risk, medication triggers, and comorbid sleep disorders. Conversely, patients with psychiatric disorders and sleep complaints should be screened for RLS. Integrated treatment may improve both nocturnal symptoms and daytime neuropsychiatric functioning.

Previous studies showed an increased risk of COVID-19 in several occupations, particularly healthcare workers. We aimed to explore whether night shift work, a possible determinant of immune suppression, might have contributed to COVID infection in the pre-vaccine months using data from 435 Italian participants (330 women, 105 men) to the COVISTRESS online survey. After adjusting for age, sex, and education, the risk of COVID-19 was elevated among night shift workers (OR = 5.5, 95% CI 2.92, 10.2), particularly among healthcare workers (OR = 8.7, 95% CI 4.07, 18.4). After excluding healthcare workers from the analysis, subjects working night shifts in other jobs also run a 5-fold elevated risk of COVID-19 (OR = 5.1, 95% CI 1.92, 18.4), which was confirmed in a sensitivity analysis excluding subjects who reported working remotely. Parenting school-aged children was also a significant predictor (OR = 2.5; 95% CI 1.20–5.21) of SARS-CoV-2 infection, but there was no interaction with night shift work. Education, marital status, smoking, and sleep quality did not account for the association with night shift work. Our results suggest that, during the 2020 COVID-19 pandemic, night shift workers run an excess risk of COVID-19 infection. Whether this was because of sleep loss-induced suppression of the immune system, confounding, or chance remains to be clarified.

Abstract Isolated/idiopathic rapid-eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early form of α -synuclein-related neurodegenerative diseases, including Parkinson’s disease and dementia with Lewy bodies. Clinical reports suggest that iRBD is more common in individuals with Post-Traumatic Stress Disorder (PTSD) compared to those without PTSD. We conducted polygenic risk score (PRS), genetic correlation, and Mendelian randomization analyses to explore potential genetic and/or causal associations between PTSD and iRBD. Dopamine transporter imaging binding status was also examined in iRBD patients with ( N = 6) and without PTSD ( N = 32). While not supporting a causal relationship, genetic analyses revealed a significant association between PTSD and iRBD, consistent with the exploratory imaging substudy. These findings suggest that individuals genetically at risk for PTSD may also be at higher risk for iRBD. Further investigation of iRBD in individuals with PTSD may help inform potential neurodegenerative risk.

STUDY OBJECTIVES:To characterize nocturnal motor activity across isolated REM sleep behavior disorder (iRBD), Parkinson's disease with REM sleep behavior disorder (PD+RBD), PD without RBD (PD-RBD), and healthy controls, with particular focus on large muscle group movements (LMMs) during sleep. MATERIALS AND METHODS:We included 109 participants: controls (n = 25; 13F/12M, age 67.6 ± 6.70 years), iRBD (n = 25; 4F/21M, 70.7 ± 8.42 years), PD+RBD (n = 31; 10F/21M, age 71.1 ± 7.30), and PD-RBD (n = 28; 9F/19M, age 67.9 ± 8.05 years). Conventional sleep architecture, REM atonia index (RAI), leg-movement subtypes, and LMM indices and duration across total sleep time (TST), NREM sleep, and REM sleep were analyzed. RESULTS:As expected, RAI showed the clearest group separation, with reduced values in iRBD and PD+RBD. Sleep instability, reflected by increased stage shifts, was greater in iRBD and PD+RBD than in controls. Among leg-movement measures, only isolated leg movement index remained significantly increased after correction, specifically in PD+RBD. LMM provided the most distinctive additional signal: total LMM index differed across TST, NREM, and REM sleep, with lower values in PD-RBD and higher polysomnography (PSG)-defined REM-related LMM activity in iRBD and PD+RBD. LMM duration was longer in all clinical groups than in controls, whereas LMM associated with arousal or wake did not differ significantly across groups. CONCLUSIONS:Quantitative assessment of LMM, together with refined leg-movement phenotyping and REM atonia measures, may improve characterization of nocturnal motor dysregulation across the synucleinopathy spectrum. LMM may represent a PSG-derived marker of sleep-state instability and REM-related motor activation, with potential relevance for iRBD progression and PD phenotyping. Statement of Significance This study suggests that the nocturnal motor phenotype of synucleinopathy is broader than REM sleep without atonia and conventional PLMS measures alone. By showing that LMM and isolated leg movements help distinguish iRBD, PD+RBD, and PD-RBD, the findings support a more refined polysomnographic framework for capturing disease-related motor disorganization during sleep. The contrasting profile of PD-RBD, with fewer but longer LMM, also points to nocturnal hypokinesia as a potentially distinct motor signature. If confirmed longitudinally, these measures could improve phenotypic stratification and help identify clinically meaningful pathways linked to progression, cognition, autonomic dysfunction, and future targeted treatments.

To define how dopamine transporter (DaT) SPECT can be used to stage neurodegeneration in neuronal alpha-synucleinopathy patients at the individual level. This is an international multicenter study involving 1067 subjects (mean age 69.8 ± 8.7 years; 63.2

STUDY OBJECTIVES:Isolated REM Sleep Behavior Disorder (iRBD) frequently presents with cognitive impairment and may precede overt α-synucleinopathies by decades. Cognitive impairment is present early in the disease course, and patients exhibit a specific pattern of cognitive involvement. This work aims to compare Mild Cognitive Impairment (MCI) in iRBD across diagnostic criteria and identify data-driven cognitive phenotypes. METHODS:We conducted a cross-sectional study including 55 consecutively enrolled vPSG-confirmed iRBD. All subjects underwent a neuropsychological evaluation, and MCI status was derived from the current classification. Data-driven clustering and PCA were performed. Candidate neuropsychological markers of MCI were evaluated using ROC analysis and logistic regression. RESULTS:MCI was found in 60% of the sample. Pathological performance was most frequently observed on executive, attentional, and visuo-spatial measures. Data-driven analysis identified three distinct cognitive profiles within MCI-RBD: (a) a memory-executive subgroup, (b) a globally impaired subgroup, and (c) a mild-preserved subgroup with performance near normality. PCA identified a prominent global cognitive efficiency factor and a secondary component that differentiated "dysexecutive" from other profiles. The best discriminative measures for MCI status were TMT-B (AUC = .85), TMT B-A (AUC = .84), and MWCST perseverative errors (AUC = .83). CONCLUSIONS:Cognitive impairment in iRBD is common and heterogeneous. Data-driven analyses suggest three distinct cognitive profiles within MCI-RBD, with executive-attentional dysfunction emerging as a prominent feature and potentially representing a key target for cognitive evaluation and risk stratification. These findings support an executive-focused conceptualization of MCI-RBD and highlight the need for in-depth cognitive investigation and the harmonization of neuropsychological measures to facilitate comparability.

This review repositions orexin/hypocretin biology within sleep medicine from a primarily wake-promoting framework toward a treatment-oriented model centered on vigilance-state stability, REM-sleep boundary control, and orderly transitions among wakefulness, NREM sleep, and REM sleep. Human and translational evidence indicates that orexin deficiency in narcolepsy type 1 produces not only sleepiness, but also cataplexy, sleep-onset REM periods, sleep paralysis, hallucinations, fragmented nocturnal sleep, and other dissociated-state phenomena. Human lumbar cerebrospinal fluid (CSF) data show only modest diurnal orexin variation, with a relative early-sleep peak and decline toward morning, a pattern not easily reducible to simple wake promotion and compatible with REM inhibition. Orexin receptor antagonists improve insomnia by attenuating wake-state stabilization rather than inducing nonspecific sedation, while generally preserving or enhancing REM sleep. Emerging orexin receptor agonists, and exploratory use of antagonists in disorders such as insomnia associated with restless legs syndrome, further expand the possible therapeutic relevance of this system. Orexin should be viewed not only as a wake-promoting system but also as a stabilizer of vigilance states and REM boundaries. This framework better integrates narcolepsy, insomnia pharmacology, parasomnia vulnerability, CSF biomarker dynamics, and future orexin-targeted treatment development.

Objectif Actuellement, aucune échelle standard n’a été validée pour évaluer la sévérité globale des symptômes du RBD à la maison. L’objectif de l’étude était d’évaluer les propriétés psychométriques de l’International RBD Severity Scale (IRBD-SSS), un nouvel outil conçu par l’International RBD Study Group. Méthodes Deux versions de l’IRBD-SSS ont été créées, une pour le patient (IRBD-SSS-PT) et une autre pour le partenaire de lit (IRBD-SSS-BP), toutes les deux structurées avec 3 composantes, à savoir les vocalisations, les mouvements corporels et les blessures, avec un quatrième composant (uniquement dans la version patient) évaluant le contenu du rêve. L’IRBD-SSS dans les deux versions a été initialement développé en anglais et ensuite traduite en français et italien selon une méthode standard. Pour coter chaque dimension, on multiplie les scores de la fréquence et la sévérité/impact des comportements au cours du mois précédent. Les propriétés psychométriques de l’IRBD-SSS ont été évaluées, y compris la reproductibilité. Résultats Un total de 188 sujets, dont n=132 patients RBD (n=94 RBD isolés et n=38 RBD symptomatiques) et n=52 partenaires de lit, ont été recrutés dans huit centres du sommeil en France et en Italie. Les participants ont complété l’échelle au départ et après une semaine. L’acceptabilité de l’échelle était excellente chez les patients (97 %) et les partenaires de lit (98 %). La cohérence interne était acceptable pour l’IRBD-SSS-PT (Cronbach alpha=0,75) tandis qu’elle était légèrement faible pour IRBD-SSS-BP (Cronbach alpha=0,49). La validité était bonne pour les versions patient (r=0,70 ; p<0,001) et partenaire de lit (r=0,69 ; p<0,001) de l’IRBD-SSS. La reproductibilité était élevée pour l’IRBD-SSS-PT (coefficient de Lin=0,85 [0,81 ; 0,90]) et bonne pour l’IRBD-SSS-BP (0,79 [0,68 ; 0,90] [p<0,001]). Conclusion Les versions patient et partenaire de lit de l’IRBD-SSS ont montré une excellente acceptabilité, une cohérence interne acceptable, une bonne validité externe et une reproductibilité élevée. L’IRBD-SSS est un instrument utile pour tester la sévérité des symptômes du RBD à la fois dans des contextes cliniques que dans les essais cliniques.

BACKGROUND:People with idiopathic/isolated REM sleep behavior disorder (iRBD) are highly heterogeneous, showing mild motor, cognitive, and dysautonomia symptoms. The aim of this study is to unveil the clinical heterogeneity of iRBD with a specific reference to overlapping features with prodromal Parkinson's disease (pPD) and prodromal dementia with Lewy bodies (pDLB) labels. METHODS:People with a polysomnography-confirmed diagnosis of iRBD were enrolled and followed over time. At baseline, pPD and pDLB criteria were assessed. RESULTS:Among the 285 iRBD people (68.2 ± 7.6 years, 81% males), due to additional signs or symptoms, 49.8% fulfilled pPD criteria only, 5.6% pDLB criteria only, and 14.4% subjects fulfilled both pPD and pDLB criteria. Conversely, about one third of iRBD people (30.2%) did not meet either pPD or pDLB criteria. At follow-up (40.6 ± 43.6 months), 28.8% subjects phenoconverted, developing PD (56.1%), DLB (39%), or multiple system atrophy (4.9%). Subjects with iRBD fulfilling either pPD or pDLB criteria, or both, have an increased risk of phenoconversion (adjusted hazard ratio, aHR 2.34, 95% confidence interval, CI 1.24-4.41). On the opposite, subjects not fulfilling prodromal criteria have a significantly reduced short-term phenoconversion likelihood (aHR 0.43, 95% CI 0.23-0.81). Notably, pPD and pDLB criteria did not predict PD and DLB diagnoses, respectively. CONCLUSIONS:People with iRBD are highly heterogeneous, and the presence of other concomitant signs and symptoms is frequent, leading to faster phenoconversion. Thus, the terms idiopathic and isolated may be poorly appropriate and possibly even confounding. These results pave the way to a more appropriate new lexicon for people with RBD.

AIMS:Obesity and sleep disorders are highly prevalent conditions with profound implications for public health. Emerging evidence highlights a bidirectional relationship between these two conditions, with each exacerbating the other in a complex interplay of behavioral, physiological, and hormonal mechanisms. Sleep deprivation and poor sleep quality contribute to energy imbalance through dysregulation of appetite hormones (e.g., leptin and ghrelin), increased caloric intake, and reduced physical activity. Conversely, sleep disorders such as obstructive sleep apnea syndrome (OSAS), insomnia, and restless leg syndrome (RLS) are significantly more common in individuals with obesity. DATA SYNTHESIS:This review explores the pathophysiological mechanisms underlying this relationship, including the roles of inflammation, autonomic dysregulation, and neuroendocrine pathways. Sleep loss exacerbates metabolic syndrome components, including insulin resistance and dyslipidemia, further perpetuating weight gain. Similarly, obesity-induced sleep disorders lead to pro-inflammatory states, vascular dysfunction, and sympathetic overactivation, compounding cardiometabolic risks. Specific conditions like OSA and RLS are examined as models of this interdependence, emphasizing their shared pathways and clinical implications. CONCLUSIONS:The bidirectional link between obesity and sleep disorders underscores the importance of integrating sleep assessment and management into obesity treatment strategies. Addressing this relationship could mitigate the progression of cardiometabolic comorbidities and improve overall health outcomes. Moreover, the intertwined dynamics between obesity, sleep disorders, and mental health-mediated by inflammatory pathways, hormonal dysregulation, and neurobehavioral factors-highlight the critical need for integrated treatment approaches targeting physical, psychological, and sleep-related dimensions to enhance health and quality of life.

IntroductionThere are conflicting findings regarding the influence of sex on idiopathic REM sleep behavior disorder (iRBD) in terms of prevalence and associated clinical characteristics. This study, conducted as part of the Italian multicenter longitudinal FARPRESTO project, aims to explore sex-related differences in the age of onset, iRBD diagnosis, and phenoconversion, as well as in cognitive and non-motor features and the occurrence of RBD-related injuries among male and female patients with iRBD.MethodsThe FARPRESTO study included 536 iRBD patients recruited from 13 Italian centers. This analysis assessed the age at iRBD diagnosis, diagnostic delay, motor and non-motor symptoms, global cognitive performance, conversion rates to neurodegenerative disorders, and the prevalence of RBD-related injuries at the time of iRBD diagnosis, stratified by sex.ResultsFemale patients were older at iRBD diagnosis compared to males (males: 67.8 years, IQR 62.5-72.6; females: 69.8 years, IQR 65.1-74.8; p = 0.003). Compared to male patients, female patients exhibited a higher prevalence of orthostatic hypotension (27.9% vs. 16.2%; p = 0.019), depression (43.9% vs. 26.6%; p = 0.010), and hallucinations (43.9% vs. 26.6%; p = 0.010) at iRBD diagnosis. Additionally, self-directed injuries were significantly more frequent in females compared to males at the first visit (71% vs. 53.2%; p = 0.034). No significant differences were observed in the phenoconversion rate between sexes.ConclusionAlthough research on sex-related differences in iRBD remains limited, this study highlights the importance of understanding sex-specific characteristics. As diagnostic and therapeutic approaches evolve, incorporating these differences will be essential for tailoring clinical strategies and improving patient outcomes.

Background: Obstructive sleep apnea (OSA) is frequent but underrecognized after stroke, worsening prognosis, recurrence, and mortality. Polysomnography is rarely feasible in acute care, and existing screening tools have limited accuracy. We aimed to identify simple OSA clinical predictors to improve risk stratification in stroke patients. Methods: In this prospective study, 116 consecutive acute stroke patients (mean age 73 years, 57% male) underwent standardized clinical evaluation, Berlin Questionnaire, Epworth Sleepiness Scale (ESS), and home sleep apnea test during hospitalization. OSA was defined as apnea–hypopnea index (AHI) ≥ 15. Logistic regression identified independent predictors; the model’s performance was assessed by accuracy, sensitivity, specificity, and ROC curves. Results: OSA was diagnosed in 42 patients (36%). OSA patients showed higher NIHSS at admission (p = 0.048) and higher ESS scores (p = 0.047), but similar vascular risk factors and stroke subtypes compared to non-OSA patients. In a multivariate analysis, age (OR 1.05; 95% CI 1.00–1.10; p = 0.036) and witnessed apneas (OR 6.20; 95% CI 1.31–29.22; p = 0.021) were OSA independent predictors. The two-variable models achieved 72.9% accuracy, 90.3% specificity, 41.2% sensitivity, Nagelkerke R2 = 0.223, and AUC = 0.739 (p < 0.001), outperforming both the Berlin Questionnaire (AUC 0.596) and ESS (AUC 0.616). Conclusions: A simple model based on age and witnessed apneas reliably identified stroke patients at high risk for OSA, with good discriminative performance and higher accuracy than standard questionnaires. Its high specificity supports targeted allocation of sleep studies in resource-limited acute settings, potentially improving early detection, secondary prevention, and care pathways after stroke.

Objective:To explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. Methods:We conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status-a marker of neurodegeneration-in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). Results:Polygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). Interpretation:Polygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.

This multicenter retrospective longitudinal study aims to evaluate the association between electroencephalographic slow oscillations (0.3-1 Hz) and slow waves (1-4 Hz) with cognitive performance, and their impact on phenoconversion in patients affected by isolated rapid eye movement (REM) sleep behavior disorder (iRBD). 69 iRBD patients underwent baseline overnight video-polysomnography, clinical assessment, and a neuropsychological evaluation. Phenoconversion was assessed with a follow-up clinical evaluation. Automatic detection of slow oscillations and slow waves was performed during non-REM sleep stage 2 (N2) and 3 (N3) on frontal and central derivations. Clinical, neuropsychological and electrophysiological measures were compared between converters and non-converters. Correlations were computed between cognitive performance and slow oscillations and slow wave densities, as well as between N2 slow oscillation density and N3 slow/fast wave densities. Time-to-event analyses, including Kaplan-Meier and Cox proportional hazards model were performed to assess phenoconversion risk and potential predictors. 30.36 % of patients phenoconverted to an overt alpha-synucleinopathy with a mean follow-up of 45.57 ± 37.26 months. Both slow wave and slow oscillation densities were significantly associated with cognitive performance. Moreover, slow oscillation density in N2 positively correlated with slow oscillation and slow wave density in N3. At baseline, patients who phenoconverted at follow-up showed significantly lower executive function performance and reduced N2 slow oscillation density. In the Cox model including covariates, only executive functions remained a significant predictor. Baseline differences in executive functions may help identify iRBD patients at greater risk of phenoconversion, whereas reduced N2 slow oscillation density may reflect early neurophysiological alterations preceding overt disease.

Rapid-eye-movement (REM)-sleep behaviour disorder (RBD) can be a prodromal stage of α-synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and provides a unique opportunity to study and understand early neurodegeneration. Previous research on RBD has identified common risk loci in several PD and DLB genes, but the full extent of its genetic architecture and disease-specific associations remain unknown. In the present study, we aimed to identify novel loci associated with RBD by conducting an updated European RBD genome-wide association study (GWAS). We performed a meta-analysis using a previous RBD GWAS and newly genotyped RBD patients and controls, resulting in a total of 3,564 RBD cases and 140,393 controls analyzed. We further assessed the functional impact of new associations using fine-mapping and colocalization analyses with adult brain expression quantitative trait loci (eQTLs). To confirm if novel RBD loci are implicated in additional synucleinopathy phenotypes, we examined common variant associations in GWASs of PD risk, DLB risk, PD with RBD risk, PD age at onset, and various measures of progression. Additionally, rare variants were analyzed with the optimal sequence kernel association test (SKAT-O) in PD and DLB whole genome sequencing cohorts. Lastly, we analyzed known PD- and DLB-risk loci for associations with RBD. We identified RCOR1 as a novel risk locus for RBD, with fine-mapping suggesting the association to be driven by a variant in intron 2. Colocalization revealed no evidence for shared genetic signals with brain eQTLs, although this may reflect a lack of statistical power to detect an association. Common and rare variants in the RCOR1 locus were not associated with PD, DLB, and additional α-synucleinopathy phenotypes. We observed several PD and DLB risk loci to be associated with RBD, including MAPT , STK39 , and SIPA1L2 . The MAPT associated variant tags the protective H2 haplotype, consistent with previous findings in PD. Several SNCA variants previously associated with PD or DLB were also associated with RBD, but with differing directions of effect, highlighting the complex genetic landscape underlying α-synucleinopathy subtypes. This study identifies new RBD loci and strengthens our understanding of the genetic modifiers underlying RBD. Further replication and functional studies will be required to validate our findings and explore their biological implications.

Background:Socio-demographic, occupational and lifestyle variables influence total sleep time. Therefore, we aimed to evaluate the influence of those variables on sleep time, and to study risk factors of being a short sleeper. Methods:The COVISTRESS international study is an online questionnaire using the secure REDCap® software. Total sleep time was evaluated using declared bedtime and time of awakening and was analyzed as a quantitative variable and as a qualitative variable. Results:We included 549 respondents to the questionnaire, divided into 10-year age groups ranging from <30yo to ≥60yo. The mean quantity of sleep was 7.11±1.43 hours per night. Factors that reduce total sleep time were age (coefficient -0.19, 95CI -0.33 to 0.06), being an employee (-0.46, -0.85 to -0.06), working time (-0.18, -0.31 to 0.05), smoking ≥5 cigarettes/day (-0.5, -0.95 to -0.20), high stress at work (-0.64, -0.96 to -0.32) and at home (-0.66, -0.97 to -0.35). Being a student (0.61, 0.02 to 1.19), working less than 25h per week (0.57, 0.17 to 0.97) and telework (0.46, 0.02 to 0.89) increased total sleep time. The risk factors of being a short sleeper were age (odds ratio 1.27, 95CI 1.07 to 1.51), being an employee (2.58, 1.36 to 4.89), smoking ≥5 cigarettes/day (2.73, 1.54 to 4.84) and a high level of stress at work (2.64, 1.45 to 4.82) and at home (3.89, 2.25 to 6.63). Physical activity ≥2.5 hours/week tended to decrease the risk of being a short sleeper by 35%. Conclusion:We demonstrated the concomitant impact of sociodemographic, occupational and lifestyle behavior on sleep, which may help to build efficient preventive strategy.