Clinical characteristics and phenoconversion in isolated REM sleep behavior disorder: a prospective single-center study in Korea, compared with Montreal cohort.

STUDY OBJECTIVES: Isolated rapid-eye movement behavior disorder (iRBD) is a prodromal synucleinopathy, but its conversion rate and subtypes can vary among different cohorts. We report the clinical characteristics and phenoconversion rate of the large single-center iRBD cohort in Korea and compared it to the Montreal cohort. METHODS: This prospective cohort study examined 238 patients with polysomnography confirmed iRBD from Seoul National University Hospital (SNUH) who completed at least one follow-up evaluation. We compared the baseline and phenoconversion data of the SNUH cohort to those of 242 iRBD patients in the Montreal cohort. RESULTS: In the SNUH cohort, age at RBD diagnosis was similar (66.4±7.8 vs 65.6±8.4, p=0.265), but the proportion of men was lower (63.0% vs. 74.0%, p=0.001), and the duration of follow-up was shorter than that in the Montreal cohort (3.7±2.0 vs. 4.8±3.6 years, p<0.001). During follow-up, 34 (11.8%) patients in the SNUH cohort converted to neurodegenerative disease: 18 (52.9%) to Parkinson's disease, 9 (26.5%) to dementia with Lewy bodies (DLB), and 7 (20.6%) to multiple system atrophy. The conversion rate in the SNUH cohort was 15% after 3 years, 22% after 5 years, and 32% after 7 years, which was significantly lower than that of the Montreal cohort (log-rank test, p=0.002). Among phenoconversion subtype, fewer subjects in the SNUH group than in the Montreal group converted to DLB (Gray's test p=0.001). CONCLUSIONS: Through a comparative analysis between the SNUH and Montreal cohorts, we identified a significant difference in phenoconversion rates, particularly for DLB patients. These findings underscore the importance of further research into the underlying factors, such as racial and geographical factors contributing to such disparities.

Associations between abnormal sleep behavior and indoor environmental risk factors among children with a chronic cough in Wuxi, China: a cross-sectional study.

BACKGROUND: Indoor environmental factors, such as pet ownership, presence of cockroaches, mattress quality, fuel usage (gas or electricity), use of biomass for cooking and heating, exposure to tobacco smoke or household molds can significantly affect the sleep quality of children with chronic cough. However, data regarding the effects of indoor environmental conditions on sleep in this population are limited. This study aimed to assess the prevalence of abnormal sleep behaviors and to establish associations between indoor environmental factors and sleep behaviors among children with chronic cough in Wuxi, China. METHODS: A cross-sectional design was employed in this study, involving children aged 3-18 years. Data on sociodemographic factors, allergies, home environmental exposures, and sleep characteristics of the participants were collected using paper-based questionnaires. The association between indoor environmental factors and sleep behaviors in children with chronic cough was analyzed using logistic regression models. RESULTS: The findings demonstrated that the prevalence of chronic cough among children in Wuxi was 15.50%. The chronic cough group exhibited a significantly higher incidence of eczema, wheezing, rhinitis, food allergy, and nasosinusitis than the non-chronic cough group. In addition, children with chronic cough also tended to have a family history of sleep disorders and adenoid hypertrophy (P < 0.01). After adjusting for confounding factors, a significant association was observed between bruxism (teeth grinding) and chronic cough (sometimes: odds ratio [OR] = 1.04; confidence interval [CI] = 1.01-1.08; always: OR = 1.11; CI = 1.04-1.19; P < 0.01). Among children with chronic cough, recent home decoration was associated with sleepwalking (OR = 1.04; CI = 1.00-1.07; P < 0.05), mold exposure was associated with bruxism (OR = 1.15; CI = 1.0-1.31; P < 0.05), and carpet use at home was associated with apnea (OR = 1.09; CI = 1.02-1.17; P < 0.05), twitching during sleep (OR = 1.13; CI = 1.00-1.27; P < 0.01) and morning headache (OR = 1.14; CI = 1.05-1.23; P < 0.01). CONCLUSION: Children with chronic cough are more prone to some abnormal sleep behaviors than children without chronic cough. Household decoration within a year, household mold exposure, and carpet use were all significantly positively associated with abnormal sleep behaviors in children with chronic cough. Our study provides novel insights into the impact of the indoor environment on children's sleep and the occurrence of chronic cough, offering guidance for tailored health promotion programs for families.

Stress-induced increase in heart-rate during sleep as an indicator of PTSD risk among combat soldiers.

STUDY OBJECTIVES: Discerning the differential contribution of sleep behavior and sleep physiology to the subsequent development of posttraumatic-stress-disorder (PTSD) symptoms following military operational service among combat soldiers. METHODS: Longitudinal design with three measurement time points: during basic training week (T1), during intensive stressed training week (T2), and following military operational service (T3). Participating soldiers were all from the same unit, ensuring equivalent training schedules and stress exposures. During measurement weeks soldiers completed the Depression Anxiety and Stress Scale (DASS) and the PTSD Checklist for DSM-5 (PCL-5). Sleep physiology (sleep heart-rate) and sleep behavior (duration, efficiency) were monitored continuously in natural settings during T1 and T2 weeks using wearable sensors. RESULTS: Repeated measures ANOVA revealed a progressive increase in PCL-5 scores from T1 and T2 to T3, suggesting an escalation in PTSD symptom severity following operational service. Hierarchical linear regression analysis uncovered a significant relation between the change in DASS stress scores from T1 to T2 and subsequent PCL-5 scores at T3. Incorporating participants' sleep heart-rate markedly enhanced the predictive accuracy of the model, with increased sleep heart-rate from T1 to T2 emerging as a significant predictor of elevated PTSD symptoms at T3, above and beyond the contribution of DASS stress scores. Sleep behavior did not add to the accuracy of the model. CONCLUSION: Findings underscore the critical role of sleep physiology, specifically elevated sleep heart-rate following stressful military training, in indicating subsequent PTSD risk following operational service among combat soldiers. These findings may contribute to PTSD prediction and prevention efforts.

The activities of daily living partially mediate the relationship between rapid eye movement sleep behavior disorder and depressive symptoms in Parkinson's disease.

Objective: A longitudinal study was conducted to investigate whether rapid eye movement sleep behavior disorder affect depression in patients with Parkinson's disease through activities of daily living. Methods: A total of 387 Parkinson's disease patients' six-year follow-up data (one follow-up per year) were obtained from the Parkinson's Progression Markers Initiative. To allow causal effects to manifest, this study increased the lag period and divided the data from the six follow-ups into two groups: wave 1 (wave refers to time points), wave 3, and wave 5 as one group, and wave 2, wave 4, and wave6 as the other group. The time interval between two time points in each group was two years. To comprehensively and deeply analyze the dynamic relationships between variables, accurately infer causal relationships, control for individual differences, and detect the stability of these relationships, this study constructed the fixed effects cross-lagged panel model (CLPM), the random effects CLPM (RE-CLPM) model, and the Equating CLPM and Equating RE-CLPM models with applied restriction conditions. Additionally, a reverse path was added to verify the reverse prediction effect. The most suitable data analysis model was selected to explore the relationships between the study variables. Furthermore, the longitudinal mediating effect of daily living activities between rapid eye movement sleep behavior disorder and depression was investigated. Results: In the models, Equating cross-lagged panel model was the best. The lag effect was positive and significant. In wave 1, 3, 5, activities of daily living mediated 11.82% on the path from rapid eye movement sleep behavior disorder to depression; in wave 2, 4, 6, it mediated 13.13%. Therefore, attention should be paid to the treatment of activities of daily living. Conclusion: Longitudinal changes in activities of daily living have indirect effects on the relationship between rapid eye movement sleep behavior disorder and depression, which highlights the importance of changes in activities of daily living ability in Parkinson's disease patients with rapid eye movement sleep behavior disorder.

Polysomnographic features prior to dream enactment behaviors in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: This study aimed to identify electroencephalogram correlates of dream enactment behaviors (DEBs) and elucidate their cortical dynamics in patients with isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: This cross-sectional study included 15 patients with iRBD. Two REM sleep periods in routine polysomnography were compared: the 60 s preceding the DEBs ("pre-representative behavior" [preR]), and the 60 s with the least submental electromyogram activity ("background" [BG]). Six EEG frequency bands and electrooculogram were analyzed; power spectra, coherence and phase-locking values in four 15-s periods were examined to assess trends. These indices were also compared between preR and BG. RESULTS: Compared with BG, significantly higher delta power in the F3 channel and gamma power in the F4 and O2 channels were observed during preR. For functional connectivity, the widespread beta-band connectivity was significantly increased during preR than BG. CONCLUSION: Before notable REM sleep behaviors, uneven distributed higher EEG spectral power in both very low and high frequencies, and increased wide-range beta band functional connectivity, were observed over 60 s, suggesting cortical correlates to subsequent DEBs. SIGNIFICANCE: This study may shed light on the pathological mechanisms underlies RBD through the routine vPSG analysis, leading to detection of DEBs.

Sleep disorders and Parkinson's disease: is there a right direction?

In the last years, the hypothesis of a close relationship between sleep disorders (SDs) and Parkinson's disease (PD) has significantly strengthened. Whether this association is causal has been also highlighted by recent evidence demonstrating a neurobiological link between SDs and PD. Thus, the question is not whether these two chronic conditions are mutually connected, but rather how and when this relationship is expressed. Supporting this, not all SDs manifest with the same temporal sequence in PD patients. Indeed, SDs can precede or occur concomitantly with the onset of the clinical manifestation of PD. This review discusses the existing literature, putting under a magnifying glass the timing of occurrence of SDs in PD-neurodegeneration. Based on this, here, we propose two possible directions for studying the SDs-PD relationship: the first direction, from SDs to PD, considers SDs as potential biomarker/precursor of future PD-neurodegeneration; the second direction, from PD to SDs, considers SDs as concomitant symptoms in manifest PD, mainly related to primary PD-neuropathology and/or parkinsonian drugs. Furthermore, for each direction, we questioned SDs-PD relationship in terms of risk factors, neuronal circuits/mechanisms, and impact on the clinical phenotype and disease progression. Future research is needed to investigate whether targeting sleep may be the winning strategy to treat PD, in the context of a personalized precision medicine.

Major Alteration Of Motor Control During Rem Sleep In Mice Models Of Sleep Disorders.

Alteration of motor control during REM sleep has been extensively described in sleep disorders, in particular in isolated REM sleep behavior disorder (iRBD) and narcolepsy type 1 (NT1). NT1 is caused by the loss of orexin/hypocretin (ORX) neurons. Unlike in iRBD, the RBD comorbid symptoms of NT1 is not associated with alpha-synucleinopathies. To determine whether the chronic absence of ORX neuropeptides is sufficient to induce RBD symptoms, we analyzed during REM sleep the EMG signal of the prepro-hypocretin knockout mice (ORX-/-), a recognized mouse model of NT1. Then, we evaluated the severity of motor alterations by comparing EMG data of ORX-/- mice to those of mice with a targeted suppression of the sublaterodorsal glutamatergic neurotransmission, a recognized rodent model of iRBD. We found a significant alteration of tonic and phasic components of EMG during REM sleep in ORX-/- mice, with more phasic events and more REM sleep episodes without atonia compared to the control wild-type mice. However, these phasic events were fewer, shorter and less complex in ORX-/- mice compared to the RBD-like ORX-/- mice. We thus show that ORX-deficiency, as seen in NT1, is sufficient to impair muscle atonia during REM sleep with a moderate severity of alteration as compared to isolated RBD mice. As described in NT1 patients, we report a major inter-individual variability in the severity and the frequency of RBD symptoms in ORX-deficient mice.

REM sleep behavior disorder and Prodromal Parkinson's Disease in patients with Essential Tremor.

Several studies suggested the presence of non-motor symptoms in Essential Tremor (ET), including REM sleep behavioral disorder (RBD). RBD is an essential criterion for Prodromal Parkinson's Disease (PPD), suggesting a link between ET and PD. Our objective was to assess the prevalence and features of ET patients with RBD and PDD. RBD was diagnosed by questionnaire screening, followed by polysomnography. PPD risk factors and prodromic markers were assessed with a structured protocol. Patients were characterized regarding tremor features. ET patients with RBD (ET-RBD) and PPD (ET-PPD) were compared to patients without RBD (ET-nonRBD) and without PPD (ET-nonPPD), respectively. ET-RBD patients were also compared with a group of isolated RBD (iRBD) regarding PPD features. We assessed a total of 64 ET patients. Five (8.3 %) and 4 (6.3 %) had criteria for RBD and PPD, respectively. ET-RBD patients did not differ from ET-nonRBD except for a higher prevalence of PPD. There were no significant differences between ET-RBD and iRBD (n = 12) groups. ET-PPD had a higher prevalence of positive DaT-Scans and RBD compared to ET-nonPPD. Three ET-RBD patients had PPD and 3 ET-PPD had RBD. Both RBD and PPD are more frequent in ET patients than in general aged population but not related with specific tremor features. ET-RBD patients did not differ significantly from iRBD patients, a group prone to develop PD. These data suggest a link between ET and PD and are in accordance with studies showing an increase incidence of lewy-body pathology and PD in ET populations.

The correlation between rapid eye movement sleep behavior disorder and the progress of Parkinson's disease: a systematic review and meta-analysis.

Background: This meta-analysis was conducted to evaluate potential differences in symptoms between PD patients with or without RBD. Methods: A systematic search was conducted in PubMed, Cochrane, Embase, and Web of Science databases (as of August 16, 2023), to identify relevant studies on PD and RBD. Statistical analysis was performed using Stata 15.0. Continuous variables were analyzed using the standardized mean difference (SMD) and 95% confidence interval (95% CI), while count data were assessed using the odds ratio (OR) and 95% CI as statistical effect sizes. Heterogeneity among all included studies was tested; for studies with low heterogeneity (I2 < 50%), a fixed-effects model was used to calculate statistical results. For studies with relatively high heterogeneity (I2 > 50%), a random-effects model was applied, followed by sensitivity and subgroup analyses to identify sources of heterogeneity. Results: A total of 5,672 subjects were involved in this study. Compared to the NRBD group, the UPDRS-III score in the RBD group was significantly higher (SMD = 0.20, 95% CI: [0.11, 0.29], P < 0.001), and the Hoehn-Yahr score in the RBD group was also significantly higher (SMD = 0.29, 95% CI: [0.03, 0.55], P < 0.001). Patients with PD in the RBD group had more severe cognitive impairments than those in the NRBD group (SMD = -0.30, 95% CI: [-0.48, -0.11], P < 0.001). The incidence of hallucination in PD patients in the RBD group was 3.0 times that of the NRBD group (OR = 3.0, 95% CI: [2.15, 4.20], P = 0.110). PD patients in the RBD group also experienced more severe anxiety symptoms (SMD = 0.13, 95% CI: [-0.26, 0.51], P < 0.001), had higher scores in depression scales (SMD = 0.22, 95% CI: [0.02, 0.43], P < 0.001), and higher scores in sleep disorder scales than those in NRBD group (SMD = 0.10, 95% CI: [-0.11, 0.31], P < 0.001). Conclusion: Results show PD patients with co-occurring RBD have more severe motor and non-motor symptoms likely due to overlapping affected regions in RBD and PD-related pathology, plus broader neurodegeneration seen in PD patients with RBD. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#searchadvanced, identifier CRD42023476331.

Gait Analysis and Magnetic Resonance Imaging Characteristics in Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Isolated rapid eye movement sleep behavioral disorder (iRBD) can precede neurodegenerative diseases. There is an urgent need for biomarkers to aid early intervention and neuroprotection. OBJECTIVE: The aim is to assess quantitative motor, cognitive, and brain magnetic resonance imaging (MRI) characteristics in iRBD patients. METHODS: Thirty-eight polysomnography-confirmed iRBD patients and 28 age- and sex-matched healthy controls underwent clinical, cognitive, and motor functional evaluations, along with brain MRI. Motor tasks included nine-hole peg test, five-times-sit-to-stand test, timed-up-and-go test, and 4-meter walking test with and without cognitive dual task. Quantitative spatiotemporal gait parameters were obtained using an optoelectronic system. Brain MRI analysis included functional connectivity (FC) of the main resting-state networks, gray matter (GM) volume using voxel-based morphometry, cortical thickness, and deep GM and brainstem volumes using FMRIB's Integrated Registration and Segmentation Tool and FreeSurfer. RESULTS: iRBD patients relative to healthy subjects exhibited a poorer performance during the nine-hole peg test and five-times-sit-to-stand test, and greater asymmetry of arm-swing amplitude and stride length variability during dual-task gait. Dual task significantly worsened the walking performance of iRBD patients more than healthy controls. iRBD patients exhibited nonmotor symptoms, and memory, abstract reasoning, and visuospatial deficits. iRBD patients exhibited decreased FC of pallidum and putamen within the basal ganglia network and occipital and temporal areas within the visuo-associative network, and a reduced volume of the supramarginal gyrus. Brain functional alterations correlated with gait changes. CONCLUSIONS: Subtle motor and nonmotor alterations were identified in iRBD patients, alongside brain structural and functional MRI changes. These findings may represent early signs of neurodegeneration and contribute to the development of predictive models for progression to parkinsonism. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High bioavailable testosterone levels increase the incidence of isolated REM sleep behavior disorder: Results from multivariable and network Mendelian randomization analysis.

OBJECTIVES: To explore the causal relationships between sex hormone levels and incidence of isolated REM sleep behavior disorder (iRBD). METHODS: In our study, we utilized Genome-Wide Association Studies (GWAS) data for iRBD, including 9447 samples with 1061 cases of iRBD provided by the International RBD Study Group. Initially, we conducted a two-sample univariate MR analysis to explore the impact of sex hormone-related indicators on iRBD. This was followed by the application of multivariable MR methods to adjust for other hormone levels and potential confounders. Finally, we undertook a network MR analysis, employing brain structure Magnetic Resonance Imaging (MRI) characteristics as potential mediators, to examine whether sex hormones could indirectly influence the incidence of iRBD by affecting brain structure. RESULTS: Bioavailable testosterone (BioT) is an independent risk factor for iRBD (Odds Ratio [95 % Confidence Interval] = 2.437 [1.308, 4.539], P = 0.005, corrected-P = 0.020), a finding that remained consistent even after adjusting for other sex hormone levels and potential confounders. Additionally, BioT appears to indirectly increase the risk of iRBD by reducing axial diffusivity and increasing the orientation dispersion index in the left cingulum and cingulate gyrus. CONCLUSIONS: Our research reveals that elevated levels of BioT contribute to the development of iRBD. However, the specific impact of BioT on different sexes remains unclear. Furthermore, high BioT may indirectly lead to iRBD by impairing normal pathways in the left cingulum and cingulate gyrus and fostering abnormal pathway formation.

Prevalence and correlates of probable rapid eye movement sleep behavior disorder among middle-aged and older adults in a psychiatric outpatient clinic: A cross-sectional survey.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is often underdiagnosed among people living with mental disorders. The present study aimed to investigate the prevalence of probable RBD (pRBD) and its associated factors among middle-aged and older adults in a psychiatric outpatient clinic. METHODS: We conducted a cross-sectional survey among 2907 people aged 45-80 years who visited the outpatient clinic between March 1 and August 31, 2022 in a psychiatric hospital. A cutoff score ≥5 on the RBD Screening Questionnaire (RBDSQ) was used to indicate the presence of probable RBD (pRBD). Potential factors associated with pRBD were also assessed with a structured checklist. The association between these factors and the presence of pRBD was examined with logistic regression. RESULTS: The response rate was 64.3 %. Among 1868 respondents [age 58.5 ± 9.6 years, male n = 738 (39.5 %), female n = 1130 (60.5 %)], 15.9 % (95 % CI 14.2-17.6 %) screened positive for pRBD. Occupational exposure to chemicals; positive family history of psychotic disorders; a late start of mental health care; a medical history of autonomic dysfunction; mood problems; and use of antidepressants, hypnotics, and acetylcholinesterase inhibitors were associated with an increased likelihood of having pRBD (P < 0.05 for all). CONCLUSION: pRBD is common among outpatients with mental disorders, especially in mental disorders due to neurological diseases and physical conditions, mood disorders and anxiety or somatoform disorders. The findings highlight the importance of identifying sleep behavior disorders among people living with mental disorders in clinical practice.

Quantitative EEG in Parkinson's disease: when REM sleep behavior disorder onset really matters.

Parkinson's Disease (PD) body-first subtype is characterized by prodromal autonomic symptoms and REM sleep behavior disorder (RBD), symmetric dopaminergic degeneration, and increased risk of dementia. On the other hand, the PD brain-first subtype has fewer non-motor symptoms and a milder motor phenotype. The temporal relationship between RBD onset and motor symptoms onset may differentiate these two subtypes. We aimed to investigate electrocortical differences between brain-first and body-first PD patients. PD patients with an available routinely collected EEG were retrospectively selected. RBD was diagnosed using the RBD screening questionnaire (≥ 6). According to the onset of RBD patients were classified into PD-RBDpre (RBD onset before motor symptoms) and PD-RBDpost (RBD onset after motor symptoms). Patients without RBD were classified as PD-RBD-. Presence of Mild Cognitive Impairment (MCI) was diagnosed according to the MDS criteria. EEG Spectral analysis was performed in resting state by computing the Power Spectral Density (PSD) of site-specific signal epochs for the common frequency bands (delta, theta, alpha, beta). Thirty-eight PD-RBD-, 14 PD-RBDpre and 31 PD-RBDpost patients were recruited. Comparing both global and site-specific absolute values, we found a significant trend toward beta band reduction going from PD-RBD-, PD-RBDpost and PD-RBDpre. No significant differences were found between PD-RBDpost and PD-RBD- patients. PD-RBDpre patients may represent a different subset of patients as compared to patients without RBD, while patients with later onset have intermediate EEG spectral features. Quantitative EEG may provide new hints in PD subtyping.

The relationship between quality of life, sleep quality, mental health, and physical activity in an international sample of college students: a structural equation modeling approach.

Objective: We assessed the direct and indirect relationships between sleep quality, mental health, and physical activity with quality of life (QOL) in college and university students. Methods: In a cross-sectional design, 3,380 college students (60% females; age = 22.7 ± 5.4) from four continents (Africa: 32%; America: 5%; Asia: 46%; and Europe: 15%; others: 2%) completed the Pittsburgh Sleep Quality Index (PSQI); Insomnia Severity Index (ISI); Epworth Sleepiness Scale (ESS); the Depression, Anxiety, and Stress Scale 21 (DASS); the International Physical Activity Questionnaire short-form (IPAQ); and the World Health Organization Quality of Life-BREF (WHOQOL-Brief). Results: We showed that sleep quality, insomnia, and depression had direct negative effects on the physical domain of QOL (ß = -0.22, -0.19, -0.31, respectively, p < 0.001). There was a strong negative direct association between depression and the psychological domain of QOL (ß = -0.60, z = -22.21, p < 0.001). Both stress and PSQI had direct effects on social relationships QOL (ß = 0.11; z = 4.09; and ß = -0.13; z = -7.40, respectively, p < 0.001). However, depression had the strongest direct impact on social relationships QOL (ß = -0.41, z = -15.79, p < 0.001). Conclusion: The overall QOL of university students is associated with their sleep quality, mental health, and physical activity warranting further interventional studies aiming at improving students' quality of life.

Association of body mass index with rapid eye movement sleep behavior disorder in Parkinson's disease.

Background: The association between body mass index (BMI) and rapid eye-movement (REM) sleep-related behavioral disorder (RBD) in Parkinson's disease (PD) remains unknown. Our study was to investigate the association of BMI with RBD in PD patients. Methods: In this cross-sectional study, a total of 1,115 PD participants were enrolled from Parkinson's Progression Markers Initiative (PPMI) database. BMI was calculated as weight divided by height squared. RBD was defined as the RBD questionnaire (RBDSQ) score with the cutoff of 5 or more assessed. Univariable and multivariable logistic regression models were performed to examine the associations between BMI and the prevalence of RBD. Non-linear correlations were explored with use of restricted cubic spline (RCS) analysis. And the inflection point was determined by the two-line piecewise linear models. Results: We identified 426 (38.2%) RBD. The proportion of underweight, normal, overweight and obese was 2.61, 36.59, 40.36, and 20.44%, respectively. In the multivariate logistic regression model with full adjustment for confounding variables, obese individuals had an odds ratio of 1.77 (95% confidence interval: 1.21 to 2.59) with RBD compared with those of normal weight. In the RCS models with three knots, BMI showed a non-linear association with RBD. The turning points of BMI estimated from piecewise linear models were of 28.16 kg/m2, 28.10 kg/m2, and 28.23 kg/m2 derived from univariable and multivariable adjusted logistic regression models. The effect modification by depression on the association between BMI and RBD in PD was also found in this study. Furthermore, the sensitivity analyses linked with cognition, education, and ethnic groups indicated the robustness of our results. Conclusion: The current study found a significant dose-response association between BMI and RBD with a depression-based difference in the impact of BMI on RBD in PD patients.

Cognitive training and promoting a healthy lifestyle for individuals with isolated REM sleep behavior disorder: study protocol of the delayed-start randomized controlled trial CogTrAiL-RBD.

BACKGROUND: Isolated REM sleep behavior disorder (iRBD) is an early α-synucleinopathy often accompanied by incipient cognitive impairment. As executive dysfunctions predict earlier phenotypic conversion from iRBD to Parkinson's disease and Lewy body dementia, cognitive training focusing on executive functions could have disease-modifying effects for individuals with iRBD. METHODS: The study CogTrAiL-RBD investigates the short- and long-term effectiveness and the feasibility and underlying neural mechanisms of a cognitive training intervention for individuals with iRBD. The intervention consists of a 5-week digital cognitive training accompanied by a module promoting a healthy, active lifestyle. In this monocentric, single-blinded, delayed-start randomized controlled trial, the intervention's effectiveness will be evaluated compared to an initially passive control group that receives the intervention in the second, open-label phase of the study. Eighty individuals with iRBD confirmed by polysomnography will be consecutively recruited from the continuously expanding iRBD cohort at the University Hospital Cologne. The evaluation will focus on cognition and additional neuropsychological and motor variables. Furthermore, the study will examine the feasibility of the intervention, effects on physical activity assessed by accelerometry, and interrogate the intervention's neural effects using magnetic resonance imaging and polysomnography. Besides, a healthy, age-matched control group (HC) will be examined at the first assessment time point, enabling a cross-sectional comparison between individuals with iRBD and HC. DISCUSSION: This study will provide insights into whether cognitive training and psychoeducation on a healthy, active lifestyle have short- and long-term (neuro-)protective effects for individuals with iRBD. TRIAL REGISTRATION: The study was prospectively registered in the German Clinical Trial Register (DRKS00024898) on 2022-03-11, https://drks.de/search/de/trial/DRKS00024898 . PROTOCOL VERSION: V5 2023-04-24.

Decreased heart rate variability in sympathetic dominant states in Parkinson's disease and isolated REM sleep behavior disorder.

INTRODUCTION: Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD). METHODS: We retrospectively assessed 102 patients with PD, 10 patients with iRBD, and 43 healthy controls. We then measured the coefficient of variation of RR intervals as an HRV parameter in sympathetic dominant states (CVRR-S) and parasympathetic dominant states (CVRR-P). Furthermore, we evaluated parameters of cardiac autonomic function, including HUT and the heart-to-mediastinum (H/M) ratio of cardiac metaiodobenzylguanidine scintigraphy. RESULTS: Patients with iRBD and PD at Hoehn and Yahr stage I exhibited a significantly decreased CVRR-S compared to healthy controls (controls vs. iRBD vs. PD; 1.82 ± 0.64 % vs. 1.13 ± 0.41 % vs. 1.15 ± 0.51 %, p < 0.001), although no further deterioration was observed in PD at more severe Hoehn and Yahr stages. CVRR-S showed a significant correlation with the H/M ratio in PD (r = 0.51, p < 0.001). Additionally, receiver operating characteristic (ROC) analysis revealed a larger area under the ROC curve in CVRR-S compared to that in CVRR-P for discriminating PD or iRBD from healthy controls. CONCLUSION: HRV in sympathetic dominant states shows the potential to be a marker of autonomic dysfunction in iRBD and early-stage PD, aiding in early diagnosis and patient stratification.

REM sleep behavior disorder in Brunner syndrome.

Brunner syndrome is a recessive X-linked disorder characterized by intellectual disability and impulsive aggressiveness associated with Monoamine Oxidase-A (MAOA) deficiency leading to increased monoaminergic activity. We report the presence of REM sleep behavior disorder (RBD) in a 46-year-old patient with Brunner syndrome due to a c.1438A>G/iVS14-2 A>G mutation of the MAOA gene. He suffered from mild intellectual disability and psychotic disturbances. He presented a 15-year history of nightmares (chase, attacks and fights), sleep-related vocalizations and motor behaviors characterized by talking, screaming, crying, gesturing, punching, and kicking. Video-polysomnography showed RBD characterized by excessive tonic and phasic muscle activity in the mentalis and limb muscles with dream enacting behaviors during REM sleep. Clonazepam achieved a significant reduction of RBD symptomatology. We conclude that RBD can be a manifestation of Brunner syndrome probably due to an increased monoaminergic neurotransmission occurring in this rare genetic disorder.

Gait Analysis with Wearable Sensors in Isolated REM Sleep Behavior Disorder Associated with Phenoconversion: An Explorative Study.

Background: Gait disturbance is a vital characteristic of motor manifestation in α- synucleinopathies, especially Parkinson's disease. Subtle gait alterations are present in isolated rapid eye movement sleep behavior disorder (iRBD) patients before phenoconversion; it is yet unclear, if gait analysis may predict phenoconversion. Objective: To investigate subtle gait alterations and explore whether gait analysis using wearable sensors is associated with phenoconversion of iRBD to α-synucleinopathies. Methods: Thirty-one polysomnography-confirmed iRBD patients and 33 healthy controls (HCs) were enrolled at baseline. All participants walked for a minute while wearing 6 inertial sensors on bilateral wrists, ankles, and the trunk (sternal and lumbar region). Three conditions were tested: (i) normal walking, (ii) fast walking, and (iii) dual-task walking. Results: Decreased arm range of motion and increased gait variation (stride length, stride time and stride velocity) discriminate converters from HCs at baseline. After an average of 5.40 years of follow-up, 10 patients converted to neurodegenerative diseases (converters). Cox regression analysis showed higher value of stride length asymmetry under normal walking condition to be associated with an early conversion of iRBD to α- synucleinopathies (adjusted HR 4.468, 95% CI 1.088- 18.349, p = 0.038). Conclusions: Stride length asymmetry is associated with progression to α- synucleinopathies in patients with iRBD. Gait analysis with wearable sensors may be useful for screening, monitoring, and risk stratification for disease-modifying therapy trials in patients with iRBD.