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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. [ABSTRACT FROM AUTHOR]

Most patients with idiopathic REM sleep behavior disorder (iRBD) present peculiar repetitive leg jerks during sleep in their clinical spectrum, called periodic leg movements (PLMS). The clinical differentiation of iRBD patients with and without PLMS is challenging, without polysomnographic confirmation. The aim of this study is to develop a new Machine Learning (ML) approach to distinguish between iRBD phenotypes. Heart rate variability (HRV) data were acquired from forty-two consecutive iRBD patients (23 with PLMS and 19 without PLMS). All participants underwent video-polysomnography to confirm the clinical diagnosis. ML models based on Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost) were trained on HRV data, and classification performances were assessed using Leave-One-Out cross-validation. No significant clinical differences emerged between the two groups. The RF model showed the best performance in differentiating between iRBD phenotypes with excellent accuracy (86%), sensitivity (96%), and specificity (74%); SVM and XGBoost had good accuracy (81% and 78%, respectively), sensitivity (83% for both), and specificity (79% and 72%, respectively). In contrast, LR had low performances (accuracy 71%). Our results demonstrate that ML algorithms accurately differentiate iRBD patients from those without PLMS, encouraging the use of Artificial Intelligence to support the diagnosis of clinically indistinguishable iRBD phenotypes. [ABSTRACT FROM AUTHOR]

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson's Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs' STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs' oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs' oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs' oligomeric α-Syn and SNARE complex components' serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a predictive nomogram for idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) in a community population in Beijing, China. Methods: Based on the validated RBD questionnaire-Hong Kong (RBDQ-HK), we identified 78 individuals with possible RBD (pRBD) in 1,030 community residents from two communities in Beijing. The least absolute shrinkage and selection operator (LASSO) regression was applied to identify candidate features and develop the nomogram. Internal validation was performed using bootstrap resampling. The discrimination of the nomogram was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, and the predictive accuracy was assessed via a calibration curve. Decision curve analysis (DCA) was performed to evaluate the clinical value of the model. Results: From 31 potential predictors, 7 variables were identified as the independent predictive factors and assembled into the nomogram: family history of Parkinson's disease (PD) or dementia [odds ratio (OR), 4.59; 95% confidence interval (CI), 1.35–14.45; p = 0.011], smoking (OR, 3.24; 95% CI, 1.84–5.81; p < 0.001), physical activity (≥4 times/week) (OR, 0.23; 95% CI, 0.12–0.42; p < 0.001), exposure to pesticides (OR, 3.73; 95%CI, 2.08–6.65; p < 0.001), constipation (OR, 6.25; 95% CI, 3.58–11.07; p < 0.001), depression (OR, 3.66; 95% CI, 1.96–6.75; p < 0.001), and daytime somnolence (OR, 3.28; 95% CI, 1.65–6.38; p = 0.001). The nomogram displayed good discrimination, with original AUC of 0.885 (95% CI, 0.845–0.925), while the bias-corrected concordance index (C-index) with 1,000 bootstraps was 0.876. The calibration curve and DCA indicated the high accuracy and clinical usefulness of the nomogram. Conclusions: This study proposed an effective nomogram with potential application in the individualized prediction for pRBD. [ABSTRACT FROM AUTHOR]

The presentation and progression of Parkinson's disease (PD) are not uniform, but the presence of rapid eye movement sleep behavior disorder (RBD) in PD patients may indicate a worse prognosis than isolated PD. Increasing evidence suggests that patients with comorbid PD and RBD (PD-RBD) are more likely to develop cognitive impairment (CI) than those with isolated PD; however, the predictors of CI in PD-RBD patients are not well understood. This study aimed to develop a prognostic model for predicting mild cognitive impairment (MCI) in PD-RBD patients. The data of PD-RBD patients were extracted from the Parkinson's Progression Markers Initiative study (PPMI), and the sample was randomly divided into a training set (n = 96) and a validation set (n = 24). PD-MCI as defined by the level II Movement Disorder Society (MDS) diagnostic criteria was the outcome of interest. The demographic features, clinical assessments, dopamine transporter (DAT) imaging data, cerebrospinal fluid (CSF) analyses and genetic data of PD patients were considered candidate predictors. We found that performance on the University of Pennsylvania Smell Identification Test (UPSIT), the mean signal and asymmetry index of the putamen on DAT imaging, p-tau/α-syn and p-tau in CSF, and rs55785911 genotype were predictors of PD-MCI in PD-RBD patients. A C-index of 0.81 was obtained with this model, and a C-index of 0.73 was obtained in the validation set. Favorable results of calibrations and decision curve analysis demonstrated the efficacy and feasibility of this model. In conclusion, we developed a prognostic model for predicting MCI in PD-RBD patients; the model displayed good discrimination and calibration and may be a convenient tool for clinical application. Larger samples and external validation sets are needed to validate this model. [ABSTRACT FROM AUTHOR]

Background: REM sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients presenting with idiopathic RBD (iRBD), and the predictive value of autonomic dysfunction for phenoconversion to a defined neurodegenerative disease. Methods: We searched our electronic medical record for patients diagnosed with iRBD who also underwent standardized autonomic function testing within 6 months of iRBD diagnosis, and who had clinical follow-up of at least 3 years following iRBD diagnosis. The composite autonomic severity score (CASS) was derived and compared between phenoconverters and non-converters using chi-square and Wilcoxon rank-sum tests. Results: We identified 18 patients who fulfilled inclusion and exclusion criteria. Average age at autonomic testing was 67 ± 6.6 years. Twelve (67%) patients phenoconverted during the follow-up period; six developed Parkinson's disease (PD), and the other six, dementia with Lewy bodies (DLB). Fifteen (83%) patients had at least mild autonomic dysfunction. There were no significant differences between overall converters and non-converters in total CASS or CASS subscores. However, iRBD patients who developed DLB had significantly higher total and cardiovagal CASS scores compared with those who developed PD (p < 0.05), and a trend for higher adrenergic CASS scores compared to those who developed PD and those who did not phenoconvert. Discussion: Autonomic dysfunction was seen in 83% of iRBD patients, and more severe baseline cardiovagal autonomic dysfunction in iRBD was associated with phenoconversion to DLB but not PD. Prospective studies are needed to confirm the value of autonomic testing for predicting phenoconversion and disease phenotype in iRBD. [ABSTRACT FROM AUTHOR]

Background: Although rapid eye movement sleep behaviour disorder (RBD) in Parkinson's disease (PD) is associated with increased non-motor symptoms, its impact on the deep brain stimulation (DBS) outcome remains unclear. This is the first study to compare the post-DBS outcome between PD patients with RBD (PD-RBD+) and without (PD-RBD-).Methods: We analysed data from PD patients who were treated with bilateral DBS in the nucleus subthalamicus. Assessments included night-polysomnography (only pre-DBS), and motor and non-motor assessments pre-DBS and post-DBS.Results: Among 50 PD patients (29 males, mean age 62.5 years, 11.8 mean PD years), 24 (48%) had RBD. Pre-DBS, the two groups were equal in respect to sociodemographic features, disease duration and PD medications. A multivariate analysis showed that the clinical profile linked to motor, non-motor and quality of life features differed significantly between PD patients with and without RBD. The most discriminative elements were Unified Parkinson's Disease Rating Scale (UPDRS)-III, apathy and depression scores. Post-DBS, UPDRS-III, Epworth sleepiness scale and PD questionnaire improved significantly in both groups. UPDRS-II scores significantly improved in the PD-RBD+ group (-45%) but remained unchanged in the PD-RBD- group (-14%). The depression score improved significantly in the PD-RBD+ (-34%) and remained unchanged in the PD-RBD- group. The apathy score remained unchanged in the PD-RBD+ group but increased significantly in the PD-RBD- group (+33%).Conclusion: While pre-DBS, PD patients with and without RBD showed different clinical profiles, post-DBS, the clinical profiles were comparable between the two groups. In respect to depressive symptoms, apathy and activities of daily living, PD-RBD+ patients show favourable post-DBS outcome. These findings highlight the importance of RBD assessment prior to DBS surgery. [ABSTRACT FROM AUTHOR]

Abstract Objectives Rapid eye movement (REM) sleep behavior disorder (RBD) in patients with Parkinson's disease (PD) is associated with increased risk of non-motor symptoms. However, the association between RBD and apathy in PD remains unclear. Aims To compare the prevalence and severity of apathy symptoms in PD patients with RBD (PD-RBD+) and without (PD-RBD-). In addition, we explored the association between apathy, depressive symptoms and RBD, taking into consideration the concomitant influence of demographic, disease- and therapy-associated variables. Methods Sixty-four PD patients were evaluated with systematic motor (unified Parkinson's disease rating scale, UPDRS-III) and non-motor assessments. The diagnosis of RBD was based on the international consensus criteria using video-polysomnography. Apathy, sleepiness, depressive symptoms and cognitive performance were assessed using the Starkstein apathy (SAS, cut-off = 14), the Epworth sleepiness (ESS), the Hamilton depression (HAM-D, cut-off = 9) scales and the mini-mental state examination (MMSE), respectively. Results Among 64 patients, 26 (40%) had RBD. In the PD-RBD+ group, apathy symptoms were more frequent (52% vs 42%) and more severe (14.3 ± 5.8 vs 11.2 ± 4.9, p < 0.05), especially in the females (17.3 ± 6.0 vs 11.4 ± 5.8 in males, p < 0.05) compared to the PD-RBD- group. A high percentage of patients, especially in the PD-RBD+ group (53%), had isolated apathy without increased depressive symptoms. Increased depressive symptoms were also more frequent (50% vs 20%) and more severe in the PD-RBD+ group. The two groups were comparable in respect to demographic and clinical characteristics. Conclusions In PD, RBD is associated with isolated apathy and increased severity of depressive symptoms, independent of medication, motor and other non-motor symptoms. Potential mechanisms underlying this association are discussed. Highlights • Apathy is significantly more prevalent among PD patients with REM sleep behavior disorder (RBD) compared to those without • Patients with RBD, especially females, have significantly higher apathy score compared to those without RBD • The presence of RBD in PD patients is associated with more frequent and more severe depressive symptoms • Differences in apathy and depression among PD patient with and without RBD are independent of PD disability and features [ABSTRACT FROM AUTHOR]

Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disorder characterized by loss of normal muscle atonia during REM sleep with recurrent dream enactment and excessive motor activity. It is a frequent feature in patients with Parkinson's disease (PD) and other alpha-synucleinopathies, and can occur at any stage of the disease. RBD could be considered a premotor clinical manifestation, and can antedate by many years the motor symptomatology. The prognostic value of RBD for the risk of developing PD still needs to be established. This review article focuses on the clinical aspects, screening and diagnostic criteria as well as therapeutic aspects of RBD in PD patients. Pathophysiological pathways are also briefly reviewed. [ABSTRACT FROM AUTHOR]

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with Parkinsonian disorders, but is also reported in narcolepsy. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. In contrast, RBD, RSWA, and hypocretin deficiency are rare in narcolepsy without cataplexy. Phasic motor activity in REM and non-REM (NREM) and dream-enacting behavior (RBD) coexist with cataplexy in narcolepsy because of hypocretin deficiency. Thus, hypocretin deficiency is linked to the two major disturbances of REM sleep motor regulation in narcolepsy: RBD and cataplexy. Moreover, it is likely that hypocretin deficiency independently predicts periodic limb movements in REM and NREM sleep, probably via involvement of the dopaminergic system. This supports the hypothesis that an impaired hypocretin system causes general instability of motor regulation during wakefulness, REM and NREM sleep in human narcolepsy. We propose that hypocretin neurons are centrally involved in motor tone control during wakefulness and sleep in humans and that hypocretin deficiency causes a functional defect in the motor control involved in the development of cataplexy during wakefulness and RBD/RSWA/phasic motor activity during REM sleep. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of our study was to evaluate the frequency of REM sleep behavior disorder (RBD) in a mixed sleep laboratory population and to assess potential associations. Moreover, we investigated referral diagnoses of patients subsequently diagnosed with RBD and assessed the frequency of incidental RBD. Methods: Charts and polysomnographic reports of 703 consecutive patients comprising the full spectrum of ICSD-2 sleep disorders [501 males, 202 females; mean age, 51.0±14.1years (range: 10–82years)] were carefully reviewed. The vast majority of patients were adults (98.7%). Patients were categorized into those with and without RBD. For associations, all concomitant sleep and neurological diagnoses and medications were evaluated. Results: Thirty-four patients (4.8%) were diagnosed with RBD (27 men; 7 women, mean age, 57.7±12.3years). RBD was idiopathic in 11 patients (1.6%; 9 men) and symptomatic in 23 patients (3.3%; 18 men) secondary to Parkinsonian syndromes (n =11), use of antidepressants (n =7), narcolepsy with cataplexy (n =4), and pontine infarction (n =1). Six out of 34 patients were referred for suspected RBD, 20 reported RBD symptoms only on specific questioning, and 8 patients had no history of RBD but showed typical RBD behavioral manifestations in the video-polysomnography. Logistic regression analysis revealed significant associations between RBD and the presence of Parkinsonian syndromes (odds ratio [OR] 16.8, 95%CI: 6.4–44.1; P <0.001), narcolepsy with cataplexy (OR 10.7, 95%CI: 2.9–40.2; P <0.001), SSRI use (OR 3.9, 95%CI: 1.6–9.8; P =0.003), and age (OR 1.5/10-year increase, 95%CI: 1.0–2.0; P =0.039). Conclusion: In this population of 703 consecutive sleep-disorder patients, RBD was uncommon. Its etiology was predominantly symptomatic. The majority of RBD patients reported RBD symptoms on specific questioning only, underlining the importance of eliciting a comprehensive sleep history for the diagnosis of RBD. [Copyright &y& Elsevier]

Background In Parkinsonism, visual hallucinations (VH) and REM sleep behavior disorder (RBD) have been thought to indicate underlying synucleinopathy. Objectives We tested the validity of this hypothesis by searching for VH and RBD symptoms in Parkinsonism related to tauopathies. Methods Patients with progressive supranuclear palsy or corticobasal degeneration were identified via a clinical data bank. Results Of 53 patients who expressed study interest by telephone, 44 returned questionnaires. VH occurred in 16% of patients. Similarly, acting out of dreams occurred in 16% of patients. Neither VH nor RBD symptoms were linked to disease duration or dopaminergic medication and there was no mutual association. Conclusion VH and RBD symptoms also occur in Parkinsonism related to tauopathies, thus refuting the initial hypothesis. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

REM sleep abnormalities are frequently encountered in disorders with alpha-synuclein pathology including Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Symptoms of REM sleep behavior disorder (RBD) may precede the onset of motor and cognitive symptoms in these underlying neurological disorders. Clinical and neuroimaging studies suggest that there may be reductions in dopaminergic mechanisms centrally in primary RBD. Anatomic studies in animals suggest dysfunction of brainstem nuclei. The treatment of RBD has not been adequately evaluated with controlled studies. Clonazepam and melatonin might be effective. [ABSTRACT FROM AUTHOR]

123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy was performed to assess cardiac autonomic dysfunction and demonstrate its correlation with clinical and polysomnographic characteristics in patients with isolated rapid eye movement (REM) sleep behavior disorder. All subjects including 39 patients with isolated REM sleep behavior disorder and 17 healthy controls underwent MIBG cardiac scintigraphy for cardiac autonomic dysfunction assessment. The isolated REM sleep behavior disorder was confirmed by in-lab overnight polysomnography. A receiver operating curve was constructed to determine the cut-off value of the early and delayed heart-to-mediastinum ratio in patients with isolated REM sleep behavior disorder. Based on each cut-off value, a comparison analysis of REM sleep without atonia was performed by dividing isolated REM sleep behavior disorder patients into two groups. MIBG uptake below the cut-off value was associated with higher REM sleep without atonia. The lower heart-to-mediastinum ratio had significantly higher REM sleep without atonia (%), both with cut-off values of early (11.0 ± 5.6 vs. 29.3 ± 23.2%, p = 0.018) and delayed heart-to-mediastinum ratio (9.1 ± 4.3 vs. 30.0 ± 22.9%, p = 0.011). These findings indicate that reduced MIBG uptake is associated with higher REM sleep without atonia in isolated REM sleep behavior disorder. [ABSTRACT FROM AUTHOR]

Rapid-eye-movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by complex motor activity associated with dreaming during REM sleep. RBD may be idiopathic or associated with various neurological diseases involving the brainstem. The association of RBD and limbic system impairment was unclear. We report a 46-year-old man with acute aseptic limbic encephalitis in association with RBD. The patient presented with subacute onset of anterograde/retrograde amnesia and persistent fever. Abnormal nocturnal behavior during sleep consisted of waving hands to fight and kicking legs. Brain magnetic resonance imaging showed damage on the bilateral unci and medial temporal lobes. Cerebrospinal fluid analysis indicated aseptic encephalitis. A polysomnography revealed augmented phasic activity in the submental and bilateral tibialis anterior muscles during REM sleep. Our finding suggests that limbic system impairment may lead to the occurrence of RBD. [ABSTRACT FROM AUTHOR]