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Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with Parkinson’s disease (PD). In this study, a smartwatch-based sensor is utilized as a convenient tool to detect the abnormal RBD phenomenon in PD patients. Instead, a questionnaire with sleep quality assessment and sleep physiological indices, such as sleep stage, activity level, and heart rate, were measured in the smartwatch sensors. Therefore, this device can record comprehensive sleep physiological data, offering several advantages such as ubiquity, long-term monitoring, and wearable convenience. In addition, it can provide the clinical doctor with sufficient information on the patient’s sleeping patterns with individualized treatment. In this study, a three-stage sleep staging method (i.e., comprising sleep/awake detection, sleep-stage detection, and REM-stage detection) based on an accelerometer and heart-rate data is implemented using machine learning (ML) techniques. The ML-based algorithms used here for sleep/awake detection, sleep-stage detection, and REM-stage detection were a Cole–Kripke algorithm, a stepwise clustering algorithm, and a k-means clustering algorithm with predefined criteria, respectively. The sleep staging method was validated in a clinical trial. The results showed a statistically significant difference in the percentage of abnormal REM between the control group (1.6 ± 1.3; n = 18) and the PD group (3.8 ± 5.0; n = 20) (p = 0.04). The percentage of deep sleep stage in our results presented a significant difference between the control group (38.1 ± 24.3; n = 18) and PD group (22.0 ± 15.0, n = 20) (p = 0.011) as well. Further, our results suggested that the smartwatch-based sensor was able to detect the difference of an abnormal REM percentage in the control group (1.6 ± 1.3; n = 18), PD patient with clonazepam (2.0 ± 1.7; n = 10), and without clonazepam (5.7 ± 7.1; n = 10) (p = 0.007). Our results confirmed the effectiveness of our sensor in investigating the sleep stage in PD patients. The sensor also successfully determined the effect of clonazepam on reducing abnormal REM in PD patients. In conclusion, our smartwatch sensor is a convenient and effective tool for sleep quantification analysis in PD patients.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

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

Abstract Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.

Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) manifests as unpleasant dreams and vigorous behaviours during REM sleep that can result in injuries. Patients with IRBD have no known neurological diseases or motor or cognitive complaints; however, this sleep disorder is not harmless. In most cases, IRBD is the prelude of the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or, less frequently, multiple system atrophy. Patients can show abnormalities that are characteristic of the synucleinopathies, and longitudinal follow-up shows that most patients develop parkinsonism and cognitive impairments with time. Thus, diagnosis of IRBD needs to be accurate and involves informing the patient of the risk of developing a neurodegenerative disease. It is extraordinary for a sleep disorder to precede the full expression of a neurodegenerative disease, which renders IRBD of particular interest in studies of the prodromal stage of the synucleinopathies, and in the development of neuroprotective interventions to stop or slow neurodegenerative deterioration before motor and cognitive symptomatology emerges. Such therapeutics do not currently exist, and thus represent an unmet need in IRBD.

Parkinson’s disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson’s patients ( n  = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n  = 18 and n  = 54 longitudinally), and healthy controls ( n  = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins—Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson’s disease. Parkinson’s disease is lacking easily accessible biomarkers. Here the authors show, that targeted blood proteomics is feasible to identify the patients and to predict the phenoconvertion in prodromal subjects up to 7 years before symptom onset.

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

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

Key Points Diagnosis of Parkinson disease (PD) requires motor symptoms, but it is now clear that the typical motor signs are preceded by preclinical and prodromal phases of the disease The utility of a marker of prodromal PD depends on the strength of evidence that it is a relevant marker, its specificity, its lead time, and the practicalities of assessment Identification of reliable markers requires prospective studies; studies in high-risk populations are susceptible to selection bias and limited generalizability The strongest marker of prodromal PD is rapid eye movement (REM) sleep behaviour disorder; other markers supported by strong evidence include subtle motor dysfunction, olfactory loss, autonomic dysfunction and affective disorders Markers of prodromal PD have been combined to predict the probability of prodromal PD, most notably in the International Parkinson Disease Movement Disorders Society task force diagnostic guidelines The earliest stages of Parkinson disease (PD) offer the best opportunity to intervene, but detecting early disease is difficult. In this Review, Postuma and Berg provide an overview of established and potential markers of prodromal PD, and consider how these markers can be combined to identify patients who have prodromal PD and could benefit from treatment. Efforts to develop neuroprotective therapy for Parkinson disease (PD) are focusing on the early stages of disease, which offer the best opportunity to intervene. Early PD can be divided into preclinical, prodromal and clinical stages; in this Review, we focus on the prodromal stage and markers that can be used to identify prodromal PD. We consider the necessary properties of a marker, before providing an overview of the proven and potential markers of prodromal PD, including clinical nonmotor markers, clinical motor markers, neuroimaging markers and tissue biomarkers. Markers for which the ability to predict conversion to PD is supported by the strongest evidence include olfactory loss, REM sleep behaviour disorder and constipation. Markers with the highest diagnostic strength include REM sleep behaviour disorder, dopaminergic imaging and subtle motor parkinsonism. The lead time — the period between the appearance of a marker and conversion to PD — is highly variable between markers, ranging from 5 years for impaired motor performance to >20 years for autonomic symptoms. The cost of screening for these markers also varies dramatically: some require just questionnaires, whereas others require sophisticated scanning techniques. Finally, we summarize how prodromal and risk markers can be combined to estimate the probability that an individual has prodromal PD, with a focus on the International Parkinson Disease and Movement Disorders Society (MDS) Prodromal Parkinson Criteria.