Parkinsonism as an outlier detection problem

Neurophysiological assessment of REM sleep behaviour disorder

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by complex behavior during REM sleep. The etiology of this disorder is still unknown, but a recent study showed that RBD precedes symptoms of Parkinson disease (PD) by several years, and in a previous study, we found reduced striatal dopamine transporters in idiopathic clinically manifest RBD. Hypothesizing that subclinical RBD shows a less severe reduction of striatal dopamine transporters than clinically manifest RBD, we studied striatal postsynaptic dopamine D2-receptors with (S)-2hydroxy-3iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide labeled with iodine 123 (IBZM) and the striatal presynaptic dopamine transporters with (N)-(3-iodopropene-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane labeled with iodine 123 (IPT) using single-photon emission computed tomography (SPECT) in the following groups: 8 patients with idiopathic subclinical RBD, 8 patients with idiopathic clinically manifest RBD, 11 controls, and 8 patients with PD stage Hoehn & Yahr I. The IPT uptake was highest in controls. There was a significant decrease in IPT uptake from controls to patients with subclinical RBD, from patients with subclinical RBD to clinically manifest RBD, and from patients with clinically manifest RBD to patients with PD (controls: right = 4.07 +/- 0.29, left = 4.07 +/- 0.30; subclinical RBD: right = 3.56 +/- 0.21, left = 3.55 +/- 0.25; clinically manifest RBD: right = 3.18 +/- 0.43, left = 3.2 +/- 0.43; PD: ipsilateral to the clinically affected body side = 3.25 +/- 0.35, contralateral to the clinically affected body side = 2.51 +/- 0.28). Muscle activity during REM sleep lasting persistently longer than 0.5 seconds was independently associated with reduction of striatal dopamine transporters (P = 0.001). The IBZM uptake was not significantly different between the groups. This study suggests that there is a continuum of reduced striatal dopamine transporters involved in the pathophysiologic mechanisms causing increased muscle activity during REM sleep in patients with subclinical RBD.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of muscle atonia during REM sleep (known as REM sleep without atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapiesinpatients with idiopathic RBD to prevent or delay α-synucleinopathy-related motorandcognitivedecline.

Over 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson disease (PD) or dementia. At present, there is no way to predict who will develop disease. Since polysomnography is performed in all patients with idiopathic RBD at diagnosis, there is an opportunity to analyze if baseline sleep variables predict eventual neurodegenerative disease. In a longitudinally studied cohort of patients with idiopathic RBD, we identified those who had developed neurodegenerative disease. These patients were matched by age, sex, and follow-up duration to patients with RBD who remained disease-free and to controls. Polysomnographic variables at baseline (i.e., before development of neurodegenerative disease) were compared between groups. Twenty-six patients who developed neurodegenerative disease were included (PD 12, multiple system atrophy 1, dementia 13). The interval between polysomnogram and disease onset was 6.7 years, mean age was 69.5, and 81% were male. There were no differences between groups in sleep latency, sleep time, % stages 2-4, % REM sleep, or sleep efficiency. However, patients with idiopathic RBD who developed neurodegenerative disease had increased tonic chin EMG activity during REM sleep at baseline compared to those who remained disease-free (62.7 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.020). This effect was seen only in patients who developed PD (72.9 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.002), and not in those who developed dementia (54.3 +/- 10.3, p = 0.28). There was no difference in phasic submental REM EMG activity between groups. In patients with REM sleep behavior disorder initially free of neurodegenerative disease, the severity of REM atonia loss on baseline polysomnogram predicts the development of Parkinson disease.

Background:Rapid eye movement (REM) sleep behavior disorder (RBD) may be a risk factor for cognitive impairment in patients with Parkinson's disease (PD). However, little is known regarding the relation between the severity of RBD and the different domains of cognitive impairment. The aim of this study was: (1) to investigate the domains of cognitive impairment in patients with PD and RBD, and (2) to explore risk factors for PD-mild cognitive impairment (PD-MCI) and the relationship between RBD severity and impairment in different cognitive domains in PD.Methods:The participants were grouped as follows: PD without RBD (PD-RBD; n = 42), PD with RBD (PD + RBD; n = 32), idiopathic RBD (iRBD; n = 15), and healthy controls (HCs; n = 36). All participants completed a battery of neuropsychological assessment of attention and working memory, executive function, language, memory, and visuospatial function. The information of basic demographics, diseases and medication history, and motor and nonmotor manifestations was obtained and compared between PD-RBD and PD + RBD groups. Particular attention was paid to the severity of RBD assessed by the RBD Questionnaire-Hong Kong (RBDQ-HK) and the RBD Screening Questionnaire (RBDSQ), then we further examined associations between the severity of RBD symptoms and cognitive levels via correlation analysis.Results:Compared to PD-RBD subjects, PD + RBD patients were more likely to have olfactory dysfunction and their Epworth Sleepiness Scale scores were higher (P < 0.05). During neuropsychological testing, PD + RBD patients performed worse than PD-RBD patients, including delayed memory function, especially. The MCI rates were 33%, 63%, 33%, and 8% for PD-RBD, PD + RBD, iRBD, and HC groups, respectively. RBD was an important factor for the PD-MCI variance (odds ratio = 5.204, P = 0.018). During correlation analysis, higher RBDSQ and RBDQ-HK scores were significantly associated with poorer performance on the Trail Making Test-B (errors) and Auditory Verbal Learning Test (delayed recall) and higher RBD-HK scores were also associated with Rey–Osterrieth complex figure (copy) results.Conclusions:When PD-RBD and PD + RBD patients have equivalent motor symptoms, PD + RBD patients still have more olfactory dysfunction and worse daytime somnolence. RBD is an important risk factor for MCI, including delayed memory. Deficits in executive function, verbal delayed memory, and visuospatial function were consistently associated with more severe RBD symptoms.

Introduction REM sleep without atonia (RSWA) is a key criteria for diagnosing REM Behavior Disorders (RBD), which has been strongly associated with Parkinson’s disease and dementia. RBD prevalence is increased in the Veteran population, and further increased in Veterans that have been diagnosed with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). PTSD and TBI share common underlying pathology that could manifest in RBD, and some data suggests RSWA is increased in these populations RSWA, therefore, may have potential to serve as a biomarker of neurodegeneration and/or sympathetic hyperactivityIn this study, we aimed to investigate whether RSWA differs between Warfighters with PTSD (PTSD+) and those without (PTSD-). Methods We compared polysomnography data of 7 PTSD+ active duty Warfighters from Walter Reed National Military Medical Center and compared these data to 5 healthy control Active Duty Warfighters. Following clinician graded sleep scoring, we used the RBDtector, an open-source software, to analyze EMG activity and sleep stages in the chin and tibialis anterior. In our initial analysis, we used a one-way ANOVA to determine if RSWA is higher in PTSD+ Warfighters compared to PTSD-. Results PTSD+ Warfighters had significantly higher phasic (0.1 – 5.0s) bouts of chin EMG activity (p &amp;lt; 0.001). Further, there was overall increased EMG activity (p = 0.003) in PTSD+ compared to controls. Data analysis is still ongoing to reach 150 participants in each group. Further analysis will include linear mixed effect models, controlling for age and medications such as serotonin norepinephrine reuptake inhibitors. Conclusion Our data show that Warfighters with PTSD had higher EMG activity during REM sleep than Warfighters without PTSD. More data will lend further insights to support these findings and provide more evidence to support the overlapping underlying neuropathologic pathways in PTSD and RBD. Such insights could enhance our understanding of the shared mechanisms underlying PTSD, RBD, and related neurodegenerative conditions. Support (if any) USU Award number: HU00012320101

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dreamenacting 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 dreamenacting 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.

Sleep is prompted by natural cycles of activity in the brain and consists of two basic states: rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. REM sleep behavior disorder (RBD) is characterized by violent motor and vocal behavior during REM sleep which represents dream enactment. The normal loss of muscle tone, with the exception of respiratory, sphincter, extra ocular and middle ear muscles, is absent in patients with RBD. The origin of RBD is frequently unknown, but can be associated with degenerative neurological disorders, such as Parkinson's disease (PD). PD patients do not necessarily express features of RBD, which is identified in approximately third to a half of them. The aim of this study was to estimate the prevalence of RBD in a cohort of PD patients, as well as to identify risk-factors for its development. In the period from December 2010 to September 2011 we recruited 97 consecutive PD outpatients, treated in the Institute of Neurology, Clinical Center of Serbia, Belgrade. After establishing the diagnosis, all the patients filled out a specially constructed questionnaire with the following items: actual age, sex, age at disease onset, disease duration, form of the disease, type of treatment, duration of treatment, the presence of constipation, lessening of smell sense, and family history of PD. At entring the study, patients disability was scored using the Unified Parkinson's Disease Rating Scale (motor part - UPDRS). Cognitive abilities were assessed by the Mini Mental Status Examination (MMSE) scale, and depression symptoms by the 21-item Hamilton Depression Rating Scale (HDRS). The patients with PD were dichotomized to those with and without RBD using the RBD Questionnaire-Hong Kong (RBDQ-HK) in the manner of an interview. Forms of PD, mode of treatment, sex, constipation and family history were investigated using the Fishers χ2 test. Symptoms and treatment duration, the presence of smell disturbances, MMSE score, UPDRS motor score and HDRS score were analyzed by implementation of the Z-test. Actual age and age at disease onset were evaluated by the unpaired t-test. The RBD-positive group contained 15 (15.5%) patients, while in the rest of them (82/97), RBD was not identified (nonRBD group). There was no difference between the two groups considering gender distribution (p = 0.847), age (p = 0.577), age at disease onset (p = 0.141 ), duration. of PD (p = 0.069), family history (p = 0.591), type of initial symptoms (p = 0.899), constipation (p = 0.353), olfaction (p = 0.32) and MMSE scores (p = 0.217). The duration of treatment in the RBD group was longer than in the non-RBD group (9.4 ± 5.3 and 6.3 ± 3.9 years, respectively; p = 0.029), and the UPDRS motor score in the RBD group was higher (19.1 ± 9.4 and 12.7 ± 8.2, respectively; p = 0.013). Also, HDRS scores were higher in patients expressing RBD (10.1 ± 6.0 and 6.4 ± 4.5, respectively; p = 0.019). We found that 15.5% of the consecutive PD patients had RBD, and that the patients with RBD differed from the non-RBD ones regarding duration of treatment, disease and depressive symptoms severity.

To compare the amounts of REM sleep without atonia (RSWA) between patients with REM sleep behavior disorder (RBD), "isolated loss of REM atonia," narcolepsy, and control subjects and determine if there were threshold values for the amount of RSWA that differentiate each group from controls. Retrospective analyses of polysomnography (PSG) records were used employing strict quantitative criteria for the measurement of phasic and tonic EMG activity during REM sleep. The PSG recordings of 47 individuals were analyzed (RBD 16, isolated loss of REM atonia 11, narcolepsy 10, control 10). Patients with the diagnosis of isolated loss of REM atonia had significantly lower levels of EMG activity during REM sleep than those with RBD but higher than control subjects. RSWA was higher in narcolepsy than in loss of REM atonia but lower than for RBD patients. Receiver operating characteristic (ROC) curves provided threshold values with high specificity and sensitivity in all patient groups with a cutoff value ≥ 1.22% (100% correctly classified) for phasic and ≥ 3.17% for tonic (92% correctly classified) EMG activity in RBD. Quantification of REM sleep EMG activity can successfully differentiate RBD and isolated loss of REM atonia patients from controls. The consistently increased amount of RSWA in patients with narcolepsy indicates that this can be an additional marker for a diagnosis of narcolepsy. Longitudinal studies of patients with isolated loss of REM atonia are needed to evaluate if these patients are at risk of developing RBD or neurodegenerative disorders.

REM sleep behavior disorder (RBD) is a parasomnia characterized by a lack of motor inhibition during REM sleep leading to potentially harmful dream-enacting behaviors. RBD affects mainly older men and its prevalence in the general population is estimated to be around 0.5%. RBD may be idiopathic or associated with other neurologic disorders. A strong association between RBD and alpha-synucleinopathies has been recently observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of patients with RBD. Small clinical follow-up studies revealed that a proportion of these patients will eventually develop a parkinsonian syndrome or a dementia of Lewy bodies type in the years following the RBD diagnosis, while some patients will never show other neurologic signs within several decades from the RBD onset. Recent studies have looked at neurophysiologic and neuropsychological functions in idiopathic RBD and have found evidences of CNS dysfunction during both wakefulness and sleep. An impairment of the cortical activity, specific neuropsychological deficits, and signs of autonomic dysfunction have been observed in a variable proportion of these patients, challenging the concept of idiopathic RBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies.

The discovery of rapid eye movement (REM) sleep and, in particular, REM sleep behavior disorder (RBD) have brought elusive nightmarish experiences to scientific scrutiny. This article summarizes a century of sleep research to examine the maladies of dreaming, their pathophysiologic significance, and management. Under healthy physiologic conditions, REM sleep is characterized by vivid mentation combined with skeletal muscle paralysis. The loss of REM sleep atonia in RBD results in vivid, potentially injurious dream enactment to patients and bed partners. RBD is common, affecting at least 1% of the population and is primarily caused by α-synuclein pathology of REM sleep-related brainstem neurons. The majority of patients with RBD ultimately develop a neurodegenerative syndrome such as Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. Among patients with Parkinson disease, RBD predicts an aggressive disease course with rapid cognitive, motor, and autonomic decline. RBD is diagnosed by the presence of dream enactment episodes (either recorded or clinically recalled) and physiologic evidence of REM sleep without atonia demonstrated on polysomnography. Bedroom safety is of paramount importance in the management of RBD while pharmacokinetic options include melatonin or clonazepam. The injurious dream enactment of RBD is common and treatable. It is a syndrome of α-synuclein pathology with most patients ultimately developing Parkinson disease, dementia with Lewy bodies, or a related disorder.

Narcolepsy with cataplexy (NC) is a chronic disease characterized by excessive daytime sleepiness, striking transitions from wakefulness into rapid eye movement (REM) sleep, typically associated with cataplexy and other phenomena due to the abnormal occurrence of REM sleep elements during wakefulness (sleep paralysis and hallucinations) and frequent sleep/wake transitions. Nocturnal sleep in NC is usually disturbed by a large cohort of phenomena: vivid frightening dreams, several nocturnal awakenings, REM sleep behavior disorder (RBD), periodic leg movement (PLM), obstructive sleep apnea (OSA), sleep-related eating disorders and other parasomnias. Several clinical and polysomnographic aspects seem to differentiate RBD in patients with narcolepsy from idiopathic or secondary RBD, suggesting the involvement of specific neurophysiological, neurochemical and neuropathological substrates.

To evaluate interrater reliability for artifact correction in the context of semiautomated quantification of rapid eye movement (REM) sleep without atonia (RWA) in the mentalis and flexor digitorum superficialis (FDS) muscles. We included video-polysomnographies of 14 subjects with apnea-hypopnea index in REM sleep (AHIREM) < 15/h and 11 subjects with AHIREM ≥ 15/h. Eight subjects had isolated REM sleep behavior disorder. A validated algorithm (www.osg.be) automatically scored phasic and "any" EMG activity in the mentalis muscle, and phasic EMG activity in the FDS muscles. Four independent expert scorers performed artifact correction according to the SINBAR (Sleep Innsbruck Barcelona) recommendations. Interrater reliability for artifact correction was computed with B-statistics. The variability across scorers of four RWA indices (phasic mentalis, "any" mentalis, phasic FDS and SINBAR-i.e. "any" mentalis and/or phasic FDS-EMG activity indices) was computed. With Friedman tests, we compared B-statistics obtained for mentalis and FDS muscles, and the variability of the RWA indices. Influence of AHIREM and REM sleep behavior disorder (RBD) diagnosis on the RWA indices variability was evaluated with linear regressions. Interrater reliability for artifact correction was higher in the FDS than in the mentalis muscle (p < 0.001). Phasic FDS activity was minimally affected by artifacts. Accordingly, the phasic FDS EMG activity index had the lowest variability across scorers (p < 0.001). Variability across scorers of the RWA indices including the mentalis muscle increased with AHIREM and was independent from RBD diagnosis. Due to the consistently found low number of artifacts, phasic FDS activity is a reliable measure of RWA.

Our understanding of rapid eye movement (REM) sleep and how it is generated remains a topic of debate. Understanding REM sleep mechanisms is important because several sleep disorders result from disturbances in the neural circuits that control REM sleep and its characteristics. This review highlights recent work concerning how the central nervous system regulates REM sleep, and how the make up and breakdown of these REM sleep-generating circuits contribute to narcolepsy, REM sleep behaviour disorder and sleep apnea. A complex interaction between brainstem REM sleep core circuits and forebrain and hypothalamic structures is necessary to generate REM sleep. Cholinergic activation and GABAergic inhibition trigger the activation of subcoeruleus neurons, which form the core of the REM sleep circuit. Untimely activation of REM sleep circuits leads to cataplexy - involuntary muscle weakness or paralysis - a major symptom of narcolepsy. Degeneration of the REM circuit is associated with excessive muscle activation in REM sleep behaviour disorder. Inappropriate arousal from sleep during obstructive sleep apnea repeatedly disturbs the activity of sleep circuits, particularly the REM sleep circuit.

Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease