REM sleep behaviour disorder

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.

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.

Seven tesla MRI of the substantia nigra in patients with rapid eye movement sleep behavior 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.

Parkinsonism, as a gradually progressive disorder, has a prodromal interval during which neurodegeneration has begun but cardinal manifestations have not fully developed. A systematic direct assessment of this interval has never been performed. Since patients with idiopathic REM sleep behaviour disorder are at very high risk of parkinsonism, they provide a unique opportunity to observe directly the development of parkinsonism. Patients with idiopathic REM sleep behaviour disorder in an ongoing cohort study were evaluated annually with several quantitative motor measures, including the Unified Parkinson's Disease Rating Scale, Purdue Pegboard, alternate-tap test and timed up-and-go. Patients who developed parkinsonism were identified from this cohort and matched according to age to normal controls. Their results on motor testing from the preceding years were plotted, and then assessed with regression analysis, to determine when markers first deviated from normal values. Sensitivity and specificity of quantitative motor markers for diagnosing prodromal parkinsonism were assessed. Of 78 patients, 20 developed parkinsonism. On regression analysis, the Unified Parkinson's Disease Rating Scale first intersected normal values at an estimated 4.5 years before diagnosis. Voice and face akinesia intersected earliest (estimated prodromal interval = 9.8 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years) and limb bradykinesia (4.2 years). Quantitative motor tests intersected normal values at longer prodromal intervals than subjective examination (Purdue Pegboard = 8.6 years, alternate-tap = 8.2, timed up-and-go = 6.3). Using Purdue Pegboard and the alternate-tap test, parkinsonism could be detected with 71-82% sensitivity and specificity 3 years before diagnosis, whereas a Unified Parkinson's Disease Rating Scale score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before diagnosis. Removal of action tremor scores improved sensitivity to 94% and specificity to 97% at 2 years before diagnosis (cut-off >3). Although distinction between conditions was often difficult, prodromal dementia with Lewy bodies appeared to have a slower progression than Parkinson's disease (prodromal interval = 6.0 versus 3.8 years). Using a cut-off of Unified Parkinson's Disease Rating Scale >3 (excluding action tremor), 25% of patients with 'still-idiopathic' REM sleep behaviour disorder demonstrated evidence of possible prodromal parkinsonism. Therefore, using direct assessment of motor examination before parkinsonism in a REM sleep behaviour disorder, we have estimated a prodromal interval of ∼4.5 years on the Unified Parkinson's Disease Rating Scale; other quantitative markers may detect parkinsonism earlier. Simple quantitative motor measures may be capable of reliably detecting parkinsonism, even before a clinical diagnosis can be made by experienced movement disorders neurologists.

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.

Background:Rapid eye movement (REM) sleep behavior disorder (RBD) and obstructive sleep apnea (OSA) are the most common sleep disorders in Parkinson's disease (PD). The aim of this study was to identify whether RBD could alleviate OSA severity in PD patients and its effect on cognitive impairment.Methods:From February 2014 to May 2017, we recruited 174 PD patients from the Second Affiliated Hospital of Soochow University, all of whom underwent polysomnography (PSG). We collected clinical data, PSG results, and compared information between patients with and without RBD or OSA by analysis of covariance. We also investigated the effect of these sleep disorders on cognitive impairment using linear regression.Results:We grouped participants as follows: PD only (n = 53), PD + OSA (n = 29), PD + RBD (n = 61), and PD + RBD + OSA (n = 31). Minimum oxygen saturation (SaO2) during whole sleep and in REM sleep was higher in PD + RBD + OSA patients than that in PD + OSA patients. PD + RBD patients had worse Mini-Mental Status Examination and Montreal Cognitive Assessment (MoCA) scores than those in the PD group (P < 0.001), especially in visuospatial/executive, attention, and memory functions. The PD + OSA group performed worse than the PD group in the delayed recall domain. After adjusting for age, sex, body mass index, education, disease severity, and other sleep disorders, MoCA was negatively associated with OSA (β = −0.736, P = 0.043) and RBD (β = −2.575,P < 0.001). The severity of RBD (tonic/phasic electromyography activity) and OSA (apnea-hypopnea index/oxygen desaturation index/minimum SaO2) were also associated with MoCA. The adjusted β values of RBD-related parameters were higher than that for OSA.Conclusions:We found that RBD alleviated OSA severity; however, RBD and OSA together exacerbated PD cognitive impairment. Further studies are needed to evaluate whether OSA treatment can improve cognition in PD.

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.

Neurophysiological assessment of REM sleep behaviour disorder

The presence of REM Behavior Disorder (RBD) has been shown to predict later development of Parkinsonism, and several questionnaire approaches [1–3] have been devised to collect spouse/caregiver reported data on such dream enactment behavior. The University of Michigan RBD Questionnaire (UMRBDQ) was developed a number of years ago [1] and has seen only sporadic use. The scale is composed of seven items. Each item is scored on a proportional basis (range: 0.0 – 1.0) and a mean item score is computed, which constitutes the patient's total score. We report here data suggesting very high internal consistency of this short scale, its utility in differentiating the conditions across the synucleinopathic spectrum, and its sensitivity/specificity in distinguishing synucleinopathic conditions versus neurologically normal subjects. Caregivers or spouses of 72 patients [55 idiopathic Parkinson's disease (IPD); 12 Dementia with Lewy Bodies (DLB); 5 idiopathic RBD (IRBD)] completed the UMRBDQ and were rated on Unified Parkinson's Disease Rating Scale (UPDRS) (motor subscale) by a movement disorders specialist. Controls (n = 15) were derived from a community-based movement disorders screening day; all were administered the UPDRS. Among controls, 7 self-completed the UMBDQ, but mean values did not differ from 8 with spouse-completion. All protocols were IRB-approved. Demographics and clinical information are shown in Table 1 and indicate that both IPD and DLB patients had significantly greater motor impairment relative to controls and IRBD. None of the controls and a very small number of IRBD received dopaminergic medications. Mean (standard deviation) levo-dopa and pergolide dose equivalence for the IPD patients was 320.1 (332.5) mg and 1.24 (1.56) mg, respectively. Mean (SD) UMRBDQ score was .34 (.25). Cronbach's alpha for the seven items on the UMRBDQ was .858, suggesting that all were highly reliable with each other, i.e., dream enactment could be encompassed as a single trait. Reported dream enactment varied across group (F = 149.66, df 3, 83, p < .001) (see Figure 1) with controls being significantly lower than IPD, DLB and IRBD and IRBD significantly higher than IPD. UMRBDQ score was associated with the patient's own reported experience of vivid dreaming (rho = .39, p < .001) and nightmares (rho = .35, p = .001) collected from a separate questionnaire given to the patients [4, 5]. After controlling for demographics, diagnosis, UPDRS score, years since diagnosis, levo-dopa equivalence and dopamine agonist equivalence, 24% of remaining variance (p < .001) in the UMRBDQ could be accounted for by the patient's own reports of vivid dreaming and nightmares. Use of a UMRBDQ cutpoint score of ≥ .30 resulted in relatively high specificity (80.0%) for differentiating controls from each of the three groups. Sensitivities were 49.1% for IPD (p = .044), 83.3% for DLB (p = .001) and 100% for IRBD (p = .002). Figure 1 Bar graph showing mean and standard deviation for UMRBDQ score for each of the 4 groups. Horizontal lines reflect statistically significant pairwise differences between groups. *** p<.001; ** p < .005 Table 1 Demographic and clinical data across groups (A-D). Mean and standard deviations are shown. Significant (p < .05) pairwise comparisons are indicated under inferential statistics. Corrected p values were used when Levene's Test for Inequality of ... Assessment of dream enactment by history is a challenging task in the exam setting and may be enhanced by polysomnography [6–9], but standardized questionnaires such as the UMRBDQ are a quick way to appreciate this important and potentially prognostic sign. The high inter-item consistency suggests that perhaps even a single question might be of value. In situations where a caregiver/spouse may not be available, the patient's own report of their experiences may also represent an important corroborating source of data.

It is established that one of the best predictors of a future diagnosis of Parkinson's disease is a current diagnosis of rapid eye movement behaviour disorder (RBD). In such patients, this provides a unique opportunity to study brain physiology and behavioural motor features of RBD that may precede early-stage Parkinson's disease. Based on prior work in early-stage Parkinson's disease, we aim to determine if the function of corticostriatal and cerebellar regions are impaired in RBD using task-based functional MRI and if structural changes can be detected within the caudate, putamen and substantia nigra in RBD using free-water imaging. To assess motor function, we measured performance on the Purdue Pegboard Test, which is affected in patients with RBD and Parkinson's disease. A cohort of 24 RBD, 39 early-stage Parkinson's disease and 25 controls were investigated. All participants were imaged at 3 Telsa. Individuals performed a unimanual grip force task during functional imaging. Participants also completed scales to assess cognition, sleep and motor symptoms. We found decreased functional activity in both RBD and Parkinson's disease within the motor cortex, caudate, putamen and thalamus compared with controls. There was elevated free-water-corrected fractional anisotropy in the putamen in RBD and Parkinson's disease and elevated free-water in the putamen and posterior substantia nigra in Parkinson's disease compared with controls. Participants with RBD and Parkinson's disease performed significantly worse on all tasks of the Purdue Pegboard Test compared with controls. The both hands task of the Purdue Pegboard Test was most sensitive in distinguishing between groups. A subgroup analysis of early-stage RBD (<2 years diagnosis) confirmed similar findings as those in the larger RBD group. These findings provide new evidence that the putamen is affected in early-stage RBD using both functional and free-water imaging. We also found evidence that the striatum, thalamus and motor cortex have reduced functional activity in early-stage RBD and Parkinson's disease. While the substantia nigra shows elevated free-water in Parkinson's disease, we did not observe this effect in early-stage RBD. These findings point to the corticostriatal and thalamocortical circuits being impaired in RBD patients.

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

BackgroundPatients with idiopathic rapid eye movement behavior disorder (IRBD) have been suggested to exhibit altered cerebral perfusion and abnormal cerebral blood flow, which imply a possibility of cerebral autoregulation (CA) impairment. We aimed to investigate the dynamic CA (dCA) in patients with IRBD during wakefulness and to explore the correlations between dCA parameters and clinical measurements.MethodsWe assessed the dCA capability of 30 patients with IRBD and 36 sex- and age-matched healthy controls by using transcranial Doppler and finger plethysmography. CA function was evaluated by transfer function analysis based on spontaneous oscillation of cerebral blood flow and arterial blood pressure. Transfer function parameters (phase difference and gain) were used to quantify the CA.ResultsNo significant differences were observed between the right and left middle cerebral artery dCA parameters (phase difference and gain) of both groups. Patients with IRBD had significantly lower phase difference than the healthy controls, indicating their impaired CA capability. Besides, the value of gain in patients with IRBD was higher than the healthy controls, but the difference did not reach statistical level.ConclusionsCA function is compromised in patients with IRBD during wakefulness, which might be an intermediate link between IRBD and neurological symptoms.

REM sleep behavior disorder (RBD) is a parasomnia characterized by motor activity during sleep with dream mentation. Aggressiveness has been considered a peculiar feature of dreams associated with RBD, despite normal score in aggressiveness scales during wakefulness. We aimed to measure daytime aggressiveness and analyze dream contents in a population of patients with Parkinson disease (PD) with and without RBD. This is a single-center prospective observational study; it concerns the description of the clinical features of a medical disorder in a case series. The study was performed in the Department of Neurosciences of the Catholic University in Rome, Italy. Three groups of subjects were enrolled: patients with PD plus RBD, patients with PD without RBD, and healthy controls. The diagnosis of RBD was determined clinically and confirmed by means of overnight, laboratory-based video-polysomnography. For the evaluation of diurnal aggressiveness, the Buss-Perry Aggression Questionnaire (BPAQ) was used. The content of dreams was evaluated by means of the methods of Hall and Van De Castle. Patients with PD without RBD displayed higher levels of anger, and verbal and physical aggressiveness than patients with PD and RBD and controls. Patients with PD and RBD and controls did not differ in hostility. It can be hypothesized that a noradrenergic impairment at the level of the locus coeruleus could, at the same time, explain the presence of RBD, as well as the reduction of diurnal aggressiveness. This finding also suggests a role for REM sleep in regulating homeostasis of emotional brain function.

REM sleep behavior disorder: From dreams to neurodegeneration