REM Sleep Behavior Disorder as a Prodromal Synucleinopathy: Updates on Clinical and Laboratory Biomarkers, and Implications for Neuroprotective Trials.

In this issue of Internal Medicine, Chen et al. (1) documented the case of a 30-year-old man who presented with an 11-month history of abnormal nocturnal behavior related to vivid dreams. Brain magnetic resonance images revealed lesions involving the pontomesencephalic junction and the upper pons, and polysomnography (PSG) findings confirmed a diagnosis of rapid eye movement (REM) sleep behavior disorder (RBD). A brainstem biopsy revealed diffuse large B-cell lymphoma. Notably, chemotherapy for lymphoma resulted in the disappearance of the lesions and reduced the frequency of RBD symptoms in the patient. RBD is a parasomnia characterized by dream-enacting behaviors and a loss of normal muscle atonia during REM sleep. The estimated prevalence of this disorder was reported to be 0.5% in a survey of approximately 4,900 subjects between the ages of 15 and 100 years (2). The dreams of patients with RBD usually include unpleasant and aggressive content, and the patient’s abnormal behavior is typically aggressive and violent, often resulting in serious injury to the patient or their bed partner (3). Based on the International Classification of Sleep Disorders, second edition (4), the use of PSG is essential for diagnosing RBD. The following criteria should be met: A, the presence of REM sleep without atonia, including excessive amounts of sustained or intermittent elevations of submental electromyographic (EMG) tone or excessive phasic submental or limb EMG twitching; B, abnormal REM sleep behavior based on the patient’s history and/or PSG findings; C, the absence of electroencephalogram (EEG) epileptiform activity during REM sleep; and D, the sleep disturbance is not better explained by medication use or another sleep, medical, neurological, mental or substance use disorder. In almost 90% of patients with RBD, the administration of clonazepam (0.5 to 1.5 mg) at bedtime is effective. Additionally, melatonin, pramipexole and Yi-Gan San alone or in conjunction with clonazepam may effectively treat RBD. The anatomic substrate for REM sleep control in humans includes a “REM-off” region, which consists of the ventrolateral part of the periaqueductal gray matter and lateral pontine tegmentum, and a “REM-on” region, which consists of the precoeruleus, sublaterodorsal nucleus, extended portion of the ventrolateral preoptic nucleus, locus coeruleus, laterodorsal tegmental nucleus, pedunculopontine nucleus and raphe nucleus (5). Motor behaviors in patients with RBD may reflect brainstem impairment, while the frightening dreams of RBD may reflect amygdala dysfunction (6). In humans, RBD can be caused secondarily by brain lesions including the brainstem nuclei, which regulate REM sleep, and the supratentorial structures, including the posterior hypothalamus, anterior thalamus and limbic system, which connect with the brainstem nuclei. Brain tumors, demyelinating plaque, strokes and limbic encephalitis have been reported to cause RBD (6), and narcolepsy is associated with RBD. Several medications can cause RBD, including antidepressants such as tricyclics, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (3). In 1996, Schenck et al. (7) first reported the delayed emergence of Parkinsonian disorders in 38% of 29 older men initially diagnosed with idiopathic RBD, with a mean interval of 3.7 years after RBD diagnosis and a mean interval of 12.7 years after RBD onset. After an additional 7year follow-up, the conversion rate from idiopathic RBD to neurodegenerative diseases increased to 65%. Additionally, Iranzo et al. (8) reported that 45% of 44 patients with idiopathic RBD developed neurodegenerative diseases (n=9, Parkinson’s disease (PD); n=6, dementia with Lewy bodies (DLB); n=4, mild cognitive impairment; n=1, multiple system atrophy) at a mean follow-up of 5.1 years and a mean of 11.5 years after RBD onset. Postuma et al. (9) reported that 28% of 93 patients with idiopathic RBD developed neurodegenerative diseases (n=14, PD; n=7, DLB; n=4, Al-

Cholinergic and striatal dopaminergic dysfunction using pet as a risk marker for developing a neurodegenerative disease in patients with idiopathic rapid eye movement sleep behaviour disorder

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder

Our objective was to examine whether rapid eye movement (REM) sleep behavior disorder occurs in disproportionally greater frequency in multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), collectively known as the synucleinopathies, compared to other nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester for parkinsonism and/or cognitive impairment. The frequency of suspected and polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects with the synucleinopathies MSA, PD, or DLB was compared to the frequency among subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for parkinsonism and/or cognitive impairment. The frequency of probable RBD among patients with PD and DLB was compared to the frequency among patients with AD and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined for possible RBD and a neurodegenerative disorder. In study 1, patients with MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%, p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2, patients with PD and DLB were more likely to have probable RBD compared to those with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients who had been questioned about possible RBD, 10 were clinically diagnosed with RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in nine, and MSA in one. Of the other 13 cases, 12 did not have a history suggesting RBD, and the one case who did had normal electromyographic atonia during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a synucleinopathy. The positive predictive values for RBD indicating a synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively. Clinically suspected and PSG-proven RBD occurs with disproportionally greater frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In the setting of degenerative dementia and/or parkinsonism, we hypothesize that RBD is a manifestation of an evolving synucleinopathy.

The association of REM sleep without atonia (RSWA) as well as REM sleep behavior disorder (RBD) with the intake of selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) is well established. Our study objective was to determine the prevalence of RSWA and RBD among a group of sleep center patients taking SSRI and SNRI. A retrospective chart review was done at our tertiary sleep center, and 10,746 consecutive records from October 1, 2007, through October 31, 2013, were searched for SSRI and SNRI names using the Sleep Cataloguer Software. The search resulted in 1,444 records, which were then reviewed for keywords of RSWA and RBD. The AASM scoring criteria were used to determine RSWA. Reports of 41 patients with known narcolepsy or α-synucleinopathies were excluded. The remaining records were mined for age, sex, presence of obstructive sleep apnea (OSA), type of antidepressant (SSRI or SNRI), and diagnosis for which antidepressant was prescribed. We used logistic regression analysis to adjust for age, OSA, and sex. Of the 1,444 participants on antidepressants, 176 (12.2%) had RSWA (all confirmed by the investigators) compared to 226 of the entire sleep lab population of 10,746 (2.1%), risk ratio (95% CI) 9.978 (8.149, 12.22). Seven of the 176 patients on antidepressants had RBD (0.48%) compared to 108 of 10,746 (1%), p = 0.005. SSRI and SNRI are associated with a higher prevalence of RSWA but not of RBD. This is independent of medication type.

Rapid eye movement sleep behavior disorder and the link to alpha-synucleinopathies

Chapter 49 - Rapid Eye Movement Sleep Behavior Disorder: Pathological Neural Circuits and Association with Parkinson's Disease

The main objective of this study was to study rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disorders in dementia with Lewy bodies (DLB). Consecutive patients with DLB and mild dementia severity were recruited irrespective of sleep complaints. Patients underwent clinical interview, assessment of sleep scales, and video-polysomnography (V-PSG). RBD was diagnosed with V-PSG based on electromyographic and audiovisual analysis. Thirty-five patients (65.7% men; mean age 77.7 ± 6.1 years) were evaluated. Poor sleep quality (54.3%), hypersomnia (37.1%), snoring (60%), and abnormal nocturnal behaviors (77.1%) were reported. Sleep-wake architecture abnormalities occurred in 75% patients and consisted of occipital slowing on awake electroencephalography (EEG; 34.4%), the absence of sleep spindles and K complexes (12.9%), slow frequency sleep spindles (12.9%), delta activity in REM sleep (19.2%), and REM sleep without atonia (44%). Three patients showed hallucinatory-like behaviors and 10 patients showed abnormal behaviors during arousals mimicking RBD. RBD was diagnosed in 50% of those patients in whom sufficient REM sleep was attained. Of these, 72.7% were not aware of displaying dream-enacting behaviors and in 63.7% RBD preceded the onset of cognitive impairment. For RBD diagnosis, the sensitivity of Mayo Sleep Questionnaire was 50%, specificity was 66.7%, positive predictive value was 83.3%, and negative predictive value was 28%. False-positive RBD cases according to clinical history had hallucinatory-like behaviors, severe obstructive sleep apnea, and prominent periodic limb movements in sleep. Occipital EEG frequency while awake and rate of electromyographic activity in REM sleep were negatively correlated, suggesting a common subcortical origin. In DLB, RBD and sleep-wake disorders are common, heterogeneous, and complex, challenging their identification without performing V-PSG.

REM Sleep Problems Predict Parkinson's, Lewy Body Dementia

Rapid Eye Movement Sleep Behavior Disorder During Childhood.

Rapid eye movement (REM) sleep behavior disorder is an important risk factor for Parkinson's disease and dementia with Lewy bodies. Approximately 50% of patients with REM sleep behavior disorder have mild cognitive impairment. Our objective was to investigate brain perfusion changes associated with mild cognitive impairment in REM sleep behavior disorder. Twenty patients with REM sleep behavior disorder, including 10 patients with mild cognitive impairment and 10 patients without mild cognitive impairment, and 20 healthy controls underwent a complete neuropsychological assessment and single-photon emission computerized tomography using (99mc) Tc-Ethylene Cysteinate Dimer. Compared with controls, both REM sleep behavior disorder groups had hypoperfusion in the frontal regions. In addition, patients with REM sleep behavior disorder and mild cognitive impairment showed cortical hypoperfusion in the occipital, temporal, and parietal regions compared with controls and patients with REM sleep behavior disorder without mild cognitive impairment. Both REM sleep behavior disorder groups had hyperperfusion in the right hippocampus and parahippocampal gyri. However, patients with REM sleep behavior disorder and mild cognitive impairment showed more pronounced anomalies in the right hippocampus and had increased perfusion in the putamen and the left paracentral gyrus. This study showed specific patterns of posterior cortical hypoperfusion and hyperperfusion in some brain areas in patients with REM sleep behavior disorder and mild cognitive impairment, similar to those found in Parkinson's disease dementia and dementia with Lewy bodies. This suggests the presence of an identifiable neuroimaging marker of synucleinopathy in REM sleep behavior disorder with mild cognitive impairment. © 2012 Movement Disorder Society.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by elaborate behaviours during REM sleep usually associated with action-filled dreams. Typical behaviours are screaming, grasping, punching, kicking and occasionally jumping out of bed, which are potentially harmful for the patient and their bed partner. Polysomnographic (PSG) recording reveals a loss of atonia and an excessive phasic motor activity during REM sleep. RBD affects mainly men over 50 years and its prevalence in the general population is estimated around 0.5%. It may occur in acute or chronic forms. The latter may be isolated (idiopathic RBD), or associated with other neurological diseases (symptomatic RBD), especially with a group of neurodegenerative disease called alpha-synucleinopathies, which includes Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy. The idiopathic form accounts for up to 60% of the cases reported in the literature. Small clinical follow-up studies revealed that a proportion of these patients will eventually develop a parkinsonian syndrome and/or a DLB in the years following the RBD diagnosis, while some patients will remain idiopathic for decades. Recent studies found evidence of neural dysfunction during both wakefulness and sleep in iRBD, such as an impairment of the cortical activity, specific neuropsychological deficits, signs of autonomic dysfunction, deficit of colour discrimination, subtle abnormalities in quantitative measures of motor and gait speed and an olfactory impairment. The notion of "idiopathic" RBD is currently challenged and the use of a more conservative term of "cryptogenic" RBD has been suggested.

We describe demographic, clinical, laboratory and aetiological findings in 93 consecutive patients with rapid eye movement (REM) sleep behaviour disorder (RBD), which consists of excessive motor activity during dreaming in association with loss of skeletal muscle atonia of REM sleep. The patients were seen at the Mayo Sleep Disorders Center between January 1, 1991 and July 31, 1995. Eighty-one patients (87%) were male. The mean age of RBD onset was 60.9 years (range 36-84 years) and the mean age at presentation was 64.4 years (37-85 years). Thirty-two per cent of patients had injured themselves and 64% had assaulted their spouses. Subdural haematomas occurred in two patients. Dream content was altered and involved defence of the sleeper against attack in 87%. The frequency of nocturnal events decreased with time in seven untreated patients with neurodegenerative disease. MRI or CT head scans were performed in 56% of patients. Although four scans showed brainstem pathology, all of these patients had apparently unrelated neurodegenerative diseases known to be associated with RBD. Neurological disorders were present in 57% of patients; Parkinson's disease, dementia without parkinsonism and multiple system atrophy accounted for all but 14% of these. RBD developed before parkinsonism in 52% of the patients with Parkinson's disease. Five of the 14 patients with multiple system atrophy were female, and thus the strong male predominance in RBD is less evident in this condition. Psychiatric disorders, drug use or drug withdrawal were rarely causally related to RBD. Clonazepam treatment of RBD was completely or partially successful in 87% of the patients who used the drug. We conclude that RBD is a well-defined condition and that descriptions from different centres are fairly consistent. It is commonest in elderly males and may result in serious morbidity to patients and bed partners. There is a strong relationship to neurodegenerative disease, especially Parkinson's disease, multiple system atrophy and dementia, and neurologists should explore the possibility of RBD in patients with these conditions. RBD symptoms may be the first manifestations of these disorders and careful follow-up is needed. Neuroimaging is unlikely to reveal underlying disorders not suspected clinically. We confirm the effectiveness of clonazepam, but note that attention to the safety of the bed environment may be sufficient for patients with contraindications to the drug.

Objective To evaluate the sleep structure and cognitive function in Parkinson’s disease (PD) patients with rapid eye movement (REM) sleep behavior disorder (RBD)，and then explore the correlation between sleep structure and cognitive function in PD patients with RBD. Methods It was a cross-sectional study.Ninety-seven patients in our sleep center，including 39 PD patients with RBD and 21 age-and sex-matched idiopathic RBD (iRBD) patients (control group)，37 PD patients without RBD (control group)，underwent video-polysomnography to acquire sleep parameters. Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA) on the same day.A multiple linear regression model was used to find the score of cognition correlated with sleep structure. Results (1) The sleep efficiency，total sleep time，non-rapid eye movement (NREM) 2 and REM sleep time were all significantly decreased in PD patients with RBD than those in iRBD patients (60.9%±16.9% vs 77.8%±16.9%，(329.7±96.5) min vs (397.1±88.9) min，(127.6±67.6) min vs (188.0±94.7) min，(45.3±33.2) min vs (70.6±25.9) min，all P<0.05)，respectively.There were no significant differences of these above parameters compared to PD patients without RBD (61.3%±21.7%，(324.9±134.6) min，(132.6±65.6) min，(47.1±31.9) min).There was no statistical significance in sleep latency，REM-sleep latency，NREM1 time，the percentage of slow wave sleep，oxygen desaturation index，apnea hyponea index and periodic leg movement in sleep among three groups. (2) PD patients with RBD had the lowest MoCA scores.The score of visuospatial and executive function in PD patients with RBD was lower than that in iRBD (3.8±1.1 vs 4.4±0.7; F=3.426，P<0.05). (3) Multiple linear regression analysis showed that there was correlation between the score of visuospatial and executive functions and the course of RBD，sleep efficiency and NREM2 in PD patients with RBD. Conclusions The PD patients with RBD have the worst sleep efficiency and cognitive function，the shortest total sleep time，NREM2 and REM sleep time.The cognitive impairment may be correlated with the change of sleep structure. Key words: Parkinson’s disease; REM sleep behavior disorder; Polysomnography; Cognition

Objective: Rapid eye movement (REM) sleep behavior disorder (RBD) is a disease characterized by dream enacting behavior and is now commonly believed to be a harbinger to alpha-synucleinopathy diseases such as dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. The aim of this study was to explore the quasi-stable topological structure of the brain in RBD by analyzing resting-state electroencephalography (EEG) microstates.Methods: We enrolled 22 participants with RBD and 46 healthy controls (HCs) with age and gender-matched. After the resting-state EEG recordings were acquired, EEG microstate features were analyzed to assess the functional networks of all participants.Results: Significant differences in the brain topological structure and temporal characteristics of sub-second brain activity were identified between the RBD and HCs. The RBD group had a shorter average duration of microstate A and microstate D when compared with HCs, and microstate B contributed more, while microstate D contributed significantly less to the RBD group. Furthermore, the average duration and proportion of microstate D were negatively correlated with the RBD questionnaire Hong Kong (RBDQ-HK) score.Conclusion: The result of this study indicates that the microstate dynamics is disturbed in RBD, which might jeopardize the flexibility and adaptability of the brain. Microstates are potential biomarkers to explore the early electrophysiological abnormality of alpha-synucleinopathy diseases.