Idiopathic REM Sleep Behavior Disorder Patients Research Articles

0899 Use of Artificial Intelligence for Early Characterization of Patients with RBD/RWA

Abstract Introduction The prevalence of polysomnography (PSG) confirmed REM sleep behavior disorder (RBD) has been estimated at 0.68% of the general population, and that of probable RBD at 5.65%. Isolated RBD is considered a pre-clinical marker of neurodegeneration with strong predictive value. Large longitudinal cohort studies demonstrate 81–91% of idiopathic RBD patients, followed for ≥14-years, will develop a definite neurodegenerative disease or mild cognitive impairment. Furthermore, high prevalence of sleep apnea (SA) exists in patients with RBD/REM without atonia (RWA), which can confound analysis of EMG tone and arousal activity. We demonstrate predictive AI models for RBD/RWA in subjects with and without SA. Methods Patients with known RBD/RWA who underwent PSG were divided into sub-groups with (n=86, RBDSA) and without SA (n=19, RBDNSA). Patient demographics, PSG characteristics, and co-morbid conditions were reviewed. Random forest (RF) models of PSG indices and Deep Learning (DL) methods identified predictive characteristics of RBD/RWA, sensitivity and specificity for RBD/RWA detection were estimated, and feature importance analysis was performed. Results Subjects with RBDSA compared to RBDNSA demonstrated greater BMI, AHI, Arousals (ArI), and Periodic Limb Movements (PLMs). In a Parkinson’s disease subgroup (n=12, RBDPD) compared to non-Parkinson’s sub-group, sleep was more fragmented, showing higher WASO, ArI, and PLMs. RF modeling demonstrated sensitivity/specificity of 67%/96% for RBDNSA subjects, and 79%/52% for RBDSA. Feature importance analysis resulted in several top-features for RBDNSA: N3 time, TST, AHI, REM duration, and sleep latency, while different top-features were observed for RBDSA: ratio of leg events in REM vs. non-REM, TST, ratio of arousals in REM vs. non-REM, REM duration, and REM time. Conclusion AI approaches including RF models produced high specificity and moderate sensitivity for RBDNSA subjects. Observed specificity was lower for RBDSA patients. We hypothesize the performance difference attributable to similarity and additional complexity in sleep disturbance characteristics between RBD and SA. Broad implementation of AI methods show potential to expand early detection and diagnosis of RBD and associated neurodegenerative conditions through expanded analysis, and follow-up, including RWA spectrum patients that don’t meet clinical thresholds for diagnosable RBD. Support (if any) None

Brain Perfusion Single-Photon Emission Computed Tomography Using an Easy Z-Score Imaging System Predicts Progression to Neurodegenerative Dementia in Rapid Eye Movement Sleep Behavior Disorder

Introduction: Longitudinal studies have reported that patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) have an increased risk of developing synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies (DLB). Clinical trials of disease-modifying therapies for IRBD patients require suitable biomarkers that can predict the short-term onset of neurodegenerative dementia. Methods: We retrospectively examined if easy Z-score imaging system-specific volume-of-interest analysis (SVA) using brain perfusion single-photon emission computed tomography (SPECT) imaging or the cingulate island sign score can predict the short-term development of neurodegenerative dementia in 30 patients with IRBD. Results: Ten patients (33.3%) who exceeded the thresholds for three indicators (severity, extent, and ratio) were included in an SVA-positive group, while 20 (66.7%) were included in an SVA-negative group. Nine (30.0%) IRBD patients had phenoconversion, of which eight had DLB and one had Parkinson’s disease with dementia. In Kaplan-Meier analysis, patients in the SVA-positive group converted to neurodegenerative dementia in a significantly shorter period of time compared to patients in the SVA-negative group. Conclusions: These data suggest that SVA-positive IRBD patients have an increased short-term risk of developing neurodegenerative dementia.

Magnetic Resonance Parkinsonism Index Is Associated with REM Sleep Behavior Disorder in Parkinson's Disease.

We investigated the association between the Magnetic Resonance Parkinsonism Index (MRPI) and REM sleep behavior disorder (RBD). We included 226 de novo PD patients (82 PD-RBD and 144 PD-noRBD) and 19 idiopathic RBD patients. Furthermore, 3T T1-weighted MR images were used for automated brainstem calculations. MRPI values were higher in the PD-RBD (p = 0.004) compared to PD-noRBD patients. Moreover, MRPI proved to be a significant predictor of REM Behavior Disorder Screening Questionnaire scores in PD (β = 0.195, p = 0.007) and iRBD patients (β = 0.582, p = 0.003). MRPI can be used as an imaging marker of RBD in patients with de novo PD and iRBD.

Comprehensive Analysis of Brain Volume in REM Sleep Behavior Disorder with Mild Cognitive Impairment.

Rapid-eye-movement sleep behavior disorder (RBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. More than a third of RBD patients have mild cognitive impairment (MCI), but their specific structural brain alterations remain poorly understood. This study aimed to investigate the local deformation and volume of gray and white matter tissue underlying MCI in RBD. Fifty-two idiopathic RBD patients, including 17 with MCI (33%), underwent polysomnography, neuropsychological, neurological, and magnetic resonance imaging assessments. MCI diagnosis was based on a subjective complaint, cognitive impairment on the neuropsychological battery, and preserved daily functioning. Forty-one controls were also included. Deformation-based morphometry (DBM), voxel-based morphometry (VBM), and regional volume analyses of the corpus callosum and cholinergic basal forebrain were performed. Multiple regression models were also computed using anatomical, cognitive (composite z scores), and motor parameters. Globally, patients with MCI displayed a widespread pattern of local deformation and volume atrophy in the cortical (bilateral insula, cingulate cortex, precuneus, frontal, temporal and occipital regions, right angular gyrus, and mid-posterior segment of the corpus callosum) and subcortical (brainstem, corona radiata, basal ganglia, thalamus, amygdala, and right hippocampus) regions compared to patients without MCI (DBM) or controls (DBM and VBM). Moreover, brain deformation (DBM) in patients were associated with lower performance in attention and executive functions, visuospatial abilities, and higher motor symptoms severity. The present study identified novel brain structural alterations in RBD patients with MCI which correlated with poorer cognitive performance. These results are consistent with those reported in patients with synucleinopathies-related cognitive impairment.

Striatal dopamine transporter degeneration in right-handed REM sleep behavior disorder patients progresses faster in the left hemisphere

ObjectiveIn right-handed patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) or Parkinson's disease (PD), dopamine transporter (DAT) single-photon emission computed tomography (SPECT) shows a predominant nigrostriatal deficit in the left striatum. To confirm this hypothesis, we longitudinally investigated whether the nigrostriatal function is asymmetric in Japanese patients with IRBD. MethodsIn 91 polysomnography-confirmed IRBD patients, which included 87 right-handed IRBD patients who underwent 33 repeat DAT-SPECT scans, we retrospectively examined the striatal dopaminergic terminals in each hemisphere using DAT-SPECT. We calculated the values of interhemispheric laterality index for the right and left sides. ResultsThe proportion of IRBD patients with lower SBR in the striatum was different between the left (n = 60, 69.0%) and right (n = 27, 31.0%) hemispheres. In the repeat DAT-SPECT scan (n = 33), the rate of decline in the striatum was greater on the left than on the right side, and the proportion of patients with lower decline rates in the left striatum (n = 25, 73.5%) was greater than the that in the right striatum (n = 3, 8.8%). The proportion of lower SBR side at baseline did not predict the development of PD or DLB. ConclusionRight-handed IRBD patients have asymmetric nigrostriatal dopaminergic function, as evidenced by the faster estimated rate of decline for the left striatum than the right striatum. The left-right hemispheric striatal predominance of the nigrostriatal deficit in the right-handed prodromal PD or DLB patients represents a difference in the early pathological process of the disease.

The Significance of Rapid Eye Movement Sleep Behavior Disorder in Neurodegenerative Diseases: An Updated Review.

Rapid eye movement (REM) sleep behavior disorder (RBD), a parasomnia, after being diagnosed, can predict the emergence of an alpha-synuclein-associated neurodegenerative disease (NDD) in 20-45% and 92% of patients within 5 and 14 years, respectively. RBD is less common in tauopathies, and the studies to evaluate its association with polyglutamine diseases have been very few. To revisit our knowledge on the significance of RBD in the emergence of NDDs and to review the recent updates in the potential biomarkers, which can help predict the risk of phenconversion into NDDs in idiopathic RBD (iRBD) patients. We also aimed to look at the potential neuroprotective therapies that can potentially be used earlier in iRBD patients. We conducted a review of the papers, after selecting them from the PubMed database. After a thorough screening, 51 articles were chosen to be included in this review. The prospective studies showed that the risk of phenoconversion of iRBD into overt NDDs increased over the longer duration of follow up. Magnetic resonance imaging (MRI) findings, Electroencephalographic findings along with subtle motor signs, autonomic dysfunction, impaired olfaction, and color vision, among others, can be used to predict the onset of an NDD in iRBD. Phytocannabinoids showed a possible neuroprotective effect in animal studies. Considering how RBD is the antecedent of NDDs, there is a need for additional studies to better understand the utility of the aforementioned biomarkers and institute potential neuroprotective therapies early in the process.

Research progress in rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by abnormal dream acting behavior such as vocalization and twitching related to dream content during REM sleep. The diagnosis requires polysomnography demonstrating a loss of normal skeletal muscle atonia during REM sleep. Both idiopathic RBD and secondary RBD are highly related to synucleinopathy including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Almost all idiopathic RBD patients will develop synucleinopathy after a few years. Therefore, RBD may be an early marker in the progression of synucleinopathy.

Reduced dopamine transporter binding predicts early transition to Lewy body disease in Japanese patients with idiopathic rapid eye movement sleep behavior disorder

PurposeWe examined dopamine transporter (DAT) binding in Japanese patients with idiopathic rapid eye movement sleep behavior disorder (IRBD) as a biomarker for the development of Lewy body disease (LBD). Methods[123I]FP-CIT SPECT (DAT-SPECT) scans of 74 IRBD patients were compared to those from healthy Japanese subjects, and the predictive value for conversion to LBD during a 5-year follow-up was evaluated. ResultsBaseline DAT deficits (Z-score ≤ −2.5) were observed in 25 (33.8%) of the IRBD patients. During follow-up, 25 patients (33.8%) developed LBD [19 Parkinson's disease and 6 dementia with Lewy bodies], with a mean latency of 2.4 ± 1.6 years from imaging. The receiver operating characteristics curve revealed that the Z-score of baseline DAT binding in the striatum of abnormal DAT-SPECT patients who later developed LBD differed from those who remained disease-free. Kaplan-Meier survival analysis showed an increased risk of LBD in patients with a Z-score ≤ −2.5 for DAT binding in the striatum of abnormal DAT-SPECT patients compared to patients with a Z-score > −2.5. ConclusionsDAT-SPECT identifies IRBD patients at short-term risk for developing LBD. Decreased DAT binding in the striatum (Z-score ≤ −2.5) predicts development of LBD within 5 years, and may be useful in future disease-prevention trials in IRBD patients.

Gender differences in clinical findings and α-synucleiopathy-related markers in patients with idiopathic REM sleep behavior disorder

BackgroundRapid eye movement (REM) sleep behavior disorder (RBD) is a male-predominant parasomnia. Earlier clinical RBD patient studies showed gender differences of clinical symptoms and polysomnographic (PSG) findings. However, no previous investigated this issue by means of validated severity scales or by neuropsychological examination related to alpha-synucleinopathy. This study elucidates gender differences in clinical, physiological, and neuropsychological findings in Japanese idiopathic RBD (iRBD) patients. MethodsFrom 220 patients with complaint of sleep-related vocalization or behaviors who visited Yoyogi Sleep Disorder Center from June 2003 through December 2016, 43 female (68.7 ± 7.3 yr) and 141 male patients (66.7 ± 6.7 yr) diagnosed as having iRBD by video-polysomnography (v-PSG) were selected. All subjects answered the RBD questionnaire (RBDQ-JP) and underwent olfactory function test (Sniffin' Sticks test) and cognitive function test (MoCA-J). ResultsFemale iRBD patients had later first symptom-witnessed age (sleep-talking 63.2 ± 10.5 yr, behaviors 60.9 ± 8.6 yr) than male patients (sleep-talking 59.1 ± 8.8 yr, behaviors 64.7 ± 8.9 yr). No gender difference was found in age at diagnosis, clinical severity (RBDQ-JP), or olfactory or cognitive function. Regarding electromyogram (EMG) findings during REM sleep, phasic EMG activity was higher in female patients (22.3 ± 17.8% vs. 16.5 ± 16.1%), although no difference was found in tonic EMG activity. ConclusionsAlthough female iRBD patient symptoms were first recognized later than those of male patients, they showed elevated EMG activity during REM sleep and showed deteriorated olfactory and cognitive function similarly to male patients at the first medical consultation. Results suggest that disease progression in female RBD patients is equivalent to that in male patients.

Comparing the accuracy and neuroanatomical correlates of the UPSIT-40 and the Sniffin’ Sticks test in REM sleep behavior disorder

BackgroundOlfactory impairment increases the risk of developing neurodegenerative diseases in patients with idiopathic REM sleep behavior disorder (IRBD). Knowing the test properties of distinct olfactory measures could contribute to their selection for clinical or research purposes. ObjectiveTo compare the accuracy in distinguishing IRBD patients from controls with the University of Pennsylvania Smell Identification Test (UPSIT-40) and Sniffin' Sticks Extended test, and to assess the gray-matter volume correlates of these tests. MethodTwenty-one patients with IRBD and 27 healthy controls were assessed using both olfactory tests. Independent logistic regressions were computed with diagnosis as a dependent variable and olfactory measures as predictive variables. Receiver operating characteristic curves were computed for each olfactory subtest. Diagnostic accuracy for IRBD was calculated according to the resulting optimal cut-off score. Structural MRI data, acquired with a 3T scanner, were analyzed with voxel-based morphometry. ResultsPatients differed from controls in all olfactory measures. The Sniffin-Identification correctly classified 89.1% of cases; the UPSIT-40, 85.4%; the Sniffin-Discrimination, 82.6%; the Sniffin-Total, 81.8%; and the Sniffin-Threshold, 77.3%. Respective AUROC, optimal cut-off, sensitivity, and specificity for each test were: 0.902, ≤26, 85.7%, and 85.2% for the UPSIT-40; 0.884, ≤29, 89.5%, and 76.0% for the Sniffin-Total; 0.922, ≤11, 90.5%, and 88.0% for the Sniffin-Identification; 0.739, ≤4, 73.7%, and 76.0% for the Sniffin-Threshold; and 0.838, ≤11, 85.7%, and 76.0% for the Sniffin-Discrimination. UPSIT-40 scores correlated with gray-matter volumes in orbitofrontal regions in anosmic patients. ConclusionsUPSIT-40 and Sniffin' Identification showed similar discrimination accuracy, but only the UPSIT-40 showed structural correlates (p ≤ .05 FDR-corrected).

Glucocerebrosidase mutations and phenoconversion of REM sleep behavior disorder to parkinsonism and dementia

BackgroundMutations in the glucocerebrosidase (GBA) gene are strongly associated with REM sleep behavior disorder (RBD). It is unclear whether GBA mutations might affect clinical phenotype or rate of phenoconversion to parkinsonism or dementia. MethodsWe sequenced GBA in polysomnographic-proven idiopathic RBD (iRBD) patients. The effect of GBA mutations on clinical neurodegenerative markers and phenoconversion rate was assessed. ResultsOf 102 patients sequenced, 13 (13%) had GBA mutations and 89 did not. Aside from lower self-reported age of RBD onset in subjects with GBA mutations, no significant differences were observed in any clinical marker between patients with and without mutations. However, GBA mutations were associated with 3.2-fold higher phenoconversion rate from RBD to parkinsonism and/or dementia (95% CI = 1.4–7.3, p = 0.006). ConclusionAlthough GBA mutations do not appear to affect clinical neurodegenerative markers (and thus are not differentiable as an independent subtype of iRBD), they may accelerate the conversion of RBD to defined neurodegenerative synucleinopathy.

Cortical Gray Matter and Hippocampal Atrophy in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

Objective: In this study we investigate cortical and subcortical gray matter structure in patients with Idiopathic REM-sleep behavior disorder (IRBD), and their relation to cognitive performance.Methods: This study includes a sample of 20 patients with polysomnography-confirmed IRBD and 27 healthy controls that underwent neuropsychological and T1-weighted MRI assessment. FreeSurfer was used to estimate cortical thickness, subcortical volumetry (version 5.1), and hippocampal subfields segmentation (version 6.0). FIRST, FSL's model-based segmentation/registration tool was used for hippocampal shape analysis.Results: Compared with healthy subjects, IRBD patients showed impairment in facial recognition, verbal memory, processing speed, attention, and verbal naming. IRBD patients had cortical thinning in left superior parietal, post-central, and fusiform regions, as well as in right superior frontal and lateral occipital regions. Volumetric and shape analyses found right hippocampal atrophy in IRBD, specifically in posterior regions. Hippocampal subfields exploratory analysis identified significant differences in the right CA1, molecular layer, granule cell layer of dentate gyrus, and CA4 of this patients. No correlations were found between cognitive performance and brain atrophy.Conclusion: This work confirms the presence of posterior based cognitive dysfunction, as well as cortical and right hippocampal atrophy in IRBD patients.

Correlations between dopaminergic dysfunction and abnormal metabolic network activity in REM sleep behavior disorder

Striatal dopamine transporter (DAT) deficiency and abnormal expression of Parkinson's disease (PD)-related pattern (PDRP) have been observed in patients with idiopathic REM sleep behavior disorder (IRBD). This study aimed to investigate the correlations between these two measures with comparison to PD using a dual tracer imaging design. Age-matched 37 IRBD patients, 86 PD patients, and 15 control subjects underwent concurrent PET scans with 11C-CFT to quantify dopaminergic dysfunction and 18F-FDG to quantify PDRP expression. IRBD patients were divided into two subgroups: those with relatively normal (IRBD-RN) or abnormal (IRBD-AB) striatal DAT binding. Significantly decreased DAT binding and increased PDRP scores were present in all patient groups, except for IRBD-RN, relative to the controls. There was a significant effect of hemisphere and hemisphere × group interaction for DAT binding but not for PDRP expression. Significant correlations were observed between DAT binding and PDRP expression in the IRBD-AB and PD groups but not in the IRBD-RN group. IRBD patients present with an intermediate state in striatal DAT distribution and PDRP activity between PD and normal controls. The modest correlations between the two measures in both IRBD and PD suggest that differences in network activity cannot be fully explained by nigrostriatal dopaminergic denervation.

Glucocerebrosidase gene variants are accumulated in idiopathic REM sleep behavior disorder

IntroductionGlucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically-defined LBD. MethodsAll GBA coding exons from 69 polysomnography-confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method. ResultsSeven missense variants (E326K, L444P, A446T, A318G, R329C, T369M, N370S) were identified in eight (11.6%) IRBD patients and in one (1.2%) control (P = 0.026). After a mean follow-up of 8.9 ± 3.8 years from IRBD diagnosis, five subjects with GBA variants developed LBD (3 DLB and 2 PD) and three remained disease-free. The risk of developing a LBD was similar in IRBD subjects with GBA variants than in those without variants (log rank test, p = 0.935). ConclusionsIn IRBD, GBA variants are 1) more frequent when compared to controls, 2) associated with impending PD and DLB but 3) not indicative of a short-term risk for LBD after IRBD diagnosis. IRBD patients carrying GBA variants could be studied with disease-modifying interventions aiming to restore the GBA metabolic pathway.

Neuropsychiatric Symptoms in Patients with Idiopathic Rapid Eye Movement Sleep Behavior Disorder

Background and Objective Idiopathic rapid eye movement sleep behavior disorder (IRBD) is a strong predictor of the development of synucleinopathies, including Parkinson’s disease. Neuropsychiatric symptoms are common in patients with Parkinson’s disease but have not been properly evaluated in IRBD. We used the Symptom Checklist-90-Revision (SCL-90-R) to evaluate the symptom profile of patients with drug-naïve IRBD. Methods Consecutive drug-naïve patients with video-polysomnography-confirmed IRBD that visited Kyung Hee University Hospital at Gangdong sleep clinic January 2009–November 2016 were reviewed. Age- and sex-matched healthy volunteers served as controls. Questionnaires evaluating sleep [Pittsburgh sleep quality index (PSQI) and insomnia severity index (ISI)] and depression [beck depression inventory-II (BDI-II)] were conducted with the SCL-90-R in IRBD patients and controls. Results Twenty patients with IRBD and 20 age- and sex-matched controls were analyzed. In IRBD patients, the mean age was 59.5, 55% were male, and the mean disease duration was 55.1 months. PSQI scores (5.7 ± 2.2 vs. 3.2 ± 1.4, p < 0.0001) and ISI scores (11.2 ± 8.7 vs. 4.1 ± 3.4, p < 0.0001) were higher in patients with IRBD than in the controls. Three IRBD patients (15%) had abnormal SCL-90-R T-scores over 70. The T-scores for phobic anxiety (p=0.009), interpersonal sensitivity (p = 0.011), psychoticism (p = 0.013), hostility (p = 0.014), anxiety (p = 0.020), and depression (p = 0.049) were higher in the patients. After adjusting for age, BDI-II scores were positively correlated with RBD disease duration (r = 0.484, p = 0.042) in IRBD patients. Conclusions The results of our study demonstrate that neuropsychiatric distress is more severe in patients with IRBD with no comorbidities than in otherwise healthy individuals. Key words: REM sleep behavior disorder, Neuropsychiatric symptom, SCL-90-R.

REM Sleep Behavior Disorder and Other Sleep Disturbances in Non-Alzheimer Dementias

The study aimed to review recent updates of our understanding of REM sleep behavior disorder (RBD) and other sleep disorders in non-Alzheimer’s disease (AD) dementias. Numerous recent discoveries have provided insight into the role of RBD and sleep in patients with non-AD dementias. Imaging modalities such as DaTscan and cerebral blood flow may be useful for monitoring phenoconversion in idiopathic RBD patients to Parkinson’s disease (PD) or dementia with Lewy bodies (DLB). Patients with isolated REM sleep without atonia have non-motor signs of neurodegenerative disease. Colon mucosal biopsies in iRBD patients have shown presence of α-synuclein aggregates. Recent genetic models of RBD and neuroimaging have furthered evidence for the locus subcoeruleus/sublateral dorsal nucleus as the center for the generation and maintenance of REM muscle atonia. Circadian rhythm disturbances likely play a large role in nighttime insomnia, daytime sleepiness, autonomic symptoms, motor variations, and hallucinations in PD and DLB. Early onset stridor in patients with multiple system atrophy (MSA) portends a worse prognosis than late onset stridor, and treatment of stridor is associated with survival. Our ability to predict phenoconversion in idiopathic RBD is improving and will be highly important as “high risk” phenoconverters are identified for enrollment in neuroprotective clinical trials. Treatments of RBD improve but do not fully eliminate DEB; therefore, the risk for sleep-related injury remains a concern even among seemingly well-treated patients. Excessive daytime sleepiness (EDS) secondary to neuropathology, sedating medications, sleep disordered breathing (SDB), restless legs syndrome (RLS), and circadian rhythm alterations are common in the non-AD dementias, leading to significant caregiver burden and worsening of cognition. Addressing primary sleep disorders is the mainstay of treatment for EDS. RLS is a frequent co-morbidity in non-AD dementias. Initial management of RLS includes ensuring serum a ferritin level of >75 μg/L and therapy with gabapentin encarbil (which is less likely to cause augmentation than dopamine agonists). All MSA patients should be evaluated for the presence of nocturnal stridor, which should be treated if present. Therapies targeting the circadian system are often an underutilized therapeutic avenue in the management of sleep, motor, autonomic, and psychiatric symptoms in PD and DLB patients.

Muscle Activity During Sleep in Human Subjects, Rats, and Mice: Towards Translational Models of REM Sleep Without Atonia.

Rapid-eye-movement (REM) sleep without atonia (RSWA) is a marker of REM sleep behavior disorder (RBD) and is common in narcolepsy. Available techniques for electromyogram (EMG) analysis are species-specific, limiting translational research on RSWA. We developed an automated technique based on distributions of normalized EMG values (DNE) to overcome this limitation. With DNE, we tested whether the control of neck and tibialis anterior (TA) muscles during sleep in wild-type rats and mice validly models the control of submentalis (chin) and TA muscles in healthy humans. We then applied DNE to REM sleep recordings of patients with idiopathic RBD and of mouse models of narcolepsy, testing for a common DNE signature of RSWA. Retrospective analysis of sleep recordings from 20 idiopathic RBD patients, 34 control subjects, 8 wild-type rats, 21 orexin-neuron deficient mice, 8 orexin knock-out mice, and 22 wild-type mice. Neck EMG of rats and mice and human chin EMG progressively decreased from wakefulness to non-REM sleep and REM sleep, whereas the effects of sleep on TA EMG differed between rats, mice, and humans. DNE discriminated idiopathic RBD patients from controls based on higher median values of normalized chin EMG during REM sleep. The same parameter, computed on neck muscle EMG, discriminated narcoleptic mice from wild-type mice. These results support the application of DNE in translational research on RSWA. Increased median values of normalized EMG of chin (humans) and neck (rats and mice) muscles may be a signature of RSWA in different species and pathological conditions.

Is increased spinal nociception another hallmark for Parkinson's disease?

Augmented spinal nociception during the "off" phase has been observed early in Parkinson's disease further increasing with disease duration. To find out whether increased spinal nociception represents a premotor feature, experimental pain sensitivity was assessed in idiopathic REM-sleep behavior disorder (IRBD) patients with or without signs of a neurodegenerative disorder compared to early Parkinson's disease (ePD) patients and healthy controls (HC). Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in 14 IRBD, 15 ePD patients in the medication-defined "off" state and 27 HC in an explorative cohort study. No significant differences between IRBD and HC were found with regard to spinal nociception (NFR) and experimental pain sensitivity. However, IRBD patient with anosmia and/or abnormal DaTSCAN tended to increased experimental pain sensitivity. In contrast, early PD patients exhibited increased NFR responses compared to HC, and a tendency for increased spinal nociception compared to IRBD patients. Increased spinal nociception may represent an early but not a premotor, non-motor feature of PD. Whether increased pain sensitivity already presents a premotor feature should be assessed in further studies.

Detecting the Cognitive Prodrome of Dementia with Lewy Bodies: A Prospective Study of REM Sleep Behavior Disorder.

Long-term studies in REM sleep behavior disorder (RBD) have shown a high rate of conversion into synucleinopathies. We aimed to prospectively follow-up a large cohort of RBD patients to identify cognitive markers for early detection of prodromal dementia. Seventy-six idiopathic RBD patients underwent polysomnography and a complete neuropsychological and neurological assessment and were then followed for a mean of 3.6 years. Cognitive characteristics at baseline were compared between patients who remained disease-free and those who developed a synucleinopathy, and between those who developed dementia first and those who developed parkinsonism first. Receiver operating characteristic curves were calculated to assess the diagnostic value of cognitive tests for detecting prodromal dementia. At follow-up, 34 patients developed a neurodegenerative disease: 19 parkinsonism-first and 15 dementia-first. RBD patients who first developed dementia were impaired at baseline in all cognitive domains (attention/executive functions, learning/memory, and visuospatial) compared to patients who developed parkinsonism. Moreover, 93% of patients who first developed dementia had mild cognitive impairment at baseline compared to 42% of patients who developed parkinsonism. RBD patients who developed parkinsonism first were similar at baseline to disease-free RBD patients on cognition. In dementia-first patients, two cognitive tests assessing attention and executive functions (Stroop Color Word Test and Trail Making Test) reliably predicted dementia (area under the curve ≥0.85) compared to parkinsonism-first patients or controls. This study shows that cognitive tests assessing attention and executive functions strongly predict conversion to dementia in RBD patients, and may be useful endpoints to determine the effectiveness of interventions to prevent cognitive deterioration in RBD patients.

REM sleep behavior disorder was associated with Parkinson's disease: a community-based study.

BackgroundOur study was aimed to validate a modified RBD (REM sleep behavior disorder) single question (RBD1Q-C), study the prevalence of probable RBD (pRBD) in a rural community based on RBD1Q-C and investigate the association between pRBD and Parkinson’s disease (PD).MethodsThe validation study of RBD1Q-C included 32 Chinese participants (14 idiopathic RBD patients and 18 controls). All participants underwent a polysomnogram (PSG). We then conducted a door-to-door survey to estimate the prevalence of pRBD assessed by RBD1Q-C, and its association with PD among 19614 residents who lived in Malu community of Shanghai, China.ResultsRBD1Q-C demonstrated a high sensitivity of 100 %, a moderate specificity of 55.6 %. The agreement between RBD1Q-C and PSG-based RBD diagnosis was good (k = 0.552). PPV of the RBD1Q-C was 63.6 % and NPV was 100 %. The prevalence of pRBD in Malu community was 4.9 %. In people over 50 years old, presence of pRBD was significantly associated with increased risk of having PD (odds ratio = 2.61, 95 % CI: 1.56–4.39).ConclusionRBD1Q-C was shown to be a useful screening tool. Based on the RBD1Q-C, we found that pRBD was not rare in Chinese rural population and associated with odds of PD, calling for more attention from patients, caregivers and physicians.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0640-1) contains supplementary material, which is available to authorized users.