Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder

More than 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson's disease or Lewy body dementia. Symptom screens and metaiodobenzylguanine (MIBG)‐scintigraphy suggest autonomic abnormalities in idiopathic RBD, but it is unclear whether autonomic abnormalities can predict neurodegenerative disease. From a cohort of 99 patients with idiopathic RBD, we selected those who developed parkinsonism or dementia. These were matched by age, sex, and follow‐up duration to patients with RBD who remained disease free and to matched controls. From the polysomnographic trace performed at baseline evaluation, measures of beat‐to‐beat RR variability including time domains (mean RR‐interval and RR‐standard deviation) and frequency domains (low and high frequency components) were retrospectively assessed. Twenty‐one patients with idiopathic RBD who developed neurodegenerative disease were included (Parkinson's disease‐11, multiple system atrophy‐1, and dementia‐9). Age at PSG was 66 years, and 86% were male. PSG was performed on average 6.7 years before defined neurodegenerative disease. Comparing all patients with idiopathic RBD to controls, there were significant reductions in RR‐standard deviation (24.6 ± 2.2 ms vs. 35.2 ± 3.5 ms, P = 0.006), very low frequency components (238.6 ± 99.6 ms² vs. 840.1 ± 188.3 ms², P < 0.001), and low frequency components (127.8 ± 26.3 ms² vs. 288.7 ± 66.2 ms², P = 0.032). However, despite clear differences between patients with idiopathic RBD and controls, there were no differences in any measure between those who did or did not develop disease. RR‐variability analysis demonstrates substantial autonomic dysfunction in idiopathic RBD. However, this dysfunction is identical in patients who will or will not develop defined neurodegenerative disease. This suggests that autonomic dysfunction is linked with RBD independent of associated Parkinson's disease or Lewy body dementia. © 2010 Movement Disorder Society     

REM sleep behavior disorder, hallucinations, and cognitive impairment in Parkinson's disease.

The objective of this study was to evaluate the relationship between REM sleep behavior disorder (RBD), hallucinations, and cognitive impairment in Parkinson's disease (PD). One hundred and ten PD patients, divided into three groups (without RBD or hallucinations; with RBD but no hallucinations; with RBD and hallucinations), were submitted to neuropsychological evaluation. The group without RBD and hallucinations showed normal neuropsychological tests when compared to normal controls. The group with hallucinations was characterized by a more severe cognitive impairment affecting both short- and long-term memory, logical abilities, and frontal functions, while the RBD-only group presented frontal impairment. The hypothesis that RBD in PD can be considered a risk factor not only of the hallucinations but also of more severe and diffuse cognitive abnormalities needs to be strengthened through a longitudinal evaluation.     

Prospective memory in idiopathic REM sleep behavior disorder with or without mild cognitive impairment: A preliminary study

Objective: The ability to execute delayed intentions, known as prospective memory (PM), is crucial to everyday living. PM failures are reported in mild cognitive impairment (MCI) and Parkinson’s disease, however, no study to date has investigated PM functioning in individuals at high risk of developing these conditions, precisely those diagnosed with idiopathic REM sleep behavior disorder (iRBD). We aimed to assess PM in iRBD according to patients’ cognitive status and to determine the underlying nature of their difficulties. Method: Fifty-eight participants, including 20 healthy controls (HC) and 38 polysomnographic-confirmed iRBD patients with (iRBD-MCI = 13) or without (iRBD-nMCI = 25) MCI participated in this study. Following a neuropsychological assessment, PM was evaluated using a self-administered questionnaire (PRMQ), a simple clinical measure (envelope test), and a laboratory cue salience task. Results: No significant group differences were noted on the PRMQ and envelope test. On the PM laboratory task, non-parametric analyses revealed better detection accuracy in HC than both iRBD groups for all high and low salient cues. While iRBD-nMCI and iRBD-MCI patients performed similarly on the high salient condition, the latter showed significant difficulty in detecting low salient cues. Multiple regression analyses revealed executive dysfunction as the best predictor to significantly account for differences in the low salient condition in iRBD. Conclusion: PM difficulties in iRBD are most important in patients with MCI (vs without MCI) and may be attributed to a gradual alteration in executive mechanisms. PM impairment could act as a promising indicator of early cognitive dysfunction in iRBD.     

Olfactory deficit in idiopathic rapid eye movements sleep behavior disorder

INTRODUCTION: REM sleep behavior disorder (RBD) is a parasomnia characterized by a loss of atonia and an increased phasic muscle activity during REM sleep. Idiopathic RBD frequently herald an alpha-synucleinopathy, including such as Parkinson's disease (PD) and dementia with Lewy Body (DLB). Pathological changes in the anterior olfactory nucleus and olfactory loss occur very early in the course of PD and DLB. The aim of the study was to assess olfactory function in a large group of idiopathic RBD patients. METHODS: Fifty-four consecutive polysomnographically-confirmed iRBD patients (44 men, 10 women; mean age: 69.2+/-8.3 years; mean Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score: 4.9+/-4.3) and 54 age and gender-matched control subjects underwent the Brief University of Pennsylvania Smell Identification Test (B-SIT). RESULTS: A marked olfactory impairment was observed in the RBD group (mean B-SIT score: 7.1+/-2.5 versus 9.4+/-1.8; p < 0.0001), with 33 (61.1%) RBD patients versus 9 (16.6%) controls showing abnormal olfactory function (p < 0.0001). No correlation was found between the degree of olfactory loss and either duration of RBD symptoms or UPDRS-III score. Deficit in recognize paint thinner odorant showed the highest positive predictive value (0.95) for identifying idiopathic RBD. CONCLUSIONS: The olfactory deficit found in most idiopathic RBD patients shares similarities with that described in PD and may be a sign of a widespread neurodegenerative process. Its detection may help in identifying subjects at higher risk of developing an alpha-synucleinopathy-mediated neurodegeneration.     

Electroencephalogram slowing in rapid eye movement sleep behavior disorder is associated with mild cognitive impairment

Background

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a well-documented risk factor for synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB). Moreover, approximately 50% of iRBD patients have mild cognitive impairment (MCI). The purpose of our study was to investigate waking electroencephalogram (EEG) abnormalities specific to iRBD patients with MCI.

Methods

Forty-two polysomnographically confirmed iRBD patients, including 23 iRBD [+]MCI patients 19 patients without MCI (iRBD [−]MCI), and 37 healthy subjects participated in the study. All participants underwent a complete neuropsychologic assessment for MCI diagnosis and a waking quantitative EEG recording.

Results

iRBD [+]MCI patients had a higher slow-to-fast frequency ratio than iRBD [−]MCI patients and controls in the parietal, temporal, and occipital regions. iRBD [+]MCI patients also had higher relative θ power in the parietal, temporal, and occipital regions and lower relative α power in the occipital region compared to iRBD [−]MCI patients and controls. Moreover, iRBD [+]MCI patients had higher relative θ power in the frontal and central areas and lower relative β power in the central, parietal, and temporal regions compared to controls. The dominant occipital frequency also was slower in iRBD [+]MCI patients compared to controls. No between-group differences were observed between iRBD [−]MCI patients and controls.

Conclusion

In iRBD patients, only those with concomitant MCI showed waking EEG slowing in the posterior cortical regions, providing a potential marker for an increased risk for developing DLB or PD.     

The Montreal Cognitive Assessment: A screening tool for mild cognitive impairment in REM sleep behavior disorder

Mild cognitive impairment (MCI) is a frequent feature in idiopathic REM sleep behavior disorder (RBD), a sleep disturbance that can be a preclinical stage of Parkinson's disease or Lewy body dementia. We evaluated the sensitivity and specificity of two brief screening tools, the Montreal Cognitive Assessment (MoCA) and the Mini‐Mental State Examination (MMSE), in detecting MCI in idiopathic RBD. Thirty‐eight idiopathic RBD patients underwent a comprehensive neuropsychological assessment, including the MoCA and the MMSE. Receiver operating characteristic curves were created for the MoCA and the MMSE to assess their ability to identify MCI in idiopathic RBD patients, with neuropsychological assessment as the gold standard. For the MoCA, a normality cutoff of 26 yielded the best balance between sensitivity (76%) and specificity (85%) with a correct classification of 79%. For the MMSE, the optimal normality cutoff was 30, with a sensitivity of 84% and a specificity of 54% and a correct classification of 74%. The MoCA is superior to the MMSE in detecting MCI in idiopathic RBD patients, showing good sensitivity and very good specificity. © 2010 Movement Disorder Society     

The fate of patients with REM sleep behavior disorder and mild cognitive impairment

ObjectiveTo investigate clinical and dopaminergic pre-synaptic brain imaging characteristics of subjects with idiopathic rapid eye movement (REM) behavior disorder (iRBD) and mild cognitive impairment (MCI), and to evaluate the combined predictive value of risk factors for short-term conversion to synucleinopathy.MethodIn sum, 44 polysomnography (PSG)-confirmed iRBD patients (68.5 ± 7.2 years; 38 males) underwent ¹²³I-FP-CIT-SPECT, comprehensive neuropsychological evaluation, clinical examination and clinical follow-up every six months (30.6 ± 21.5 months). Step-wise logistic regression was applied to identify those features discriminating iRBD patients with (iRBD-MCI; n = 14) and without MCI (normal cognition [NC], iRBD-NC; n = 30). The risk of neurodegeneration was estimated with Kaplan–Meier analysis. Predictors of phenoconversion were assessed with Cox proportional-hazards analysis, adjusting for age, gender and education. A generalized linear model (GLM) was applied to define the best combination of risk factors predicting conversion at follow-up.ResultsAt baseline, patients with iRBD-MCI showed reduced striatal dopamine transporter (DAT) specific to non-displaceable binding ratio (SBR) and more constipation compared with iRBD-NC patients (p < 0.0001). During the follow-up, 10 patients (22.7%) develop an overt synucleinopathy. GLM analysis showed that patients with orthostatic hypotension, non-motor experiences of daily living, reduced putaminal DAT-SPECT SBR, and cognitive impairment in verbal memory/visuoconstruction abilities were at higher risk of phenoconversion (Hazard Ratio [HR] 26.05; Sensitivity 90%; Specificity 100%; Accuracy 97.73%; Positive Predictive Value 100%; Negative Predictive Value 97.14%).ConclusionsiRBD-MCI patients showed a more severe dopaminergic neuroimaging and clinical phenotype. Combining clinical and neuroimaging markers allowed to achieve excellent ability in identifying iRBD patients at high risk of developing a synucleinopathy within about three years from diagnosis.     

Follow-up study of cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder

Background: Cardiac ¹²³I‐metaiodobenzylguanidine (¹²³I‐MIBG) uptake in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is markedly reduced, as in Parkinson’s disease (PD). Methods: We performed ¹²³I‐MIBG scintigrams on patients with iRBD and PD. After the initial ¹²³I‐MIBG scintigram, we retested subjects after a mean of 2.8 years. Results: The delayed heart‐to‐mediastinum (H/M) ratio of cardiac ¹²³I‐MIBG uptake was not significantly reduced between the first and second study in either group (P = 0.050, P = 0.091, respectively) . Follow‐up imaging revealed a mean decline of 4.21 ± 9.06% or 6.40 ± 19.02% in the delayed H/M ratio in those with iRBD or PD, respectively. Conclusions: The ¹²³I‐MIBG uptake findings might indicate progression early in the course of iRBD or PD, but the progression is heterogeneous and independent of development of motor symptoms.     

Idiopathic REM sleep behavior disorder in the transition to degenerative disease

Idiopathic REM sleep behavior disorder (RBD) predicts Parkinson's disease (PD) and dementia. However, the nature of the disease that emerges from RBD has not been fully characterized. Since 2004, we have been conducting a prospective study of idiopathic RBD patients, providing an opportunity to directly observe patients as they transitioned to a defined neurodegenerative syndrome. Patients with idiopathic RBD underwent an extensive annual evaluation of motor function, olfaction, color vision, autonomic function, cognition and psychiatric symptoms. Neurodegenerative disease was defined according to standard criteria. We compared these measures in patients who had developed PD to those with dementia, all within the first year of developing disease. Of 67 patients, 6 developed PD and eleven developed dementia. Except for cognitive functioning, all tests of olfaction, color vision, autonomic function, depression, and quantitative measures of motor speed were similar in patients with PD and dementia. Of dementia patients, seven met criteria for probable Lewy body dementia (LBD) and four for Alzheimer's disease (or, possible LBD). In all probable LBD cases, the diagnosis was made because of parkinsonism, with no patient experiencing hallucinations or fluctuations. Patients with “Alzheimer's disease” seemed to have LBD, as they demonstrated typical LBD cognitive profiles on neuropsychological testing and were indistinguishable from LBD patients in ancillary measures. Therefore, among RBD patients with new‐onset LBD, hallucinations or fluctuations are absent, suggesting that RBD is a reliable early sign of LBD. The indistinguishability of dementia and PD in all ancillary measures suggests a single unitary “RBD‐then‐neurodegeneration” process, the clinical presentation of which depends upon selective neuronal vulnerability. © 2009 Movement Disorder Society     

Regional cerebral blood flow changes in patients with idiopathic REM sleep behavior disorder

Background: Recent studies have shown an association between rapid eye movement sleep behavior disorder (RBD) and neurodegenerative disorders, especially alpha‐synucleinopathies. Objective: We investigated regional cerebral blood flow (rCBF) changes using single photon emission computed tomography (SPECT) in patients with idiopathic RBD (iRBD), to determine functional brain alterations associated with the disorder. Methods: The SPECT data of 24 patients with iRBD were compared with those of 18 age‐matched normal controls using statistical parametric mapping 2. Results: We found decreased rCBF in the parietooccipital lobe (precuneus), limbic lobe, and cerebellar hemispheres in patients with iRBD, which is commonly seen in patients with Lewy body disease (Parkinson’s disease and dementia with Lewy bodies) or multiple system atrophy. Conclusion: Our SPECT study suggests that iRBD can be a presymptomatic stage of alpha‐synucleinopathies.     

A predictive model of neurodegeneration in idiopathic REM-sleep behavior disorder

ObjectiveTo investigate whether Parkinson's disease (PD) and dementia are competing risks in subjects with idiopathic rapid-eye-movement sleep behavior disorder (RBD).MethodsThe number of incidental PD cases observed in 11 longitudinal RBD studies was compared with the corresponding expected number as estimated by a simple mathematical model based on population parameters for PD age-of-onset.ResultsThe expected number of incidental PD cases exceeded observed PD cases (p-value < 0.001) but was in agreement with the sum of observed PD cases and observed mild cognitive impairment/dementia cases (p-value = 0.34). Sensitivity analyses confirmed the results.ConclusionIn the RBD population, PD and dementia cases are competing risks, suggesting that alpha-synuclein pathology occurs simultaneously in substantia nigra and neocortex. This observation has implications for the design and analysis of trials of neuroprotection.     

The prospective memory of patients with idiopathic REM sleep behavior disorder

BackgroundIdiopathic rapid eye movement sleep behavior disorder (iRBD) likely represents the prodromal stage of synucleinopathy. The present study was to investigate if there was prospective memory (PM) impairment and the relationship between different PM tasks and traditional cognitive tests in patients with iRBD.MethodsA total of 28 patients with iRBD, 25 with Parkinson's disease (PD) and 21 healthy controls were included. The Cambridge Prospective Memory Test (CAMPROMPT) was used to measure the PM including time-based (TBPM) and event-based PM (EBPM). Standard cognitive tests were administered to all participants.ResultsEBPM scores were lower only in patients with iRBD, while the obvious PM abnormalities were found in patients with PD. The patients with iRBD and PD performed worse on delayed recall of the Rey Auditory Verbal Learning Test (RAVLT) and copy of the Rey–Osterrieth complex figure (ROCF). The EBPM correlated with attention, executive function, and immediate memory besides working memory in patients with iRBD. The PM tasks involved in more memory functions in PD patients.ConclusionsThe patients with iRBD were impaired on both episodic memory and EBPM tasks that correlated with attention, executive function, and immediate memory. The PM abnormality was an early cognitive change in iRBD to which more attention should be paid more attention.     

Evaluation of brain iron content in idiopathic REM sleep behavior disorder using quantitative magnetic resonance imaging

BackgroundNeuroimaging studies in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) show similar structural and functional changes to alpha-synucleinopathies, including PD. Until now, there have been few attempts to characterize brain iron deposition in iRBD. The aim of this study was to investigate brain iron content in patients with iRBD using quantitative magnetic resonance imaging (MRI).Methods3-T MRI was performed in 15 patients with iRBD and 20 age-matched healthy control subjects. In order to evaluate the iron-related neurodegenerative changes, we assessed volume and transverse relaxation rate (R2*) simultaneously. We used both region-based and voxel-based analysis.ResultsNo significant differences in R2* values were found between iRBD groups and healthy control subjects. There were no areas of significantly reduced or increased gray matter and white matter volume in the iRBD group. Instead, lateral ventricle volumes measured automatically by FreeSurfer were significantly larger in patients with iRBD than in healthy controls (P < 0.05).ConclusionThe present study suggests that iron-related R2* values may not be an imaging biomarker for neurodegeneration in iRBD.     

47例REM睡眠行为障碍分析

目的 分析REM睡眠行为障碍的临床表现,探讨其病因、发病机制和治疗方法 .方法 回顾性分析47例REM睡眠行为障碍患者的病历资料.结果 47例患者均为中、老年人,均在熟睡过程中突然出现表现多样的行为障碍,多导睡眠图均为REM睡眠期出现肌弛缓现象消失而伴随肌电活动;病因为5例为帕金森病,3例为酒精戒断,1例为脑外伤,2例多系统萎缩,4例为药物滥用,32例为原发性;治疗应用氯硝西泮,或/和卡马西平、左旋多巴,所有患者有效.结论 REM睡眠行为障碍病因复杂、临床表现多样,经过合理药物、心理治疗,可以取得理想的治疗效果.     

Circadian rhythms of melatonin and peripheral clock gene expression in idiopathic REM sleep behavior disorder

ObjectiveTo evaluate changes in the expression of clock genes and melatonin levels in patients with idiopathic REM sleep behavior disorder (RBD) as a potential early stage of synucleinopathies.MethodsWe assessed the rhythmicity of circadian clock genes using real time-quantitative polymerase chain reaction and 24-h blood melatonin profiles using radio-immunoassay in 10 RBD patients and nine age-matched controls.ResultsThe RBD patients did not show circadian rhythmicity for clock genes Per2, Bmal1, and Nr1d1 but the rhythmicity of Per 1 remained, and the amplitude of Per3 was diminished. The 24-h melatonin rhythm did not differ between RBD patients and healthy control subjects. Melatonin profile in RBD patients was delayed by 2 h compared to controls, the habitual sleep phases were phase delayed by about 1 h, however no phase shift occurred in any of the clock genes studied. The control group had stable acrophases of melatonin rhythms of approximately 5 h whereas the RBD patients had a more dispersed range over 11 h.ConclusionsOur results suggest that RBD could be associated with altered expression of clock genes and delayed melatonin secretion. Thus, we argue that circadian system dysregulation could play a role in RBD.     

Systematic video-analysis of motor events during REM sleep in idiopathic REM sleep behavior disorder,follow-up and DAT-SPECT

Abnormal motor manifestations in REM sleep are the most visible feature of idiopathic REM sleep behavior disorder (iRBD), which precedes the overt alpha-synucleinopathy. The aim of this study was to perform a systematic visual analysis of the motor events (ME) captured during video-polysomnography, and clarify their relation to the disease severity.Thirty-four iRBD patients (5 women, 29 men; age 67.7 ± 7.2) with a mean follow-up duration 2.9 ± 1.1 years. and 33 controls (10 women, 23 men; age 61.5 ± 8.2) were examined. The ME captured during REM sleep were classified into four categories, previously defined by Frauscher et al. according to clinical severity: minor/simple jerks, major, complex and violent.An average frequency of 110.8 ± 75.2 ME per hour were identified in iRBD, 7.5 ± 11.6 in the controls (p < 0.001). Of these ME, 68.4% were classified as minor/simple jerks, 9.3% as major, 21.7% as complex and 0.7% as violent. The ME frequency was negatively associated with tracer binding on dopamine transporter single-photon emission computed tomography (DAT-SPECT); the association was stronger for caudate nucleus compared to putamen. During follow-up seven patients (24.1%) phenoconverted, yielding a yearly phenoconversion rate 8.3%. Violent ME were associated with increased hazard ratio for phenoconversion in frequency (p = 0.012) and total duration (p = 0.007).Patients with higher amounts of violent ME had a greater risk of phenoconversion; therefore, their role as a predictor should be considered. Additionally, ME were associated with nigrostriatal degeneration, according to DAT-SPECT. These findings indicate that the degree of the clinical severity of motor manifestations in iRBD reflects the severity of the disease.     

快速动眼睡眠行为障碍症10例报告

目的 介绍快速眼动(REM)睡眠行为障碍症(RBD)的临床表现，探讨其原因和可能的发病机制。方法 对由多导睡眠图确诊的10例RBD患者进行回顾性分析。结果 10例患者发病年龄均为中老年人，男性9例，表现睡梦中出现粗暴动作、喊叫和其他行为异常，其中4例为帕金森病患者，2例多系统萎缩，1例脑外伤，3例原因不明；睡前服用氯硝安定可控制发作。全部多导睡眠图(PSG)均为REM睡眠期肌弛缓现象消失而伴随肌电活动。结论 对睡眠中出现的异常行为特别是粗暴动作者．应考虑本病的可能，PSG有助确诊并与癫痫鉴别，氯硝安定治疗有效?     

Melatonin therapy for REM sleep behavior disorder.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia with clinical symptoms that include punching, kicking, yelling and leaping out of bed in sleep. Polysomnographic (PSG) finding showed REM sleep without muscle atonia. Clonazepam is generally used for treating RBD symptoms but melatonin was reported to be effective so we reconfirmed the effect of melatonin on RBD patients in the present study. We used melatonin (3-9 mg/day) which could ameliorate problem sleep behaviors remarkably, as well as %tonic activity in PSG variables. In the present study, melatonin was reconfirmed to be effective in RBD symptoms, especially for patients with low melatonin secretion, while its mechanism was not clearly known in the present study.