Plasma immune markers in an idiopathic REM sleep behavior disorder cohort

IntroductionIncreasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear.MethodsWe collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years.ResultsTNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01–1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47–11.81).ConclusionsOur study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.     

Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder

IntroductionCognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains.MethodsParkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ ≥ 6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates.ResultsThe baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (β = −0.34, 95%CI −0.54, −0.13, p < 0.001), Symbol Digit Modalities Test (β = −0.69, 95%CI −1.3, −0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (β = −0.21, 95%CI −0.41, −0.013, p = 0.037).ConclusionsPossible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.     

Significance of hyposmia in isolated REM sleep behavior disorder

Journal of Neurology - To determine if hyposmia in isolated REM sleep behavior disorder (IRBD) predicts short-term conversion to any α-synucleinopathy and declines with time. Olfaction was...     

The role of pedunculopontine nucleus in isolated REM sleep behavior disorder and REM sleep without atonia

IntroductionThe aim of this study was to analyze the functions of pedunculopontine nucleus (PPN) in isolated REM sleep behavior disorder (iRBD) and REM sleep without atonia (RSWA) to investigate the role of PPN in dream-enacting motor behaviors in RBD. We evaluated the activity of PPN through the prepulse modulation (PPM) together with other brainstem reflexes to investigate the differences in changes at brainstem.MethodsWe included nine patients with isolated RSWA and 10 patients with iRBD. For diagnosis, all patients underwent polysomnography. None of the patients had parkinsonism or dementia. We also included 17 healthy participants with similar age and sex. Blink reflex (BR), PPM of BR, recovery excitability of BR, and auditory startle reflex (ASR) were recorded in all participants.ResultsThere was a prepulse inhibition deficit in iRBD and RSWA groups compared to healthy subjects. The BR-R2 recovery at 200 ms interval was also higher in patients with iRBD and RSWA. In ASR recordings, the response probabilities were higher in the RBD group compared to RSWA and control groups.ConclusionThe PPM was abnormal in both iRBD and RSWA whereas ASR was enhanced in iRBD. We suggest that there are certain similarities and differences in the pathophysiologies of iRBD and RSWA.     

REM sleep behavior disorder and REM sleep without atonia in Parkinson's disease

OBJECTIVE: To determine the frequency of REM sleep behavior disorder (RBD) among patients with PD using both history and polysomnography (PSG) recordings and to further study REM sleep muscle atonia in PD. BACKGROUND: The reported occurrence of RBD in PD varies from 15 to 47%. However, no study has estimated the frequency of RBD using PSG recordings or analyzed in detail the characteristics of REM sleep muscle atonia in a large group of unselected patients with PD. METHODS: Consecutive patients with PD (n = 33) and healthy control subjects (n = 16) were studied. Each subject underwent a structured clinical interview and PSG recording. REM sleep was scored using a method that allows the scoring of REM sleep without atonia. RESULTS: One third of patients with PD met the diagnostic criteria of RBD based on PSG recordings. Only one half of these cases would have been detected by history. Nineteen (58%) of 33 patients with PD but only 1 of 16 control subjects had REM sleep without atonia. Of these 19 patients with PD, 8 (42%) did not present with behavioral manifestations of RBD, and their cases may represent preclinical forms of RBD associated with PD. Moreover, the percentage of time spent with muscle atonia during REM sleep was lower among patients with PD than among healthy control subjects (60.1% vs 93.2%; p = 0.003). CONCLUSIONS: RBD and REM sleep without atonia are frequent in PD as shown by PSG recordings.     

Loss of REM sleep features across nighttime in REM sleep behavior disorder

ObjectivesMelatonin is a chronobiotic treatment which also alleviates rapid eye movement (REM) sleep behavior disorder (RBD). Because the mechanisms of this benefit are unclear, we evaluated the clock-dependent REM sleep characteristics in patients with RBD, whether idiopathic (iRBD) or associated with Parkinson's Disease (PD), and we compared findings with PD patients without RBD and with healthy subjects.MethodsAn overnight videopolysomnography was performed in ten iRBD patients, ten PD patients with RBD (PD + RBD+), ten PD patients without RBD (PD + RBD−), and ten controls. The rapid eye movement frequency per minute (REMs index), the tonic and phasic electromyographic (EMG) activity of the levator menti muscle, and the duration of each REM sleep episode were evaluated. A generalized linear model was applied in each group, with the REM sleep cycle (four ordinal levels) as the dependent variable, as a function of REMs index, REM sleep duration, and tonic and phasic EMG activity.ResultsFrom the first to the fourth sleep cycle, REM sleep duration progressively increased in controls only, REMs index increased in subjects without RBD but not in patients with RBD, whether idiopathic or associated with PD, whereas tonic and phasic EMG activity did not change.ConclusionsPatients with PD or iRBD lost the physiologic nocturnal increase in REM sleep duration, and patients with RBD (either with or without PD) lost the increase of REMs frequency across the night, suggesting an alteration in the circadian system in RBD. This supports the hypothesis of a direct effect of melatonin on RBD symptoms by its chronobiotic activity.     

Treatment outcomes in REM sleep behavior disorder

ObjectiveREM sleep behavior disorder (RBD) is usually characterized by potentially injurious dream enactment behaviors (DEB). RBD treatment aims to reduce DEBs and prevent injury, but outcomes require further elucidation. We surveyed RBD patients to describe longitudinal treatment outcomes with melatonin and clonazepam.MethodsWe surveyed and reviewed records of consecutive RBD patients seen at Mayo Clinic between 2008–2010 to describe RBD-related injury frequency–severity as well as RBD visual analog scale (VAS) ratings, medication dosage, and side effects. Statistical analyses were performed with appropriate non-parametric matched pairs tests before and after treatment, and with comparative group analyses for continuous and categorical variables between treatment groups. The primary outcome variables were RBD VAS ratings and injury frequency.ResultsForty-five (84.9%) of 53 respondent surveys were analyzed. Mean age was 65.8 years and 35 (77.8%) patients were men. Neurodegenerative disorders were seen in 24 (53%) patients and 25 (56%) received antidepressants. Twenty-five patients received melatonin, 18 received clonazepam, and two received both as initial treatment. Before treatment, 27 patients (60%) reported an RBD associated injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS ratings were significantly improved following both treatments (p_m = 0.0001, p_c = 0.0005). Melatonin-treated patients reported significantly reduced injuries (p_m = 0.001, p_c = 0.06) and fewer adverse effects (p = 0.07). Mean durations of treatment were no different between groups (for clonazepam 53.9 ± 29.5 months, and for melatonin 27.4 ± 24 months, p = 0.13) and there were no differences in treatment retention, with 28% of melatonin and 22% of clonazepam-treated patients discontinuing treatment (p = 0.43).ConclusionsMelatonin and clonazepam were each reported to reduce RBD behaviors and injuries and appeared comparably effective in our naturalistic practice experience. Melatonin-treated patients reported less frequent adverse effects than those treated with clonazepam. More effective treatments that would eliminate injury potential and evidence-based treatment outcomes from prospective clinical trials for RBD are needed.     

Pathophysiologic mechanisms in REM sleep behavior disorder

REM sleep behavior disorder (RBD) is a fascinating experiment in nature predicted by animal studies in 1964. A defining feature of REM sleep is active paralysis of all somatic musculature (sparing the diaphragm to permit respiration). RBD is characterized by the absence of REM atonia, permitting the appearance of dream-enacting behaviors. These oneiric behaviors may be violent or injurious. RBD typically affects men over the age of 50 years. Longitudinal follow-up has shown that the majority of individuals with RBD will eventually develop additional signs and symptoms of a number of neurodegenerative disorders, most notably one of the synucleinopathies (Parkinson’s disease, dementia with Lewy body disease, multiple system atrophy, or pure autonomic failure), often after a prolonged interval lasting more than 10 years. RBD is also a common manifestation of narcolepsy. RBD may be induced by medications, especially the tricyclic antidepressants and serotonin-specific reuptake inhibitors. In most cases, clonazepam is a highly effective treatment.     

Magnetic resonance findings in REM sleep behavior disorder

Rapid eye movement (REM) sleep behavior disorder is characterized by bizarre acts during nocturnal sleep that may lead to physical injuries. Dream content suggests that motor overactivity is an attempted dream enactment and polygraphic studies reveal REM stage without atonia, an alteration of REM sleep generation that facilitates excessive motor activity. In 6 patients with REM sleep behavior disorder. MRI of the brain showed multifocal signal intensity lesions suggestive of lacunar infarcts in periventricular regions (5 patients) and in dorsal pontomesencephalic areas (3 patients). REM sleep behavior disorder may be the result of injury to the midrostral tegmentum nuclei, the tegmentoreticular tracts, or both. This condition is easily controlled with clonazepam.     

Midbrain hyperechogenicity in idiopathic REM sleep behavior disorder

Recent studies have reported an increased risk to develop Parkinson's disease (PD) in patients with idiopathic RBD (iRBD). Midbrain hyperechogenicity is a common transcranial sonography (TCS) finding in PD and has been suggested as a PD risk‐marker in nonparkinsonian subjects. The objective of this study is to assess midbrain echogenicity by TCS in patients with iRBD and compare the findings with the healthy controls. TCS was performed in 55 iRBD patients and in 165 age and sex‐matched controls. The area of echogenicity in the SN region in the iRBD group was significantly increased compared with the control group (P < 0.001). About 19 (37.3%) of patients with iRBD were found to have SN hyperechogenicity when compared with 16 (10.7%) of the controls (P < 0.001). This is the first case‐control study assessing midbrain echogenicity in a large iRBD cohort compared to age‐ and sex‐matched healthy individuals. The finding of an increased prevalence of hyperechogenicity in a subgroup of individuals with a priori increased risk for PD supports the potential role of hyperechogenicity as a risk marker for PD. The prospective follow‐up of this iRBD cohort is needed to establish if those with midbrain hyperechogenicity will go on to develop clinically defined PD or not. © 2009 Movement Disorder Society     

Olfactory dysfunction in idiopathic REM sleep behavior disorder

BackgroundOlfactory dysfunction is frequently observed in patients with idiopathic REM sleep behavior disorder (iRBD) such as Parkinson’s disease or dementia with Lewy bodies.MethodsOlfactory function tests using Sniffin’ Sticks and Odor Stick Identification Test for Japanese (OSIT-J) were performed in 73 consecutive middle-aged (range, 50–69 years) patients with iRBD, 33 consecutive older-aged (71–82 years) patients with iRBD, and 28 control subjects (55–70 years).ResultsOdor identification was more frequently impaired than odor threshold or discrimination among the iRBD group and allowed better discrimination between the middle-aged iRBD group and age-adjusted control subjects. The area under the curve for threshold, discrimination, identification, TDI score and OSIT-J score determined from receiver operating characteristic curves were 0.831 (0.753–0.909), 0.761 (0.666–0.855), 0.938 (0.894–0.982), 0.939 (0.897–0.981), and 0.965 (0.931–0.999), respectively. Discrimination and identification scores were significantly lower in the older-aged iRBD group than in the middle-aged iRBD group. A significant correlation was observed between the identification score on Sniffin’ Sticks and OSIT-J score (r = 0.5910, P < 0.0001, n = 106, Spearman’s rank).ConclusionAnosmia/hyposmia may be a feature of iRBD. Olfactory dysfunction in iRBD is a consistent, widespread central nervous abnormality of different olfactory modalities with different cognitive complexity.     

Impaired decision-making in idiopathic REM sleep behavior disorder

BackgroundPatients with REM sleep behavior disorder (RBD) frequently develop Parkinson’s disease (PD), which can impair decision-making ability. This study was undertaken to investigate decision-making ability and its relation to olfactory function in patients with idiopathic RBD.MethodsThis study used the Iowa Gambling Task (IGT) and the Sniffin’ Stick Test for examination of 38 patients with idiopathic RBD (iRBD) and 34 age-matched healthy control subjects (HC). Associations between these test results and other clinical RBD variables were also assessed.ResultsTotal IGT score and Sniffin’ Stick Test scores were significantly lower in the iRBD group than in the HC group. The iRBD group IGT scores in the first, third, and final blocks were significantly lower than those of the HC group. In the iRBD group, no association was found between the total IGT score and the Sniffin’ Stick Test score or any clinical RBD variable.ConclusionsImpaired decision-making associated with iRBD can herald PD. However, decision-making disability is thought to appear irrespective of olfactory dysfunction and progression of RBD pathology.     

Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder

IntroductionIn vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex.MethodsWe used ¹¹C(R)-PK11195 and ¹¹C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. ¹¹C(R)-PK11195 binding potential (BP_ND) and ¹¹C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic.ResultsWe found that a lower cortical ¹¹C-Donepezil DVR correlated with a higher ¹¹C(R)-PK11195 BP_ND in the SI (r = −0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes.ConclusionOur results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.