Abnormal metabolic network activity in REM sleep behavior disorder.

OBJECTIVE: To determine whether the Parkinson disease-related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion. METHODS: For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with (18)F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values. RESULTS: PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p < 0.04; cohort 2: p < 0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r(2) = 0.64, p < 0.0001). CONCLUSIONS: Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.

Abnormal occipital event-related potentials in Parkinson's disease with concomitant REM sleep behavior disorder.

BACKGROUND: Rapid eye movement sleep behavior disorder is found in 33-46% of patients with Parkinson's disease and was shown to be associated with cognitive deficits. Our goal was to improve our understanding of the role of this sleep disorder in cerebral dysfunction occurring in Parkinson's disease using a visual cognitive task and event-related potentials. METHODS: Sixteen patients with Parkinson's disease and rapid eye movement sleep behavior disorder, 15 patients with Parkinson's disease without rapid eye movement sleep behavior disorder and 16 healthy control subjects were included. The amplitude and latency of event-related potentials were compared between groups. RESULTS: No group differences were found for reaction times or accuracy. A Group effect was found for P2 wave amplitude; patients with rapid eye movement sleep behavior disorder had increased P2 in comparison with the control group (p < 0.05). Patients with Parkinson's disease alone were not different from the two other groups for this component. Prolonged novelty P3 latencies on Cz were associated with longer disease durations among patients with Parkinson's disease (p < 0.01). CONCLUSION: Co-morbid Parkinson's disease and rapid eye movement sleep behavior disorder were associated with abnormal visual P2 component of event-related potentials. Although patients with Parkinson's disease alone were not significantly different from patients with combined Parkinson's disease and rapid eye movement sleep behavior disorder, their P2 amplitudes were not sufficiently abnormal to differ from that of control subjects. This study confirms that rapid eye movement sleep behavior disorder accentuates cerebral dysfunctions in Parkinson's disease.

Hippocampal perfusion predicts impending neurodegeneration in REM sleep behavior disorder.

OBJECTIVES: Patients with idiopathic REM sleep behavior disorder (IRBD) are at risk for developing Parkinson disease (PD) and dementia with Lewy bodies (DLB). We aimed to identify functional brain imaging patterns predicting the emergence of PD and DLB in patients with IRBD, using SPECT with (99m)Tc-ethylene cysteinate dimer (ECD). METHODS: Twenty patients with IRBD were scanned at baseline during wakefulness using (99m)Tc-ECD SPECT. After a follow-up of 3 years on average, patients were divided into 2 groups according to whether or not they developed defined neurodegenerative disease (PD, DLB). SPECT data analysis comparing regional cerebral blood flow (rCBF) between groups assessed whether specific brain perfusion patterns were associated with subsequent clinical evolution. Regression analysis between rCBF and clinical markers of neurodegeneration (motor, color vision, olfaction) looked for neural structures involved in this process. RESULTS: Of the 20 patients with IRBD recruited for this study, 10 converted to PD or DLB during the follow-up. rCBF at baseline was increased in the hippocampus of patients who would later convert compared with those who would not (p < 0.05 corrected). Hippocampal perfusion was correlated with motor and color vision scores across all IRBD patients. CONCLUSIONS: (99m)Tc-ECD SPECT identifies patients with IRBD at risk for conversion to other neurodegenerative disorders such as PD or DLB; disease progression in IRBD is predicted by abnormal perfusion in the hippocampus at baseline. Perfusion within this structure is correlated with clinical markers of neurodegeneration, further suggesting its involvement in the development of presumed synucleinopathies.

Brain perfusion anomalies in rapid eye movement sleep behavior disorder with mild cognitive impairment.

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 sleep behavior disorder and risk of dementia in Parkinson's disease: a prospective study.

One of the most devastating nonmotor manifestations of PD is dementia. There are few established predictors of dementia in PD. In numerous cross-sectional studies, patients with rapid eye movement (REM) sleep behavior disorder (RBD) have increased cognitive impairment on neuropsychological testing, but no prospective studies have assessed whether RBD can predict Parkinson's dementia. PD patients who were free of dementia were enrolled in a prospective follow-up of a previously published cross-sectional study. All patients had a polysomnogram at baseline. Over a mean 4-year follow-up, the incidence of dementia was assessed in those with or without RBD at baseline using regression analysis, adjusting for age, sex, disease duration, and follow-up duration. Of 61 eligible patients, 45 (74%) were assessed and 42 were included in a full analysis. Twenty-seven patients had baseline RBD, and 15 did not. Four years after the initial evaluation, 48% with RBD developed dementia, compared to 0% of those without (P-adjusted = 0.014). All 13 patients who developed dementia had mild cognitive impairment on baseline examination. Baseline REM sleep atonia loss predicted development of dementia (% tonic REM = 73.2 ± 26.7 with dementia, 40.8 ± 34.5 without; P = 0.029). RBD at baseline also predicted the new development of hallucinations and cognitive fluctuations. In this prospective study, RBD was associated with increased risk of dementia. This indicates that RBD may be a marker of a relatively diffuse, complex subtype of PD.

Brain perfusion and markers of neurodegeneration in rapid eye movement sleep behavior disorder.

Potential early markers of neurodegeneration such as subtle motor signs, reduced color discrimination, olfactory impairment, and brain perfusion abnormalities have been reported in idiopathic rapid eye movement sleep behavior disorder, a risk factor for Parkinson's disease and Lewy body dementia. The aim of this study was to reproduce observations of regional cerebral blood flow abnormalities in a larger independent sample of patients and to explore correlations between regional cerebral blood flow and markers of neurodegeneration. Twenty patients with idiopathic rapid eye movement sleep behavior disorder and 20 healthy controls were studied by single-photon emission computerized tomography. Motor examination, color discrimination, and olfactory identification were examined. Patients with rapid eye movement sleep behavior disorder showed decreased regional cerebral blood flow in the frontal cortex and in medial parietal areas and increased regional cerebral blood flow in subcortical regions including the bilateral pons, putamen, and hippocampus. In rapid eye movement sleep behavior disorder, brain perfusion in the frontal cortex and occipital areas was associated with poorer performance in the color discrimination test. Moreover, a relationship between loss of olfactory discrimination and regional cerebral blood flow reduction in the bilateral anterior parahippocampal gyrus, a region known to be involved in olfactory functions, was found. This study provides further evidence of regional cerebral blood flow abnormalities in rapid eye movement sleep behavior disorder that are similar to those seen in Parkinson's disease and Lewy body dementia. Moreover, regional cerebral blood flow anomalies were associated with markers of neurodegeneration.

Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder.

OBJECTIVE: For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying "preclinical" neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein-mediated neurodegenerative disease--this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease. METHODS: Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease-free. RESULTS: Out of 64 patients, 62 (97%) participated in annual follow-up. During follow-up, 21 developed disease, and 41 remained disease-free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease-free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex-adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth-Munsell 100-Hue color test [FM-100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan-Meier 5-year-disease-free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease-free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages. INTERPRETATION: Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages.

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.

Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease.

OBJECTIVE: To investigate the frequency and subtypes of mild cognitive impairment (MCI) in idiopathic rapid eye movement sleep behavior disorder (RBD) and Parkinson's disease (PD) in association with RBD. METHODS: One hundred and twelve subjects without dementia or major depression including 32 idiopathic RBD patients, 22 PD patients with polysomnography-confirmed RBD, 18 PD patients without RBD, and 40 healthy control subjects, underwent a comprehensive neuropsychological evaluation. We compared the proportion of patients with MCI between groups using standard diagnostic criteria. RESULTS: MCI was found in 50% of idiopathic RBD patients and 73% of PD patients with RBD. In contrast, only 11% of PD patients without RBD and 8% of control subjects had MCI. The presence of MCI was significantly greater in idiopathic RBD patients and PD patients with RBD than in PD patients without RBD and control subjects. PD patients with RBD also performed worse than idiopathic RBD patients on neuropsychological tests assessing visuoconstructional and visuoperceptual abilities. INTERPRETATION: In both its association with PD and its idiopathic form, RBD is an important risk factor for MCI. Except for visuoconstructional and visuoperceptual problems, RBD may be an important determinant of cognitive impairment in PD. Ann Neurol 2009;66:39-47.

Manifestations of Parkinson disease differ in association with REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is commonly associated with Parkinson disease (PD), but it is unclear whether this association has implications for disease manifestations. We evaluated 36 PD patients for the presence of RBD by polysomnography. Patients underwent an extensive evaluation by a movement disorders specialist blinded to polysomnography results. Severity of motor manifestations, autonomic, visual, psychiatric, and olfactory dysfunctions and quality of life (QOL) were assessed, and compared using regression analysis that adjusted for disease duration, age and sex. Severity of motor manifestations did not differ between groups. However, the presence of RBD in PD was strongly associated with symptoms and signs of orthostatic hypotension (systolic blood pressure lying to standing = -25.7 +/- 13.0 mmHg vs. -4.9 +/-14.1, P < 0.001); and orthostatic symptom prevalence = 71% vs. 27%, P = 0.0076). There was no association between RBD and other autonomic symptoms. Color vision was worse in patients with RBD, but olfactory dysfunction did not differ between groups. The prevalence of depression, hallucinations, paranoia, and impulse disorders did not differ between groups. Emotional functioning and general health QOL measures were lower in those with RBD, but there were no differences between groups on disease-specific indices or on measures of overall physical QOL. These findings suggest that the pathophysiology of RBD and nonmotor manifestations of PD, particularly autonomic dysfunction, are linked.

REM sleep characteristics in narcolepsy and REM sleep behavior disorder.

STUDY OBJECTIVES: To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) in narcolepsy; and to quantify REM sleep parameters in patients with narcolepsy, in patients with "idiopathic" RBD, and in normal controls. DESIGN: Sleep laboratory study PARTICIPANTS: Sixteen patients with narcolepsy and cataplexy matched for age and sex with 16 patients with "idiopathic" RBD and with 16 normal controls were studied. MEASUREMENTS AND RESULTS: Higher percentages of REM sleep without atonia, phasic electromyographic (EMG) activity, and REM density were found in patients with narcolepsy than normal controls. In contrast, RBD patients had a higher percentage of REM sleep without atonia but a lower REM density than patients with narcolepsy and normal controls. Based on a threshold of 80% for percentage of REM sleep with atonia, 50% of narcoleptics and 87.5% of RBD patients had abnormal REM sleep muscle activity. No significant behavioral manifestation in REM sleep was noted in either narcoleptics or controls. We also found a higher frequency of periodic leg movements during wake (PLMW) and during sleep (PLMS) in narcoleptic patients compared to controls. CONCLUSIONS: The present study demonstrates abnormalities in REM sleep motor regulation with an increased frequency of REM sleep without atonia, phasic EMG events and PLMS in narcoleptic patients when compared to controls. These abnormalities were seen more prominently in patients with RBD than in narcoleptics, with the exception of the PLMS index. We proposed that dysfunctions in hypocretin/dopaminergic system may lead to motor dyscontrol in REM sleep that results in dissociated sleep/wake states.

Slow-wave sleep and delta power in rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by the loss of normal muscle atonia during REM sleep, leading to an increase of phasic muscle activity and complex motor behaviors during the night. There is some evidence that RBD patients have more of slow-wave sleep (SWS) than healthy elderly subjects. No study has looked at quantitative electroencephalogram analysis during non-REM sleep in either primary or secondary RBD. The aim of this study was to assess the increase of SWS and to analyze different electroencephalographic frequency ranges during non-REM sleep in 28 idiopathic RBD patients compared with 28 age- and sex-matched healthy volunteers. Idiopathic RBD patients spent more time in SWS (men: 1.4%; women: 5.9%) than control subjects (men: 0.4%; women: 0.6%; p = 0.004). Spectral analyses demonstrated that idiopathic RBD patients had increased all-night delta power in comparison with control subjects (p = 002). This study shows an increase of SWS and power in the delta band during non-REM sleep in idiopathic RBD patients compared with control subjects. Results are discussed about the possible nigrostriatal dopaminergic impairment in RBD patients and the association between RBD and neurodegenerative disorders.